The 3 criteria must be detected for diagnosis
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
§ Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
§ Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
§ Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favour chronic ABMR if there is no prior history of TCMR, but are not required.
2-Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following
• Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
• At least moderate microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis
• Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated
3-Serologic evidence of circulating donor-specific antibodies (DSA to HLA or other antigens). C4d staining or expression
Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA (posttransplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis of chronic active or active ABMR
Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA(Continues)C4d staining without evidence of rejection; all 4 features must be present for diagnosisc
1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
2. Criterion 1 for active or chronic active ABMR not met
3. No molecular evidence for ABMR as in criterion 2 for active and chronic active ABMR4. No acute or chronic active TCMR, or borderline changes
Reference
Loupy A et al.The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection. Am J Transplant. 2020;20:2318–2331.
3 components are required for the diagnosis of chronic active ABMR :
Histologic evidence of chronic tissue injury (transplant glomerulopathy-cg, multilayering of the PTC BM or chronic arteriopathy with fibrous intimal thickening) and no evidence of acute inflammation
Evidence of antibody interaction with vascular endothelium (C4d staining in peritubular capillaries)
Serologic evidence of circulating DSAs
– If the patient has the first criteria and only one of the other 2 criteria, the patient is considered to have chronic active ABMR, this means C4d staining can replace DSA, and C4d negative chronic active ABMR exists
– But if the patient is lacking for both criteria and only have morphological criteria , diagnosis will be suspicious for chronic ABMR
Update the diagnostic criteria(Banff 2019 for chronic ABMR) Chronic active ABMR:
ALL 3 criteria to be met for the diagnosis
1) morphological evidence of chronic tissue injury include one or more of the following:
Transplant glomerulopathy(cg>0) include evidence by EM(cg1a)
Severe PTC base membrane layering (require EM)
Arterial intimal fibrosis of new onset after exclusion of other causes
2) Evidence of current antibody interaction with vascular endothelial include one or more of the following:
linear c4d staining in the PTC or medullary vasa recta(c4d2 or c4d3) by IF or c4d>0 by IHC
At least moderate microvascular inflammation (Ig+ptc) 2 or more
Increase expression of gene transcript in tissue biopsy strongly associated with ABMR
3) Serological evidence of circulating DSA(to HLA and non-HLA antigens)
In renal biopsy meeting criteria 1 but not 2 with current or prior evidence of DSA (post transplant) may be stated as chronic ABMR but DSA should not be considered for diagnosis of chronic active ABMR or chronic inactive ABMR Reference:
Loupy A et al.The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection. Am J Transplant. 2020;20:2318–2331
All 3 criteria must be satisfied for making diagnosis :
A.Morphological evidence of chronic tissue injury including 1 or more of the following –
transplant glomerulopathy (cg>0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; including changes evident by electron microscopy (EM) alone (cg1a)
Severe peritubular capillary basement membrane multi layering (ptcm1; requires EM)
Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic Intima favor chronic ABMR if there is no prior history of TCMR, but are not required.
B. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following
Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections or C4d>0 by IHC on paraffin sections)
Atleast moderate microvascular inflammation ([g + ptc] > 2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc >2 alone is not sufficient and g must be >1.
Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated.
C. Serological evidence of circulating DSA to HLA or other antigens. C4d staining or expression of validated transcripts/classifiers as noted in criterion 2 may substitute for DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised when criteria 1 and 2 are met.
Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA post transplant may be stated as showing chronic ABMR, but remote DSA should not be considered for diagnosis of chronic active or active ABMR.
Chronic inactive ABMR
A.cg>0 and/or severe ptcml (ptcml1)
B.Absence of current or recent antibody interaction with the endothelium
C.Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA.
References
Loupy,A; Haas, M; et al. The Banff 2019 kidney meeting report (I) : Updates on and clarification of criteria for T cell- and antibody mediated rejection . Am J o Trans. 20 (9). 2020. https://doi.org/10.1111/ajt.15898
Chronic active ABMR; all 3 criteria must be met for diagnosis
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
Transplant glomerulopathy (cg >0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
Severe peritubular capillary basement membrane multilayering (requires EM)
Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more 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) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated
3. Serologic evidence of donor‐specific antibodies (DSA to HLA or other antigens). C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA; however thorough DSA testing, including testing for non‐HLA antibodies if HLA antibody testing is negative, is strongly advised whenever criteria 1 and 2 are met
Chronic ABMR is divided into 2 forms: chronic active ABMR and chronic inactive ABMR
Chronic active ABMR; all 3 criteria must be met for diagnosis (1)
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
a) Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
b) Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
c) Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:
a) Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
b) At least moderate MVI, microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
c) Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated
3. Serologic evidence of circulating donor-specific antibodies (DSA to HLA or other antigens). C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA; however thorough DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised whenever criteria 1 and 2 are met. Biopsies meeting criterion 1 but not criterion 2 withcurrent or prior evidence of DSA (posttransplant) may be statedas showing chronic ABMR, however remote DSA should not beconsidered for diagnosis of chronic active or active ABMR
Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
The differences between 2013 and 2019 classification:
1) Classifiying chronic (inactive) ABMR
2) TG in absence of chronic/recurrent de novo GN
3) leukocytes within intima not required
4) Linear C4d staining of medullary vasa recta
5) For MVI, in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
6) C4d staining or expression of validated transcripts/classifiers may substitute for DSA (criteria 3)
7) Biopsies meeting criterion 1 and 3 ( with current or prior evidence of DSA – posttransplant) without criterion 2 may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis.
Reference:
Loupy A, Haas M, Roufosse C, Naesens M, Adam B, Afrouzian M, Akalin E, Alachkar N, Bagnasco S, Becker JU, Cornell LD, Clahsen-van Groningen MC, Demetris AJ, Dragun D, Duong van Huyen JP, Farris AB, Fogo AB, Gibson IW, Glotz D, Gueguen J, Kikic Z, Kozakowski N, Kraus E, Lefaucheur C, Liapis H, Mannon RB, Montgomery RA, Nankivell BJ, Nickeleit V, Nickerson P, Rabant M, Racusen L, Randhawa P, Robin B, Rosales IA, Sapir-Pichhadze R, Schinstock CA, Seron D, Singh HK, Smith RN, Stegall MD, Zeevi A, Solez K, Colvin RB, Mengel M. The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am J Transplant. 2020 Sep;20(9):2318-2331. doi: 10.1111/ajt.15898. Epub 2020 May 28. PMID: 32463180; PMCID: PMC7496245.
Evidence of chronic tissue injury including one or more of the following-
Transplant glomerulopathy By EM
Multilayering of PTC membrane BY EM
Chronic arteriopathy without evidence of acute inflammation.
Evidence of antibody interaction with vascular endothelium.
Linear Positive c4d staining in peritubular capillaries or medullary vasa recta- C4d2 or C4d3 by IF on frozen section or C4d >0 by IHC On paraffin section
·
Moderate Micro vascular inflammation in the absence of the recent or denovo glomerulonephritis.
Increased expression of gene transcripts in the biopsy
Evidence of Circulating DSA If there is evidence of chronic tissue injury with one of the other two criteria’s it is labelled as Chronic ABMR
Chronic active ABMR; all 3 criteria must be met for diagnosis
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
Arterial intimal fibrosis of new-onset, excluding other causes; leukocytes within the sclerotic intima favour chronic ABMR if there is no prior history of TCMR, but are not required .
2-Evidence of current/recent antibody interaction with vascular endothelium, which includes one or more of the factors listed below.
In peritubular capillaries or the medullary vasa recta, linear C4d staining was seen (C4d2 or C4d3 by immunofluorescence on frozen sections, or C4d > 0 by immunohistochemistry on paraffin sections).
• The presence of at least mild microvascular inflammation ([g + ptc] 2) in the absence of recurrent or de novo glomerulonephritis.
When adequately confirmed, increased expression of gene transcripts/classifiers in biopsy tissue has been shown to be significantly linked with ABMR.
3-Serologic evidence of donor-specific antibodies in circulation (DSA to HLA or other antigens). The presence or absence of C4d staining or expression
In the case of biopsies that fit criterion 1 but not criterion 2 and that have current or past evidence of DSA (posttransplant), the diagnosis of chronic ABMR may be made; however, distant DSA should not be considered for the diagnosis of chronic active or active ABMR, respectively.
Chronic AMR was classified into 4 categories according to the Banff 2019 consensus,these are:
1) Chronic inactive AMR
2) Chronic active Antibody mediated rejectiAccommodations
3) Accomodation: where C4d staining is positive without evidence of rejection.
Diagnostic criteria for active AMR is consistant of 3 features:
a) Histologic evidence of acute tissue injury including :Capillaritis in the form of glomerulitis (g )and peritubular capillaritis( ptc) with g+ptc>2 score is qualifying for this , other acute tissue injury pattern are,acute tubular injury ,thrombotic microangiopathy,and less commonly, endothelitis ,fibrinoid necrosis or transmural inflammation.
b) evidence of recent or current antibody-endothelial interaction in the form of C4d staining or validated transcript .Microvascular inflammation MVI ,g +ptc score of >2 may substitute for C4d staining. C4d detected by IF or IHC.
C) Circulating Donor Specific Antibodies DSAs, however C4d staining or validated transcrip may substitute for it.
Diagnostic criteria of chronic AMR:
a)Transplant Glomerulopathy TG. (g>0).in the absence of thrombotic microangiopathy and recurrent /de novo Gn.
b) Peritubular Capillary basement membrane Multilayring PTCML(detected by EM).
c) Arterial intimal fibrosis of new onset. (Lukocytes within the sclerosis intima favor chronic AMR,if there is no prior history of CMR.
Chronic Active AMR:
Combined features of chronic features and active features.
Smoldering ,Accomodation : C4d deposition in ptc without features of chronic or active AMR. (no MVI)..
Reference:
Lynn D.Cornell.Histologic features of antibody mediated rejection:the Banff classification and beyond.fronties in immunology.2021
Updates on Banff criteria 2019 Chronic active ABMR
All 3 criteria must be satisfied for making diagnosis: 1. Evidence of chronic tissue injuryincluding 1 or more of the following –
transplant glomerulopathy (cg>0) if no evidence of
chronic TMA
chronic recurrent/de novo glomerulonephritis; including changes evident by electron microscopy (EM) alone (cg1a)
Severe peritubular capillary basement membrane multi layering (ptcm1; requires EM)
Arterial intimal fibrosis of new onset, excluding other causes+ leukocytes within the sclerotic Intima favor chronic ABMR if there is no prior history of TCMR.
2. Evidence antibody interaction with vascular endothelium, including 1 or more of the following
In PTC: Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections or C4d>0 by IHC on paraffin sections)
In MV: At least moderate microvascular inflammation [g + ptc] > 2) in
the absence of recurrent or de novo glomerulonephritis
in case of acute TCMR, borderline infiltrate, or infection>> ptc >2 alone is not sufficient and g must be >1.
Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated.
3. Serological evidence of circulating DSA to HLA or non HLA antigens. · testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised when criteria 1 and 2 are met. · C4d staining or expression of validated transcripts/classifiers substitute for DSA testing, · Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA post-transplant considered as chronic inactive ABMR and remote DSA not considered for diagnosis of chronic active or active ABMR. Chronic inactive ABMR · criterion 1: include cg>0 and/or severe ptcml (ptcml1) · Absence of criterion 2: current or recent antibody interaction with the endothelium · Criterion 3: Prior diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA.Updates on Banff criteria 2019 Chronic active ABMR
All 3 criteria must be satisfied for making diagnosis: 1. Evidence of chronic tissue injuryincluding 1 or more of the following –
transplant glomerulopathy (cg>0) if no evidence of
chronic TMA
chronic recurrent/de novo glomerulonephritis; including changes evident by electron microscopy (EM) alone (cg1a)
Severe peritubular capillary basement membrane multi layering (ptcm1; requires EM)
Arterial intimal fibrosis of new onset, excluding other causes+ leukocytes within the sclerotic Intima favor chronic ABMR if there is no prior history of TCMR.
2. Evidence antibody interaction with vascular endothelium, including 1 or more of the following
In PTC: Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections or C4d>0 by IHC on paraffin sections)
In MV: At least moderate microvascular inflammation [g + ptc] > 2) in
the absence of recurrent or de novo glomerulonephritis
in case of acute TCMR, borderline infiltrate, or infection>> ptc >2 alone is not sufficient and g must be >1.
Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated.
3. Serological evidence of circulating DSA to HLA or non HLA antigens. · testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised when criteria 1 and 2 are met. · C4d staining or expression of validated transcripts/classifiers substitute for DSA testing, · Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA post-transplant considered as chronic inactive ABMR and remote DSA not considered for diagnosis of chronic active or active ABMR. Chronic inactive ABMR · criterion 1: include cg>0 and/or severe ptcml (ptcml1) · Absence of criterion 2: current or recent antibody interaction with the endothelium · Criterion 3: Prior diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA.
· Chronic active AMR diagnosis according to Banff 2017/19 depends on presence of :
o Histologic evidence of chronic tissue injury as transplant glomerulopathy (cg> 0)., peritubular capillary BM multilayering and arterial intimal fibrosis.,
o Evidence of antibody interaction with vascular endothelium (c4d) +ve staining by IHC or IF..
o Circulating DSA. the 1st criterion plus either DSA or c4d is diagnostic for chronic active AMR.
Chronic active ABMR 3 criteria are required for diagnosis : A.Morphological evidence of chronic tissue injury including 1 or more of the following – · transplant glomerulopathy (cg>0) absence of TMA · Severe peritubular capillary basement membrane multi layering · Anew onset arterial intimal fibrosis B. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following · Linear C4d staining in peritubular capillaries deposition · moderate microvascular inflammation · Increased expression of gene transcripts. C. Serological evidence of circulating DSA to HLA or other antigens. C4d staining or expression of validated transcripts/classifiers as noted in criterion 2 may substitute for DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised when criteria 1 and 2 are met. Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA post transplant may be stated as showing chronic ABMR, but remote DSA should not be considered for diagnosis of chronic active or active ABMR. Chronic inactive ABMR A.cg>0 and/or severe ptcml (ptcml1) B.Absence of current or recent antibody interaction with the endothelium C.Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA.
Please summarise this article
Chronic antibody mediated rejection characterized by progressive renal graft dysfunction with worsening proteinuria.
Banff 2013 diagnostic criteria has three elements:
1-Histologically characterized by presence at least one of the following:
*Transplant glomerulopathy (cg . 0) in the absence of chronic thrombotic microangiopathy.
*Severe peritubular capillary basement membrane multilayering by electron microscopy.
New-onset arterial intimal fibrosis with no other known aetiology.
2- Current/recent histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
*Linear C4d staining in peritubular capillaries (at least 10% by immunofluorescence [IF] on frozen sections or any positivity by immunohistochemistry on paraffin sections).
*At least moderate microvascular inflammation (g 1 ptc . 2)
*Increased expression of tissue gene transcripts indicative of endothelial injury.
3-Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
Differential Diagnosis:
MPGN
Chronic thrombotic microangiopathy
Chronic hypertension and ageing. ( arterial intimal fibrosis).
Chronic TCMR. ( intimal T cells and foam cells infiltration).
Chronic ABMR is divided into 2 forms: chronic active ABMR and chronic inactive ABMR Chronic active ABMR; all 3 criteria must be met for diagnosis (1)
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
a) Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
b) Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
c) Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:
a) Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
b) At least moderate MVI, microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
c) Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated
3. Serologic evidence of circulating donor-specific antibodies (DSA to HLA or other antigens). C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA; however thorough DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised whenever criteria 1 and 2 are met. Biopsies meeting criterion 1 but not criterion 2 withcurrent or prior evidence of DSA (posttransplant) may be statedas showing chronic ABMR, however remote DSA should not beconsidered for diagnosis of chronic active or active ABMR Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA The differences between 2013 and 2019 classification:
1) Classifiying chronic (inactive) ABMR
2) TG in absence of chronic/recurrent de novo GN
3) leukocytes within intima not required
4) Linear C4d staining of medullary vasa recta
5) For MVI, in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
6) C4d staining or expression of validated transcripts/classifiers may substitute for DSA (criteria 3)
7) Biopsies meeting criterion 1 and 3 ( with current or prior evidence of DSA – posttransplant) without criterion 2 may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis.
update of 2019 Banff classification for chronic active ABMR :
All 3 criteria must be met for diagnosis.
Morphologic evidence of chronic tissue injury, including 1 or more of the following :
Transplant glomerulopathy (cg>0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy alone.
Severe peritubular capillary basement membrane multilayering (ptcml; requires EM)
Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intimata factor chronic ABMR if there is no prior history of TCMR, but are not required.
Identical to criterion 2 for active ABMR, above
Identical to criterion 3 for active ABMR, above, including strong recommendation for DSA testing whenever criteria 1 and 2 are met. Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of posttransplant DSA may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis of chronic active or active ABMR.
Chronic inactive ABMR
cg>0 and/or severe ptcml (ptcml1)
Absence of criterion 2 of current or recent antibody interaction with the endothelium.
Prior documented diagnosis of active or chronic ABMR not met
No molecular evidence for ABMR as in criterion 2 for active and chronic active ABMR
No acute or chronic active TCMR, or borderline changes
Wee Leng Gan
2 years ago
Diagnostic criteria of Chronic antibody-mediated rejection according to the Banff 2013 classification.
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy.
b. Severe peritubular capillary basement membrane.
c. New-onset arterial intimal fibrosis without other etiology
2. Current/recent histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in peritubular capillaries
b. At least moderate microvascular inflammation
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Presence of donor-specific antibodies DSA.
Chronic AMR leads to progressive loss of kidney function with proteinuria. Early stages may not be identifiable other than through protocol biopsies.
Endothelial injury is seen due to presence of DSA and its interaction with mismatched HLA or non HLA molecules.
Podocyte injury and foot process effacement are common findings.
Basement membrane duplication, segmental sclerosis are all seen.
Differential diagnosis include lupus nephritis, immunoglobulin A nephropathy, cryoglobulinemic glomerulonephritis.
Arterial intimal fibrosis is seen here, which is also seen in chronic hypertension and aging.
ahmed saleeh
2 years ago
Diagnostic criteria according to the Banff 2013 classification
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following: a. Transplant glomerulopathy (cg . 0) in the absence of chronic thrombotic microangiopathy b. Severe peritubular capillary basement membrane multilayering by electron microscopy c. New-onset arterial intimal fibrosis with no other known etiology 2. Current/recent histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following: a. Linear C4d staining in peritubular capillaries (at least 10% by immunofluorescence [IF] on frozen sections or any positivity by immunohistochemistry on paraffin sections) b. At least moderate microvascular inflammation (g 1 ptc .2) c. Increased expression of tissue gene transcripts indicative of endothelial injury 3. Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
Glomerular basement membrane duplication is also found in other conditions associated with chronic endothelial damage, causing a membranoproliferative pattern of injury
Peritubular capillary basement membrane multilayering, especially if not severe (,7 layers), is not specific to chronic antibody-mediated rejection.
Arterial intimal fibrosis is a common finding, often associated with chronic hypertension and aging. Scattered T cells and foam cells may be present in the expanded intima, but are not specific for chronic antibody-mediated rejection and may also be seen in chronic T-cell–mediated rejection.
AMAL Anan
3 years ago
Please summerize this article:
Chronic antibody mediated rejection (cAMR) is a condition characterized by graft dysfunction and proteinuria. It involves interaction of donor specific antibodies (DSA) with mismatched HLA or non-HLA molecules leading to repetitive endothelial injury causing GBM (glomerular basement membrane) duplication (transplant glomerulopathy, TG) with segmental sclerosis and peritubular capillary basement membrane multilayering (ptcml).
Diagnostic criteria for c-AMR according to Banff 2013 include presence of DSA with histological evidence of chronic tissue injury (either TG or ptcml or new onset arterial intimal fibrosis) and histological evidence of antibody interaction with vascular endothelium (either linear C4d staining or at least moderate microvascular inflammation or increased tissue gene transcript expression).
Differential diagnosis of cAMR include:
A) GBM duplication can be seen with:
1) Chronic endothelial damage (membranoproliferative type injury)
2) Chronic TMA (associated with acute TMA or vascular changes)
3) MPGN due to lupus nephritis, IgA nephropathy, cryoglobulinemic GN
B) Arterial intimal fibrosis seen with:
1) Chronic hypertension
2) Ageing
Please update the diagnostic criteria mentioned in this article based on the recent Banff classification
Chronic ABMR is divided into 2 forms: chronic active ABMR and chronic inactive ABMR Chronic active ABMR; all 3 criteria must be met for diagnosis (1)
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
a) Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
b) Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
c) Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:
a) Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
b) At least moderate MVI, microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
c) Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated
3. Serologic evidence of circulating donor-specific antibodies (DSA to HLA or other antigens). C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA; however thorough DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised whenever criteria 1 and 2 are met. Biopsies meeting criterion 1 but not criterion 2 withcurrent or prior evidence of DSA (posttransplant) may be statedas showing chronic ABMR, however remote DSA should not beconsidered for diagnosis of chronic active or active ABMR Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA The differences between 2013 and 2019 classification:
1) Classifiying chronic (inactive) ABMR
2) TG in absence of chronic/recurrent de novo GN
3) leukocytes within intima not required
4) Linear C4d staining of medullary vasa recta
5) For MVI, in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
6) C4d staining or expression of validated transcripts/classifiers may substitute for DSA (criteria 3)
7) Biopsies meeting criterion 1 and 3 ( with current or prior evidence of DSA – posttransplant) without criterion 2 may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis.
Reference:
Loupy A, Haas M, Roufosse C, Naesens M, Adam B, Afrouzian M, Akalin E, Alachkar N, Bagnasco S, Becker JU, Cornell LD, Clahsen-van Groningen MC, Demetris AJ, Dragun D, Duong van Huyen JP, Farris AB, Fogo AB, Gibson IW, Glotz D, Gueguen J, Kikic Z, Kozakowski N, Kraus E, Lefaucheur C, Liapis H, Mannon RB, Montgomery RA, Nankivell BJ, Nickeleit V, Nickerson P, Rabant M, Racusen L, Randhawa P, Robin B, Rosales IA, Sapir-Pichhadze R, Schinstock CA, Seron D, Singh HK, Smith RN, Stegall MD, Zeevi A, Solez K, Colvin RB, Mengel M. The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am J Transplant. 2020 Sep;20(9):2318-2331. doi: 10.1111/ajt.15898. Epub 2020 May 28. PMID: 32463180; PMCID: PMC7496245.
Balaji Kirushnan
3 years ago
The above describe chronic active ABMR in the Banff 2019 criteria….Chronic ABMR is an ongoing process which is associated with graft injury and leads to irreversible graft injury…In chronic ABMR there is continuous activation of the endothelium by the antibody which leads to multi layering of the peritubular capillary wall… >7 layers are considered significant. The repetitive endothelial damage inside the glomerulus is seen as glomerular basement membrane duplication which later leads to podocyte injury….Differential diagnosis of chronic ABMR includes Chronic TMA, MPGN, Cryoglobulinemia…
The updated diagnostic criteria of chronic ABMR which was revised in the Banff 2019 meeting are
All the 3 criteria have to be present for chronic ABMR
Morphological evidence of chronic tissue injury – 1 or more of the following: Transplant glomerulopathy (cg>0)including evidence by EM; Severe PTC basement membrane layering of more than 7 (seen by EM), new onset arterial intimal fibrosis after excluding other causes.
Evidence of current antibody interaction with vascular endothelium include one or more of the following – Linear C4d staining in the PTC or medullary vasa recta by IF >10% or any positivity by IHC; microvascular inflammation in moderate degree; Increase expression of gene transcript in tissue biopsy strongly associated with ABMR
Serological evidence of circulating DSA (to HLA and non HLA)
1+3 – possible chronic ABMR
Reference:
Loupy A et al.The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection. Am J Transplant. 2020;20:2318–2331
Nasrin Esfandiar
3 years ago
Q1:
Diagnosis of chronic ABMR is important because it may lead to proteinuria and graft loss. Banff criteria (2013) for cABMR includes presence of all of three criteria.
1) Chronic injury defined by:
a. TG (cg > 0)
b. In EM: Sever multilayering of capillary BM.
c. Arterial intimal fibrosis without other etiology.
2) Evidence of Ab reaction in endothelium by:
a. C4d positive by IF or IHC
b. Moderate MVI (g + ptc > 2)
c. expression of gone transcripts of endothelial injury.
Chronic and repetitive endothelial injury leads to new GBM formation and TG with segmental Sclerosis and food process effacement.
Differential diagnosis for TG includes MPGN and chronic TMA. For example, if multilayering of peritubular capillary BM is not sever it is not specific for cABMR.
Q2:
Banff 2017: TG and / or PTCCBM multilayering in the absence of criteria for group 2 but with a prior diagnosis of active or c-aABMR or prior evidence of DSA.
histologic features of AMR chronicity:
– Banff lesion scone cg > 0 excluding cTMA
– 7 or more layers in cortical PTC and 5 or more in 2 additional capillaries
– GBM multilayering
– Arterial intimal fibrosis of new onset to rule outother causes. Absenceof criteria for group 2 Ab interaction with tissue:
1- C4d positive
2- moderate MVI in the absence of GN
3- Expression of gene transcripts in the biopsy tissue Roufosse, Candice MD, PhD1,2; Simmonds, Naomi MD3; Clahsen-van Groningen, Marian MD, PhD4; Haas, Mark MD, PhD5; Henriksen, Kammi J. MD6; Horsfield, Catherine MD3; Loupy, Alexandre MD7; Mengel, Michael MD8; Perkowska-Ptasińska, Agnieszka MD9; Rabant, Marion MD, PhD10; Racusen, Lorraine C. MD11; Solez, Kim MD8; Becker, Jan U. MD12A 2018 Reference Guide to the Banff Classification of Renal Allograft Pathology, Transplantation: November 2018 – Volume 102 – Issue 11 – p 1795-1814
kumar avijeet
3 years ago
CHRONIC ANTIBODY MEDIATED REJECTION
It is one of the common cause of graft dysfunction.
It is diagnosed by presence of all of the following-
1.histologic evidence of chronic tissue injury (atleast one)
A.transplant glomerulopathy in absence of tma (d/d-chronic tma,ig mpgn)
B.severe peritubular capillary basement membrane multilayering in em.(If not severe that is 7 layered than not specific of abmr)
C.new-onset arterial intimal fibrosis (d/d-hypertension,aging)
2.current/recent histologic evidence of ab interaction with endothelium(atleast one)-
A.c4d staining c4d2,c4d3 in IF or any intensity in IHC .
B.at least moderate microvascular inflammation.(g+ptc>2)
C.increased expression of gene transcript of endothelial injury.
3.presence of DSA(HLA,nonHLA)
Theepa Mariamutu
3 years ago
Chronic active ABMR from Banff 2019
All 3 criteria must be satisfied for making diagnosis :
Morphological evidence of chronic tissue injury including 1 or more of the following –
transplant glomerulopathy (cg>0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; including changes evident by electron microscopy (EM) alone (cg1a)
Severe peritubular capillary basement membrane multi layering (ptcm1; requires EM)
Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic Intima favor chronic ABMR if there is no prior history of TCMR, but are not required.
B. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following
Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections or C4d>0 by IHC on paraffin sections)
At least moderate microvascular inflammation ([g + ptc] > 2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc >2 alone is not sufficient and g must be >1.
Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated.
C. Serological evidence of circulating DSA to HLA or other antigens. C4d staining or expression of validated transcripts/classifiers as noted in criterion 2 may substitute for DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised when criteria 1 and 2 are met.
Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA post transplant may be stated as showing chronic ABMR, but remote DSA should not be considered for diagnosis of chronic active or active ABMR.
Chronic inactive ABMR
A.cg>0 and/or severe ptcml (ptcml1)
B.Absence of current or recent antibody interaction with the endothelium
C.Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA.
how it differs from 2013
1) Classifiying chronic (inactive) ABMR 2) TG in absence of chronic/recurrent de novo GN 3) leukocytes within intima not required 4) Linear C4d staining of medullary vasa recta 5) For MVI, in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1 6) C4d staining or expression of validated transcripts/classifiers may substitute for DSA (criteria 3) 7) Biopsies meeting criterion 1 and 3 ( with current or prior evidence of DSA – posttransplant) without criterion 2 may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis.
Reference Loupy A et al.The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection. Am J Transplant. 2020;20:2318–2331.
Jamila Elamouri
3 years ago
Diagnostic criteria according to the Banff classification 2013 include the presence of all of the following that must meet:
1- Histological evidence of chronic tissue injury, includes at least one of the following:
a- Transplant glomerulopathy (cg>0) in absence of chronic thrombotic microangiopathy, (or chronic recurrent/ de novo GN; including changes evident by electron microscopy (EM) alone {cg1a} 2019)
b- Severe peritubular capillary basement membrane multilayering by electron microscopy (ptcml1; require EM)
c- New-onset arterial intimal fibrosis with no other known cause.
2- Current/recent histologic evidence of antibody interaction with vascular endothelium, includes one or more of the following:
a- Linear C4d staining in peritubular capillaries (10% or more by IF or any positivity by IHC
2019; ptc or medullary vasa recta (C4d2 or C4d3 by IF or C4d > 0 by IHC)
b- At least moderate microvascular inflammation (g + ptc > 2)
(2019; {g+ ptc} ≥ 2)
c- An increased expression of tissue gene transcripts indicative of endothelial injury.
3- Presence of DSA in the serum (HLA or non-HLA DSA)
2019 Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA (posttransplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for the diagnosis of chronic active or active ABMR
Key features are:
· Transplant glomerulopathy (GBM duplication that can be present in membranoproliferative conditions like lupus nephritis)
· Peritubular capillary basement membrane multilayering which if not severe > 7 is not specific of c ABMR.
· Peritubular capillary C4d staining
Chronic (inactive) ABMR 1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium 3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA C4d staining without evidence of rejection; all 4 features must be present for diagnosis:
1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
2. Criterion 1 for active or chronic active ABMR not met
3. No molecular evidence for ABMR as in criterion 2 for active and chronic active ABMR
4. No acute or chronic active TCMR, or borderline changes
(1)
1. Loupy A, Haas M, Roufosse C, Naesens M, Adam B, Afrouzian M, et al. The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am J Transplant [Internet]. 2020/05/28. 2020 Sep;20(9):2318–31. Available from: https://pubmed.ncbi.nlm.nih.gov/32463180
Jamila Elamouri
3 years ago
The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection
Drtalib Salman
3 years ago
How can we differentiated between thrombotic microangiopathy and Antibody mediated rejection ?
although it is histologically similar finding and difficult to differentiate so we should depend on clinical finding Ex thrombotic microangiopathy look for blood film shistocyte or fragmented RBC ,increase in LDH ,family HX ,primary disease ,CNS manifestation ,anaemia ,thrombocytopenia .
in antibody mediated rejection hx of previos sensitzation ,oligouria or inrease in DSA and decrease in GFR
Drtalib Salman
3 years ago
Chronic Antibody-Mediated Rejection:
Diagnostic criteria according to the Banff 2013 classification include
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy (cg . 0) in the absence of chronic thrombotic microangiopathy
b. Severe peritubular capillary basement membrane multilayering by electron microscopy c. New-onset arterial intimal fibrosis with no other known etiology
2. Current/recent histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in peritubular capillaries (at least 10% by immunofluorescence [IF] on frozen sections or any positivity by immunohistochemistry on paraffin sections)
b. At least moderate microvascular inflammation (g 1 ptc . 2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
Glomerular basement membrane duplication is also found in a membranoproliferative pattern of injury.
Chronic thrombotic microangiopathy may be indistinguishable from transplant glomerulopathy on a morphologic basis unless features of concomitant acute thrombotic microangiopathy or vascular changes are present.
Peritubular capillary basement membrane multilayering, especially if not severe (less than 7 layers), is not specific to chronic antibody-mediated rejection.
Arterial intimal fibrosis is a common finding, often associated with chronic hypertension and aging.
Please update the diagnostic criteria mentioned in this article based on the recent Banff classification? View / Download
Banff 2017 permits the use of this term for biopsy specimens showing TG and/or peritubular
capillary basement membrane multilayering in the absence of criterion of current/recent antibody
interaction with the endothelium (Criteria Group 2) but with a prior documented diagnosis of Active or
Chronic Active AMR or documented prior evidence of DSA
Criteria Group 4 Histologic features of AMR chronicity
CARLOS TADEU LEONIDIO
3 years ago
Please summarise this article
Clinical and Pathologic Features Chronic antibody-mediated rejection is commonly associated with progressive loss of kidney function and proteinuria, although early stages may be subclinical and recognizable only through protocol biopsies. Diagnostic criteria according to the Banff 2013 classification include the presence of all of the following: 1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following: a. Transplant glomerulopathy (cg . 0) in the absence of chronic thrombotic microangiopathy b. Severe peritubular capillary basement membrane multilayering by electron microscopy c. New-onset arterial intimal fibrosis with no other known etiology
2. Current/recent histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following: a. Linear C4d staining in peritubular capillaries (at least 10% by immunofluorescence [IF] on frozen sections or any positivity by Immuno histochemistry on paraffin sections) b. At least moderate microvascular inflammation (g 1 ptc . 2) c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
Etiology/Pathogenesis
Similar to acute antibody-mediated rejection, endothelial injury results from interaction between DSA with primarily mismatched HLA or non-HLA molecules. Repetitive and chronic endothelial damage is associated with new basement membrane formation, which in glomeruli manifests as glomerular basement membrane duplication (transplant glomerulopathy), often with resulting segmental sclerosis, and multilayering of the peritubular capillary basement membrane. Podocyte injury and foot process effacement are common findings.
Differential Diagnosis
Glomerular basement membrane duplication is also found in other conditions associated with chronic endothelial damage, causing a membranoproliferative pattern of injury. Chronic thrombotic microangiopathy may be indistinguishable from transplant glomerulopathy on a morphologic basis unless features of concomitant acute thrombotic microangiopathy or vascular changes are present. In such cases, correlation with clinical history will be important. Membranoproliferative glomerulonephritis due to immune complex processes (lupus nephritis, immunoglobulin A nephropathy, cryoglobulinemic glomerulonephritis, etc) must be ruled out by IF and electron microscopy. Peritubular capillary basement membrane multilayering, especially if not severe (,7 layers), is not specific to chronic antibody-mediated rejection. Arterial intimal fibrosis is a common finding, often associated with chronic hypertension and aging. Scattered T cells and foam cells may be present in the expanded intima, but are not specific for chronic antibody-mediated rejection and may also be seen in chronic T-cell–mediated rejection.
Please update the diagnostic criteria mentioned in this article based on the recent Banff classification
Revised Banff 2017 classification of antibody-mediated rejection (ABMR)
Chronic active ABMR:
All 3 criteria must be met for diagnosis:
1.Morphologic evidence of chronic tissue injury, including 1 or more of the following
– Transplant glomerulopathy (cg >0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
– Severe peritubular capillary basement membrane multilayering (requires EM)
– Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2.Identical to criterion 2 for active ABMR, above
3.Identical to criterion 3 for active ABMR, above, including strong recommendation for DSA testing whenever criteria 1 and 2 are met C4d Staining without Evidence of Rejection; all 4 features must be present for diagnosis:
– Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d>0 by IHC on paraffin sections)
– Criterion 1 for active or chronic, active ABMR not met
– No molecular evidence for ABMR as in criterion 2 for active and chronic, active ABMR
Reem Younis
3 years ago
Diagnostic criteria for chronic antibody-mediated rejection according to the Banff 2013 classification include the presence of all of the
following:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy (cg . 0) in the absence of chronic thrombotic microangiopathy
b. Severe peritubular capillary basement membrane multilayering by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
2. Current/recent histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in peritubular capillaries .
b. At least moderate microvascular inflammation
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
– Repetitive and chronic endothelial damage is associated with new basement membrane formation, which in glomeruli manifests as glomerular
basement membrane duplication (transplant glomerulopathy),
often with resulting segmental sclerosis, and multilayering of the peritubular capillary basement membrane.
Differential Diagnosis
Glomerular basement membrane duplication is also found in:
1.Chronic thrombotic microangiopathy.
2. Membranoproliferative glomerulonephritis due to immune
complex processes (lupus nephritis, immunoglobulin A nephropathy, cryoglobulinemic glomerulonephritis, etc).
3. chronic hypertension and aging.
-Chronic active ABMR; all 3 criteria must be met for diagnosis:.Bannff 2017
1.Morphologic evidence of chronic tissue injury, including 1 or more of the following:
Transplant glomerulopathy (cg >0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
Severe peritubular capillary basement membranemultilayering (requires EM)
Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2.Strong recommendation for DSA testing .
3.C4d Staining .
Zahid Nabi
3 years ago
This article explains the Banff 2013 diagnostic criteria for chronic antibody mediated rejection which is as follows
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy (cg . 0) in the ab-
sence of chronic thrombotic microangiopathy
b. Severe peritubular capillary basement mem- brane multilayering by electron microscopy
c. New-onset arterial intimal fibrosis with no other
known etiology
2. Current/recent histologic evidence of antibody
interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in peritubular capillaries (at
least 10% by immunofluorescence [IF] on frozen sections or any positivity by immuno- histochemistry on paraffin sections)
b. At least moderate microvascular inflammation (g 1 ptc.2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
According to Banff 2017
Patients with the first two criteria but no evidence of DSAs can be diagnosed with chronic active ABMR if there is C4d-positive staining of PTCs or expression of validated gene panels associated with ABMR . If neither is present, such patients are considered to be “suspicious” for chronic active ABMR.
Esmat MD
3 years ago
Chronic AMR is associated with decline in kidney function and proteinuria. It may be subclinical and only be detected in protocol biopsy.
Based on Banff 2013 classification, it is defined by the presence of all three features consisting of histologic evidence of chronic tissue injury (presence of at least one of transplant glomerulopathy, severe peritubular BM multilayering, and new onset arterial intimal necrosis), histologic evidence of antibody interaction with endothelium (at least one of linear C4d staining in peritubular capillaries, moderate MVI, and increased tissue gene transcripts), and presence of DSA.
Chronic endothelial damage due to repetitive interaction between DSA with alloantigens leads to transplant glomerulopathy with duplication of GBM, IFTA, PTC basement membrane multilayering, and podocyte injury.
MPGN and chronic TMA are differential diagnosis of TG. MPGN due to immune complex processes such as SLE, IgA nephropathy, and cryoglobulinemic GN can be distinguished by IF. The PTC multilayering less than 7 layers is not specific for chronic AMR. Intimal fibrosis can be seen in chronic hypertension and aging. Scattered T cells and foamy cells in intima can be seen in chronic AMR and chronic TCMR.
Key diagnostic features are TG, PTC basement membrane multilayering, and PTC C4d staining.
Based on the Banff 2019 classification, chronic ABMR is categorized into two groups: chronic active ABMR and chronic inactive ABMR.
Chronic active ABMR; all 3 criteria must be met for diagnosis
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:
• Linear C4d staining in peritubular capillaries or medullary vasarecta (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
• At least moderate microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
• Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated
3. Identical to criterion 3 for active ABMR, above, including strong recommendation for DSA testing whenever criteria 1 and 2
are met. Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA (posttransplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis of chronic active or active ABMR
Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA C4d staining without evidence of rejection; all 4 features must be present for diagnosis
1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
2. Criterion 1 for active or chronic active ABMR not met
3. No molecular evidence for ABMR as in criterion 2 for active and chronic active ABMR
4. No acute or chronic active TCMR, or borderline changes
Dalia Eltahir
3 years ago
Chronic Antibody-Mediated Rejection Chronic antibody-mediated rejection lead to progressive allograft loss and proteinuria.It can be subclinical and can be detected only by protocol biopsies in early stage. Diagnostic criteria (Banff 2013) included the presence of all of the following: 1. Histologic evidence of chronic tissue injury (at least one of: Transplant glomerulopathy (no TMA), Severe PTC basement membrane multilayering by EM or New-onset arterial intimal fibrosis). 2. Current/recent histologic evidence of endothelial injury (at least one of: linear PTC C4d staining, moderate microvascular inflammation or increased expression of tissue gene transcripts. 3. Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the circulation . Due to the chronicity of antibodies interaction with the endothelium, new glomeruli basement membrane formation occur (transplant glomerulopathy), resulting in segmental sclerosis, and multilayering of the PTC basement membrane with podocyte injury. Glomerular basement membrane duplication can be found in cases with membranoproliferative histpathology (lupus nephritis, Ig A nephropathy, cryoglobulinemic glomerulonephritis) Chronic TMA have similar morphology and can be distinguished by clinical history, concomitant acute thrombotic microangiopathy or vascular changes Not severe PTC basement membrane multilayering (less than 7 layers), is not specific to chronic antibody-mediated rejection. Arterial intimal fibrosis can occur in chronic hypertension and aging. Scattered T cells and foam cells in expanded intima can occur in chronic T-cell–mediated rejection.
Mohamed Essmat
3 years ago
Chronic active AMR presents by slow decline of renal functions associated with proteinuria, In order to diagnose chronic active ABMR : evidence of chronic tissue injury as Tx glomerulopathy or chronic arteriopathy with no evidence of acute injury.C4d +ve staining or capilliritis and Serologic evidence of circulating DSAs All the above corners were needed for the diagnosis of chronic active AMR but in recent Banff classification diagnosis of chronic ABMR requires the presence of the chronic tissue injury and only one of the other 2 criteria.
Last edited 3 years ago by Mohamed Essmat
Murad Hemadneh
3 years ago
Please summarise this article
Chronic antibody mediated rejection characterized by progressive renal graft dysfunction with worsening proteinuria. Banff 2013 diagnostic criteria has three elements:
First: Histologically characterized by presence at least one of the following:
Transplant glomerulopathy (cg . 0) in the absence of chronic thrombotic microangiopathy.
Severe peritubular capillary basement membrane multilayering by electron microscopy.
New-onset arterial intimal fibrosis with no other known aetiology.
Second: Current/recent histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
Linear C4d staining in peritubular capillaries (at least 10% by immunofluorescence [IF] on frozen sections or any positivity by immunohistochemistry on paraffin sections).
At least moderate microvascular inflammation (g 1 ptc . 2)
Increased expression of tissue gene transcripts indicative of endothelial injury.
Third: Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
Differential Diagnosis:
MPGN
Chronic thrombotic microangiopathy
Chronic hypertension and ageing. ( arterial intimal fibrosis).
Chronic TCMR. ( intimal T cells and foam cells infiltration).
manal jamid
3 years ago
Chronic antibody-mediated rejection is commonly associated with progressive loss of kidney function and proteinuria, although early stages may be subclinical and recognizable only through protocol biopsies.
Diagnostic criteria according to the Banff 2013 classification (Haas et al, Am J Transplant 2014: 14(2):272-283) include the presence of all of the following:
1. Transplant glomerulopathy
2. Peritubular capillary basement membrane multilayering ,especially if not severe (7 layers), is not specific to chronic antibody-mediated rejection.
3.Peritubular capillary C4d staining
Etiology/Pathogenesis
DSA with primarily mismatched HLA or non-HLA molecules. Repetitive and chronic endothelial damage is associated with glomerular basement membrane duplication (TG), often with segmental sclerosis, and multilayering of the peritubular capillary basement membrane. Podocyte injury and foot process effacement are common findings.
Differential Diagnosis:
1. membranoproliferative pattern of injury.
2. Chronic thrombotic microangiopathy
Better to correlate with clinical history
. Arterial intimal fibrosis is a common finding, often associated with chronic hypertension and aging.
As of 2019, the Banff schema recognizes four diagnostic categories: 1. Active ABMR, requires 3 diagnostic criteria:1. histologic evidence of acute tissue injury (glomerulitis (g) score + peritubular capillaritis (ptc) score of 2 or greater), 2. evidence of current or recent antibody interaction with the endothelium (usually C4d),3. and serologic evidence of DSA (although C4d staining or validated transcripts may substitute for DSA). 2. Chronic active ABMR, has a similar three criteria, but with histologic evidence of chronic tissue injury, (TG) attributable to ABMR. 3. Chronic (inactive) ABMR, shows histologic evidence of chronic tissue injury, but without capillaritis and without C4d deposition in peritubular capillaries. 4. final category is peritubular capillary C4d staining without evidence of rejection, previously referred to as “accommodation”. This category primarily applies to ABO blood group incompatible transplants, which show positive C4d staining in even 80% of protocol biopsies and the staining does not correlate with peritubular capillaritis the state of accommodation in patients with anti-HLA DSA is likely temporary and unstable
Histopathologic Features of Antibody Mediated Rejection: The Banff Classification and Beyond
Filipe prohaska Batista
3 years ago
Chronic active ABMR; we need ALL 3 criteria
Morphologic evidence of chronic tissue injury, including 1 or more of the following:
Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
Arterial intimal fibrosis of new-onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required.
Evidence of current/recent antibody interaction with vascular endothelium, which includes one or more of the factors listed below.
In peritubular capillaries or the medullary vasa recta, linear C4d staining was seen (C4d2 or C4d3 by immunofluorescence on frozen sections, or C4d > 0 by immunohistochemistry on paraffin sections).
The presence of at least mild microvascular inflammation ([g + ptc] 2) in the absence of recurrent or de novo glomerulonephritis.
When adequately confirmed, increased expression of gene transcripts/classifiers in biopsy tissue has been shown to be significantly linked with ABMR.
Serologic evidence of donor-specific antibodies in circulation (DSA to HLA or other antigens). The presence or absence of C4d staining or expression
In the case of biopsies that fit criterion 1 but not criterion 2 and that have current or past evidence of DSA (posttransplant), the diagnosis of chronic ABMR may be made; however, distant DSA should not be considered for the diagnosis of chronic active or active ABMR, respectively. But if the patient is lacking for both criteria and only have morphological criteria, the diagnosis will be suspicious for chronic ABMR
Ramy Elshahat
3 years ago
Chronic antibody-mediated rejection Banff 2013
Clinical and Pathologic Features is commonly associated with
1. progressive loss of kidney function
2. proteinuria,
3. subclinical and recognizable only by protocol biopsies.
Diagnostic criteria according to the Banff 2013 classification
the presence of all of the following:
1. Histologic evidence of chronic tissue injury, at least one of the following:
a. in the glomerulus: Transplant glomerulopathy (cg . 0) in the absence of chronic thrombotic microangiopathy
b. in the PTC: Severe peritubular capillary basement membrane multilayering by electron microscopy
c. in the blood vessels: New-onset arterial intimal fibrosis with no other etiology
2. histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. in the PTC: Linear C4d staining in peritubular capillaries (at least 10% by immunofluorescence [IF] on frozen sections or any positivity by immunohistochemistry on paraffin sections)
b. in the MV: At least moderate microvascular inflammation (g 1 ptc . 2)
c. gene transcripts: Increased expression of tissue gene transcripts indicative of endothelial injury
3. Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum Etiology/Pathogenesis
endothelial injury results from interaction between DSA with primarily mismatched HLA or non-HLA molecules. >>>> Repetitive and chronic endothelial damage is associated with new basement membrane formation, which
· in glomeruli manifests as glomerular basement membrane duplication (transplant glomerulopathy), often with resulting segmental sclerosis
· in PTC: multilayering of the peritubular capillary basement membrane. Podocyte injury and foot process effacement are common findings.
Differential Diagnosis (a membranoproliferative pattern of injury.)
· Chronic thrombotic microangiopathy may be indistinguishable from transplant glomerulopathy on a morphologic basis unless features of concomitant acute thrombotic microangiopathy or vascular changes are present. In such cases, correlation with clinical history will be important.
· Membranoproliferative glomerulonephritis due to immune complex processes (lupus nephritis, immunoglobulin A nephropathy, cryoglobulinemic glomerulonephritis, etc) must be ruled out by IF and electron microscopy.
Peritubular capillary basement membrane multilayering, especially if not severe (,7 layers), is not specific to chronic antibody-mediated rejection.
Arterial intimal fibrosis is a common finding, often associated with chronic hypertension and aging. Scattered T cells and foam cells may be present in the expanded intima, but are not specific for chronic antibody-mediated rejection and may also be seen in chronic T-cell–mediated rejection.
Key Diagnostic Features Transplant glomerulopathy +Peritubular capillary basement membrane multilayering + Peritubular capillary C4d staining
Updates on Banff criteria 2019 Chronic active ABMR
All 3 criteria must be satisfied for making diagnosis: 1. Evidence of chronic tissue injuryincluding 1 or more of the following –
transplant glomerulopathy (cg>0) if no evidence of
chronic TMA
chronic recurrent/de novo glomerulonephritis; including changes evident by electron microscopy (EM) alone (cg1a)
Severe peritubular capillary basement membrane multi layering (ptcm1; requires EM)
Arterial intimal fibrosis of new onset, excluding other causes+ leukocytes within the sclerotic Intima favor chronic ABMR if there is no prior history of TCMR.
2. Evidence antibody interaction with vascular endothelium, including 1 or more of the following
In PTC: Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections or C4d>0 by IHC on paraffin sections)
In MV: At least moderate microvascular inflammation [g + ptc] > 2) in
the absence of recurrent or de novo glomerulonephritis
in case of acute TCMR, borderline infiltrate, or infection>> ptc >2 alone is not sufficient and g must be >1.
Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated.
3. Serological evidence of circulating DSA to HLA or non HLA antigens. · testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised when criteria 1 and 2 are met. · C4d staining or expression of validated transcripts/classifiers substitute for DSA testing, · Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA post-transplant considered as chronic inactive ABMR and remote DSA not considered for diagnosis of chronic active or active ABMR. Chronic inactive ABMR · criterion 1: include cg>0 and/or severe ptcml (ptcml1) · Absence of criterion 2: current or recent antibody interaction with the endothelium · Criterion 3: Prior diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA. References
Loupy,A; Haas, M; et al. The Banff 2019 kidney meeting report (I) : Updates on and clarification of criteria for T cell- and antibody mediated rejection . Am J o Trans. 20 (9). 2020. https://doi.org/10.1111/ajt.15898
Nazik Mahmoud
3 years ago
Chronic active AMR is difficult to diagnose as it has several entities :
A: histological evidence of AMR:
1-TG>0 in absence of TMA
2-sever PTC multiplayering
3-new onset arterial intemal fibrosis
B:recent evidence of antibodies interaction with vascular endotheliam
1-positive C4d
2-moderate microvasular inflammation
3-increase expression of tissue gene transcripts
C:presence of DSA(HLA or non HLA)
Pathogenesis :the recurrent attack of antibodies to the vascular endotheliam lead to multilayered PTC basement membrane ,podocytes injury and effacement
New dignostic criteria due to banff 2019:
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2. Identical to criterion 2 for active ABMR, above
3. Identical to criterion 3 for active ABMR, above, including strong recommendation for DSA testing whenever criteria 1 and 2
are met.
Despite the fact that early phases of chronic antibody-mediated rejection may be asymptomatic and only detectable by routine biopsies, chronic antibody-mediated rejection is frequently accompanied by increasing loss of kidney function and proteinuria.
According to the Banff 2013 categorization, diagnostic criteria include the presence of all of the following signs and symptoms:
a-Chronic tissue damage as evidenced by histologic examination.
b-Present histologic evidence of antibody interaction with the endothelium of the vascular system.
c-Presence of donor-specific antibodies (DSA) in the blood, whether they are HLA or non-HLA.
Indications of chronic tissue damage on histology are indicated by the presence of at least one of the following characteristics:
a. Chronic thrombotic microangiopathy in the absence of transplant glomerulopathy (cg. 0).
By electron microscopy, severe peritubular capillary basement membrane multilayering was seen in the capillary basement membrane.
c. New-onset arterial intimal fibrosis with no known etiological factor
Histologic evidence of antibody interaction with vascular endothelium that is current or recent in nature, as defined by the presence of at least one of the following:
a. C4d staining in peritubular capillaries with a linear pattern (at least 10 per cent by immunofluorescence [IF] on frozen sections or any positivity by immunohistochemistry on paraffin sections)
b. Microvascular inflammation that is at least mild (g 1 ptc . 2)
Inflammatory gene transcripts in the tissues are suggestive of endothelial damage.
Endothelial damage that occurs repeatedly and chronically is associated with the formation of new basement membranes, which manifests itself in the glomeruli as glomerular basement membrane duplication, which frequently results in segmental sclerosis and the multilayering of the peritubular capillary basement membrane. Podocyte damage and foot process effacement are two of the most often seen results.
Differential Diagnosis is a medical term that refers to the process of determining whether or not anything is wrong.
Chronic thrombotic microangiopathy is a condition in which the blood vessels get clogged with clots.
If electron microscopy is performed, it must be determined that the patient does not have immunological complex processes (lupus nephritis, immunoglobulin A nephropathy, cryoglobulinemic glomerulonephritis, etc).
Chronic hypertension and ageing are two issues that need to be addressed.
Chronic antibody mediated rejection (cAMR) is characterized by graft dysfunction and proteinuria as a result of interaction of donor specific antibodies (DSA) with mismatched HLA or non-HLA molecules leading to endothelial injury causing GBM transplant glomerulopathy, (TG) with segmental sclerosis and peritubular capillary basement membrane multilayering (ptcml).
Diagnostic criteria for c-AMR according to Banff 2013 include presence of DSA with histological evidence of chronic tissue injury (either TG or ptcml or new onset arterial intimal fibrosis) and histological evidence of antibody interaction with vascular endothelium (either linear C4d staining or at least moderate microvascular inflammation or increased tissue gene transcript expression).
Differential diagnosis of cAMR include:
A) GBM duplication can be seen with:
1) Chronic endothelial damage (membranoproliferative type injury)
2) Chronic TMA (associated with acute TMA or vascular changes)
3) MPGN due to lupus nephritis, IgA nephropathy, cryoglobulinemic GN
B) Arterial intimal fibrosis seen with:
1) Chronic hypertension
2) Aging
Updates of Banff classification of chronic ABMR 2019 Chronic Active ABMR
ALL 3 criteria to be met for the diagnosis
1) morphological evidence of chronic tissue injury include one or more of the following:
Transplant glomerulopathy(cg>0) include evidence by EM(cg1a)
Severe PTC base membrane layering (require EM)
Arterial intimal fibrosis of new onset after exclusion of other causes
2) Evidence of current antibody interaction with vascular endothelial include one or more of the following:
linear c4d staining in the PTC or medullary vasa recta(c4d2 or c4d3) by IF or c4d>0 by IHC
At least moderate microvascular inflammation (Ig+ptc) 2 or more
Increase expression of gene transcript in tissue biopsy strongly associated with ABMR
3) Serological evidence of circulating DSA(to HLA and non-HLA antigens)
In renal biopsy meeting criteria 1 but not 2 with current or prior evidence of DSA (post transplant) may be stated as chronic ABMR but DSA should not be considered for diagnosis of chronic active ABMR or chronic inactive ABMR
Chronic (inactive) ABMR:
1. Chronic glomerulitis > 0 and/or severe peritubular capillaries multilayering (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
IV. AJKD Atlas of Renal Pathology:
Chronic Antibody-Mediated Rejection
Please summarise this article
*Chronic antibody mediated rejection is associated with progressive loss of kidney function, proteinuria, early stages may be subclinical and recognizable only through protocol biopsies.
*Diagnostic criteria according to the Banff 2013 classification
1) Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a.Transplant glomerulopathy (cg . 0) in the absence of CTMA
b. Severe peritubular capillary basement membrane multilayering by EM
c. New onset arterial intimal fibrosis with no other known etiology
2) Current/recent histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a* Linear C4d staining in peritubular capillaries at least 10% by IF or any positivity by IHC
b* At least moderate microvascular inflammation (g 1 ptc . 2)
c* Increased expression of tissue gene transcripts indicative of endothelial injury
3) Presence of DSA HLA or non HLA in the serum
# Etiology
* Endothelial injury results from interaction between
DSA with primarily mismatched HLA or non HLA molecules.
* Repetitive and chronic endothelial damage result in transplant glomerulopathy and multilayring of PTCBM
*Podocyte injury and foot process effacement are common finding
# Differential Diagnosis
*Glomerular basement membrane duplication:
Chronic thrombotic microangiopathy
Membranoproliferative glomerulonephritis due to immune complex processes like:
lupus nephritisImmunoglobulin
A nephropathy
Cryoglobulinemic glomerulonephritis,
( must be ruled out by IF and EM)
*Peritubular capillary basement membrane multilayering, especially if not severe is not specific to CAMR
*Arterial intimal fibrosis is a common finding:
Chronic hypertension
Aging.
*Chronic T cell mediated rejection.
# Please update the diagnostic criteria mentioned in this article based on the recent Banff classification
An update of the diagnostic criteria according banff 2019 to: https://pubmed.ncbi.nlm.nih.gov/32463180/
Chronic active ABMR; all 3 criteria must be met for diagnosis
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
** Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
** Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
** Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2.Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:
– Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
– At least moderate microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
– Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated
* *( Identical to criterion 2 for active ABMR)
3. Serologic evidence of circulating donor-specific antibodies (DSA to HLA or other antigens). C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA; however thorough DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised whenever criteria 1 and 2 are met
* * (Identical to criterion 3 for active ABM including strong recommendation for DSA testing whenever criteria 1 and 2 are met.)
* * Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA (posttransplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis of chronic active or active ABMR
Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSAC4d staining without evidence of rejection; all 4 features must be present for diagnosisc
1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
2. Criterion 1 for active or chronic active ABMR not met
3. No molecular evidence for ABMR as in criterion 2 for active and chronic active ABMR
4. No acute or chronic active TCMR, or borderline changes
Ref:
Alexandre Loupy et al. Am J “The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection” Transplant. 2020
This article is concerned with Chronic antibody mediated rejection and the response of the body to it in terms of pathological features.
CAMR is typically seen with progressive loss of kidney function along with proteinuria.
Banff 2013 diagnostic criteria :
A.Histological evidence of chronic tissue injury
Transplant glomerulopathy
Peritubular capillary basement membrane multi layering
New onset arterial intimal fibrosis
B.Histological evidence of antibody interaction with vascular endothelium
Linear C4d staining in peritubular capillaries seen with IF
Moderate microvascular inflammation
Endothelial injury evidenced by increased expression of tissue gene transcripts
C.Presence of serum DSA, HLA or non-HLA.
Chronic endothelial damage leads to formation of new layers of the basement membrane, which is seen as glomerular basement membrane duplication and peritubular capillaries multi layering, with segmental sclerosis. Common findings are podocyte injuries and foot process effacement.
Manal Malik
3 years ago
Chronic Antibody-Mediated Rejectionc ABMR associated with graft loss and proteinurea,and in the early stage may be sub-clinical and only diagnosis by protocol biopsy Diagnostic criteria according to the Banff13 classification:
1) histological evidence of chronic tissue injury defined by present of one of the following:
Transplant glomerulopathy
multilayering of peritubular capillary base membrane (by EM)
new onset arterial intimal fibrosis
2) current histological evidence of Ab interaction,defined by the present at least one of the following:
linear c4d staining PTC (at least 10% by IFon frozen section or any +ve by IHC on paraffin section)
at least moderate microvascular inflammation
increase expression of tissue gene indicated of endothelial injury
3) presence of donor specific antibody (DSA,HLA or non-HLA) in the serum Etiology-Pathogensis:
endothelial injury result from interaction between DSAs with mismatch HLA and non-HLA molecules so lead to duplication of GBM,segmental sclerosing and multilayering of peritubular capillary basement membrane
foot process effacement as a result of podocyte injury
Differential diagnosis:
GBM duplication found in condition associated with chronic endothelial damage:
chronic TMA
membranoprolifrative GN due to immune complex in such condition :
lupus nephritis
IgA nephropathy
cryoglobulonemia GN
All can be ruled out by IF and EM
peritubular BM multilayring if less than 7 layers not specific for chronic AMR
Arterial intimal fibrosis can be in chronic hypertension and aging
scatterd T cells and Foam cells in the intima not specific for chronic ABMR also seen in TCMR
Key diagnosis features:
transplant glomerulopathy
PTC base membrane multi layering
Peritubular capillary C4d staining
Update the diagnostic criteria(Banff 2019 for chronic ABMR) Chronic active ABMR:
ALL 3 criteria to be met for the diagnosis
1) morphological evidence of chronic tissue injury include one or more of the following:
Transplant glomerulopathy(cg>0) include evidence by EM(cg1a)
Severe PTC base membrane layering (require EM)
Arterial intimal fibrosis of new onset after exclusion of other causes
2) Evidence of current antibody interaction with vascular endothelial include one or more of the following:
linear c4d staining in the PTC or medullary vasa recta(c4d2 or c4d3) by IF or c4d>0 by IHC
At least moderate microvascular inflammation (Ig+ptc) 2 or more
Increase expression of gene transcript in tissue biopsy strongly associated with ABMR
3) Serological evidence of circulating DSA(to HLA and non-HLA antigens)
In renal biopsy meeting criteria 1 but not 2 with current or prior evidence of DSA (post transplant) may be stated as chronic ABMR but DSA should not be considered for diagnosis of chronic active ABMR or chronic inactive ABMR Reference: Loupy A et al.The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection. Am J Transplant. 2020;20:2318–2331.
Chronic Antibody mediated Rejection Defined as gradual progressive loss of kidney functions associated with proteinuria due to presence of antibodies directed against allograft kidney
according to Banff 2017 Chronic active ABMR;
A-Histological evidence one or more
1-Transplant glomerulopathy (if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis,) 2- EM doubling and multilayring of Peritubular capillaries glomerular basement membrane 3- fibrosis of arterial intima B- Tissue evidence of antibody affection C4d Linear staining C4d 2 or 3 by IF C4d > 0 by IHC glomerulitis + Peritubular capiliritis ≥2 increased expression of gene transcripts/classifiers in the biopsy tissue strongly C- DSA in serum ( HLA or NonHLA )
1st criteria in addition ton 2nd or 3rd needed for diagnosis
Chronic (inactive) ABMR 1. Chronic glomerulitis > 0 and/or severe peritubular capillaries multilayering (ptcml1) 2. Absence of criterion 2 of current/recent antibody interaction with the endothelium 3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
Pathogenesis : Antibody against mismatches HLA and non HLA >> inflammation >> multilayering of GBM Glomerular sclerosis and intimal fibrosis of arteries Differential diagnosis : Membranoproliferative GN ( due to IgA , Lupus and Cryoglobulinemia ) >> GBM doubling Chronic Thrombotic microangiopathy >> Vascular affection Chronic fibrosis of arterial intima >> Aging and hypertension
The introduction of ABMR into the Banff classification was in 2003,since then the criteria for diagnosis of ABMR have become more complex, with major modifications in 2013 and 2017 which have improved diagnostic sensitivity and predictive value for graft outcomes.
A major residual issue within the classification is that it still subclassifies ABMR into active or chronic active and chronic inactive.
Active ABMR; all 3 criteria must be met for diagnosis
1. Histologic evidence of acute tissue injury, including 1 or more of the following:
•Microvascular inflammation in the absence of recurrent or de novo glomerulonephritis,
• Intimal or transmural arteritis
• Acute thrombotic microangiopathy, in the absence of any other cause or
• Acute tubular injury, in the absence of any other apparent cause
2. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:
• Diffuse Linear C4d staining in peritubular capillaries or medullary vasa recta by IF on frozen sections, or by IHC on paraffin sections
• At least moderate microvascular inflammation in the absence of recurrent or de novo glomerulonephritis
• Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR.
3. Serologic evidence of circulating donor-specific antibodies (DSA to HLA or non-HLA antibodies if HLA antibody testing is negative) Chronic active ABMR; based on 3 criteria must be met for diagnosis
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
-Transplant glomerulopathy if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis, Severe peritubular capillary basement membrane multilayering (requires EM) Arterial intimal fibrosis of new onset, excluding other causes.
2 and 3 Criteria same as active ABMR
Chronic (inactive) ABMR:
1. Chronic glomerulitis > 0 and/or severe peritubular capillaries multilayering (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
Referrences
-De Serres SA, Noël R, Côté I, et al. 2013 Banff criteria for chronic active antibody-mediated rejection: assessment in a real-life set[1]ting. Am J Transplant. 2016;16(5):1516-1525
Chronic AMR associated with graft loss and diagnostic by progressive loss of kidney function and proteinuria.
Diagnostic criteria according to banff classification 2013:
1. TG in absence of chronic TMA
2. severe PTC basement membrane multilayering by electron microscopy
3. new onset of arterial intimal fibrosis
4. current or recent histological evidence
– [ ] linear c4d staining
– [ ] micro vascular inflammation
– [ ] increase expression of gene transcription indicates endothelial injury
– [ ] presence of Circulating DSA (HLA or non HLA).
Pathogenesis:
– [ ] transplant glomerulopathy due to react of circulating DSA on surface of endothelium leading to *multilayering basement membrane
– [ ] *segmental sclerosis *peritubular capillary basement membrane duplication
– [ ] *podocyte injury and foot process effacement
Differential diagnosis:
1. chronic TMA
2. membrano proliferative GN
– [ ] lupus nephritis
– [ ] IgA nephropathy
– [ ] cryoglobulinemia GN
Q2: Morphologic evidence of chronic tissue injury, including 1 or more of the following:
• 1. Transplant glomerulopathy (cg >O) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by EM alone (cgla)
• 2. Severe peritubular capillary basement membrane multilayering
• 3. Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR
2. Identical to criterion 2 for active ABMR,
3. Identical to criterion 3 for active ABMR, including strong recommendation for DSA testing whenever criteria 1 and 2 are met.
references:
Alexandre loupy et al. The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection: American Journal of TransplantationVolume 20, Issue 9 p. 2318-2331; First published: 28 May 2020 https://doi.org/10.1111/ajt.15898
Chronic antibody-mediated rejection is commonly associated with progressive loss of kidney function and proteinuria, although early stages may be subclinical and recognizable only through protocol biopsies.
Diagnostic criteria according to the Banff 2013 classification include the presence of all of the following:
1-Histologic evidence of chronic tissue injury .
2-Current histologic evidence of antibody interaction with vascular endothelium .
3-Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
Histologic evidence of chronic tissue injury; defined by the presence of at least one of the following:
a. Transplant glomerulopathy (cg . 0) in the absence of chronic thrombotic microangiopathy
b. Severe peritubular capillary basement membrane multilayering by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
Current/recent histologic evidence of antibody interaction with vascular endothelium ;
defined by the presence of at least one of the following:
a. Linear C4d staining in peritubular capillaries (at least 10% by immunofluorescence [IF] on frozen sections or any positivity by immunohistochemistry on paraffin sections)
b. At least moderate microvascular inflammation (g 1 ptc . 2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
Pathogenesis;
1-Endothelial injury results from interaction between DSA with primarily mismatched HLA or non-HLA molecules.
2-Repetitive and chronic endothelial dam- age is associated with new basement membrane formation, which in glomeruli manifests as glomerular basement membrane duplication.
3-often with resulting segmental sclerosis and multilayering of the peritubular capillary basement membrane.
4-Podocyte injury and foot process effacement are common findings.
Differential Diagnosis;
1- Glomerular basement membrane duplication is also found in;
a- Membranoproliferative glomerulonephritis due to immune complex processes
b-lupus nephritis
c-immunoglobulin A nephropathy
d-cryoglobulinemic glomerulonephritis .
2-Chronic thrombotic microangiopathy may be indistinguishable from transplant glomerulopathy on a morphologic basis unless features of concomitant acute thrombotic microangiopathy or vascular changes are present.
3-Arterial intimal fibrosis is a common finding in;
a-hypertension
b-aging.
2-Please update the diagnostic criteria mentioned in this article based on the recent Banff classification;
Updates of 2019 Banff classification for chronic ABMR ;
Chronic active ABMR; all 3 criteria must be met for diagnosis
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
a- Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
b- Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
c- Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:
a- Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
b- At least moderate microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
c- Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated
3. Serologic evidence of circulating donor-specific antibodies (DSA to HLA or other antigens). C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA; however thorough DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised whenever criteria 1 and 2 are met.
Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
Please update the diagnostic criteria mentioned in this article based on the recent Banff classification
AJKD Atlas of Renal Pathology: Chronic Antibody-Mediated Rejection Clinical and Pathologic Features
Diagnostic criteria according to the Banff 2013 classification include the presence of all of the following: 1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following: a. Transplant glomerulopathy (cg . 0) in the absence of chronic thrombotic microangiopathy b. Severe peritubular capillary basement membrane multilayering by electron microscopy c. New-onset arterial intimal fibrosis with no other known etiology 2. Current/recent histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in peritubular capillaries (at least 10% by immunofluorescence [IF] on frozen sections or any positivity by immunohistochemistry on paraffin sections)
b. At least moderate microvascular inflammation (g + ptc > 2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury 3. Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum Etiology/Pathogenesis Repetitive and chronic endothelial damage is associated with new basement membrane formation, which in glomeruli manifests as glomerular basement membrane duplication often with resulting segmental sclerosis, and multilayering of the peritubular capillary basement membrane. Podocyte injury and foot process effacement are common findings Differential Diagnosis
Chronic thrombotic microangiopathy
Membranoproliferative glomerulonephritis due to immune complex processes (lupus nephritis, immunoglobulin A nephropathy, cryoglobulinemic glomerulonephritis, etc) must be ruled out by IF and electron microscopy.
chronic hypertension and aging. Key Diagnostic Features Transplant glomerulopathy
Peritubular capillary basement membrane
multilayering
Peritubular capillary C4d staining Updates of Banff classification of chronic ABMR 2019 Chronic active ABMR; all 3 criteria must be met for diagnosis 1. Morphologic evidence of chronic tissue injury, including 1 or more of the following: – Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a) – Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM) – Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required 2. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:
Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
At least moderate microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated
3. Serologic evidence of circulating donor-specific antibodies (DSA to HLA or other antigens). C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA; however thorough DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised whenever criteria 1 and 2 are met. Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA (posttransplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis of chronic active or active ABMR Chronic (inactive) ABMR 1. cg > 0 and/or severe ptcml (ptcml1) 2. Absence of criterion 2 of current/recent antibody interaction with the endothelium 3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA C4d staining without evidence of rejection; all 4 features must be present for diagnosisc 1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections) 2. Criterion 1 for active or chronic active ABMR not met 3. No molecular evidence for ABMR as in criterion 2 for active and chronic active ABMR 4. No acute or chronic active TCMR, or borderline changes
Summary: CHRONIC ABMR:
Chronic Antibody-Mediated Rejection is characterised by gradual onset Proteinuric Renal Allograft Dysfunction.
Diagnostic criteria for Chronic ABMR is according to the Banff 2013 and should include ALL the below mentioned Broad Criteria:
1.Histologic evidence of chronic tissue injury
2. Evidence of histologic evidence of Antibody interaction with the Vascular Endothelium
3.Presence of DSAs in the Serum
Criteria 1.Histologic evidence of chronic tissue injury: Glomerulus: Presence of Transplant Glomerulopathy (>G0) in the absence of Chronic TMA / Severe PTC multilayering by EM/ New onset arterial intimal fibrosis / New onset intimal arterial fibrosis in the absence of other aetiologies
Criteria 2. Evidence of histologic evidence of Antibody interaction with the Vascular Endothelium:
Linear c4d Staining – > 10% by IF – Frozen sections or any degreee of positivity on IHC – Paraffin sections
ETIO PATHOGENESIS:
Repetitive interaction of DSA with unmatched HLA/Non HLA antigens leads to chronic and cumulative injury.
Chronic and cumulative injury is manifested as multilayering of glomeruli and PTC, which ultimately culminate as glomerulosclerosis. On Electron Microscopy, podocyte injury and foot process effacement would be evident
DIFFERENTIAL DIAGNOSIS:
GBM DUPLICATION: Any chronic and repetitive injury can result in this such as chronic TMA / Chronic MPGN due to any cause 9especially due to Hepatitis C)
It is worth noting that PTC BM multiplication of < 7 years is not characteristic of Chronic ABMR
UPDATES ABOUT CHRONIC ABMR:
ABMR is classified as Acute ABMR, Chronic Active ABMR and Chronic Inactive ABMR.
After the introduction of the word ABMR in 2003, major modification were brought in 2013 and 2017.
The Updates in Banff 2017 revision include:
Update in Criteria 2: Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated
new criteria allowing for the diagnosis of ABMR in the absence of detectable DSAs has been incorporated: in Criteria 3: C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA ( This doers not mean that DSAs are not important. It simply means that the current methods of detecting DSAs may not detect the whole range of DSAs including few of the Non HLA DSAs)
A New class of Classification has been introduced: C4d Staining without Evidence of Rejection; all 4 features must be present for diagnosis 1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d>0 by IHC on paraffin sections)2. Criterion 1 for active or chronic, active ABMR not met3. No molecular evidence for ABMR as in criterion 2 for active and chronic, active ABMR4. No acute or chronic active TCMR, or borderline changes
Leukocytes within intima not required
The potentially confusing categories of “suspicious for active ABMR” and “suspicious for chronic active ABMR” are now eliminated.
The word Acute has been dropped from acute/active ABMR
Prior DSA evidence (Post Transplant) can be regarded as a surrogate evidence of current DSA ( This does not mean that remote DSA should be taken as a valid substitute for current DSA)
Ref:
Haas M, Loupy A, Lefaucheur C, Roufosse C, Glotz D, Seron D, Nankivell BJ, Halloran PF, Colvin RB, Akalin E, Alachkar N, Bagnasco S, Bouatou Y, Becker JU, Cornell LD, Duong van Huyen JP, Gibson IW, Kraus ES, Mannon RB, Naesens M, Nickeleit V, Nickerson P, Segev DL, Singh HK, Stegall M, Randhawa P, Racusen L, Solez K, Mengel M. The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant. 2018 Feb;18(2):293-307. doi: 10.1111/ajt.14625. Epub 2018 Jan 21. PMID: 29243394; PMCID: PMC5817248.
Loupy A, Haas M, Roufosse C, Naesens M, Adam B, Afrouzian M, Akalin E, Alachkar N, Bagnasco S, Becker JU, Cornell LD, Clahsen-van Groningen MC, Demetris AJ, Dragun D, Duong van Huyen JP, Farris AB, Fogo AB, Gibson IW, Glotz D, Gueguen J, Kikic Z, Kozakowski N, Kraus E, Lefaucheur C, Liapis H, Mannon RB, Montgomery RA, Nankivell BJ, Nickeleit V, Nickerson P, Rabant M, Racusen L, Randhawa P, Robin B, Rosales IA, Sapir-Pichhadze R, Schinstock CA, Seron D, Singh HK, Smith RN, Stegall MD, Zeevi A, Solez K, Colvin RB, Mengel M. The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am J Transplant. 2020 Sep;20(9):2318-2331. doi: 10.1111/ajt.15898. Epub 2020 May 28. PMID: 32463180; PMCID: PMC7496245.
Chronic antibody-mediated rejection
CABMR in early stages could be subclinical and diagnosed through renal biopsy,
Mean features is progressive loss of graft funcation plus proteinuria. Diagnostic criteria according to the Banff 2013
1. Histologic evidence of chronic tissue injury,defined by the presence of at least one of the following:
a. Transplant glomerulopathy (cg . 0) in the absence of chronicthrombotic microangiopathy
b. Severe peritubular capillary basement membrane multilayering by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
2. Current/recent histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in peritubular capillaries (at least 10% by immunofluorescence [IF] on frozen sections or any positivity by immuno- histochemistry on paraffin sections)
b. At least moderate microvascular inflammation (g 1 ptc . 2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum.
Etiology and pathogenesis
Interaction between DSA and primarily mismatched HLA or non-HLA molecules leading to chronic endothelial damage and transplant glomerulopathy which result in segmental sclerosis and multilayering of the peritubular capillary basement membrane, Podocyte injury and foot process effacement are common findings.
Differential diagnosis of cAMR include:
A) GBM duplication can be seen with:
Chronic endothelial damage (membranoproliferative type injury), Chronic TMA (associated with acute TMA or vascular changes), MPGN due to lupus nephritis, IgA nephropathy, cryoglobulinemic GN.
B) Arterial intimal fibrosis seen with:
Chronic hypertension, Ageing
update of the diagnostic criteria according banff 2019 to:
all 3 criteria must be met for diagnosis
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
Severe peri-tubular capillary basement membrane multi-layering (ptcml1; requires EM)
Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2. Identical to criterion 2 for active ABMR, above
3. Identical to criterion 3 for active ABMR, above, including strong recommendation for DSA testing whenever criteria 1 and 2 are met. Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA (post transplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis of chronic active or active ABMR
Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
C4d staining without evidence of rejection; all 4 features must be present for diagnosis.
1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
2. Criterion 1 for active or chronic active ABMR not met
3. No molecular evidence for ABMR as in criterion 2 for active and chronic active ABMR
4. No acute or chronic active TCMR, or borderline changes https://pubmed.ncbi.nlm.nih.gov/32463180/
Chronic antibody mediated rejection
presents with progressive deterioration of kidney function and proteinuria while early stages may be subclinical and are recognized in protocol biopsies. Diagnostic criteria according to Banff 2013 classification:
All of the following criteria should be present: Histologic evidence of chronic tissue injury:
transplant glomerulopathy in absence of TMA.
peritubular capillary basement membrane by electron microscopy
New onset arterial intimal fibrosis with no other cause. Current/recent histologic evidence of antibody interaction with vascular endothelium:
linear C4d staining in peritubular capillaries
moderate microvascular inflammation
increased expression of tissue gene transcripts indicating endothelial injury Presence of DSA (HLA or non-HLA) in serum. Pathogenesis:
DSA interact with primarily mismatched HLA or non-HLA molecules leading to chronic endothelial damage and transplant glomerulopathy which result in segmental sclerosis and multilayering of the peritubular capillary basement membrane. Differential diagnosis Glomerular basement membrane duplication: may occur with chronic endothelial damage causing membranoproliferative pattern of injury due to immune complex process, ruled out by immunofluorescence and electron microscopy transplant glomerulopathy: differentiated from Chronic TMA if features of concomitant acute TMA and vascular changes are present. Peritubular capillary basement membrane multilayering not specific to chronic antibody mediated rejection. Arterial intimal fibrosis may occur in chronic hypertension and with ageing. Recent update of Banff classification (Banff 2017)
It stated that both C4d staining and validated molecular assays could be considered as potential alternatives to DSAs in the diagnosis of ABMR.
Haas M, Loupy A, Lefaucheur C, Roufosse C, Glotz D, Seron D, et al. The Banff 2017 kidney meeting report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant 2018;18:293-307
Thanks Heba for the update, but it is more than this
Last edited 3 years ago by Professor Ahmed Halawa
Amit Sharma
3 years ago
IV. AJKD Atlas of Renal Pathology: Chronic Antibody-Mediated Rejection
Please summarise this article
Chronic antibody mediated rejection (cAMR) is a condition characterized by graft dysfunction and proteinuria. It involves interaction of donor specific antibodies (DSA) with mismatched HLA or non-HLA molecules leading to repetitive endothelial injury causing GBM (glomerular basement membrane) duplication (transplant glomerulopathy, TG) with segmental sclerosis and peritubular capillary basement membrane multilayering (ptcml). Diagnostic criteria for c-AMR according to Banff 2013 include presence of DSA with histological evidence of chronic tissue injury (either TG or ptcml or new onset arterial intimal fibrosis) and histological evidence of antibody interaction with vascular endothelium (either linear C4d staining or at least moderate microvascular inflammation or increased tissue gene transcript expression).
Differential diagnosis of cAMR include: A) GBM duplication can be seen with: 1) Chronic endothelial damage (membranoproliferative type injury) 2) Chronic TMA (associated with acute TMA or vascular changes) 3) MPGN due to lupus nephritis, IgA nephropathy, cryoglobulinemic GN B) Arterial intimal fibrosis seen with: 1) Chronic hypertension 2) Ageing
Please update the diagnostic criteria mentioned in this article based on the recent Banff classification
Chronic ABMR is divided into 2 forms: chronic active ABMR and chronic inactive ABMR
Chronic active ABMR; all 3 criteria must be met for diagnosis (1)
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
a) Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
b) Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
c) Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:
a) Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
b) At least moderate MVI, microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
c) Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated
3. Serologic evidence of circulating donor-specific antibodies (DSA to HLA or other antigens). C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA; however thorough DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised whenever criteria 1 and 2 are met. Biopsies meeting criterion 1 but not criterion 2 withcurrent or prior evidence of DSA (posttransplant) may be statedas showing chronic ABMR, however remote DSA should not beconsidered for diagnosis of chronic active or active ABMR
Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
The differences between 2013 and 2019 classification:
1) Classifiying chronic (inactive) ABMR
2) TG in absence of chronic/recurrent de novo GN
3) leukocytes within intima not required
4) Linear C4d staining of medullary vasa recta
5) For MVI, in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1 6) C4d staining or expression of validated transcripts/classifiers may substitute for DSA (criteria 3) 7) Biopsies meeting criterion 1 and 3 ( with current or prior evidence of DSA – posttransplant) without criterion 2 may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis.
Reference: Loupy A, Haas M, Roufosse C, Naesens M, Adam B, Afrouzian M, Akalin E, Alachkar N, Bagnasco S, Becker JU, Cornell LD, Clahsen-van Groningen MC, Demetris AJ, Dragun D, Duong van Huyen JP, Farris AB, Fogo AB, Gibson IW, Glotz D, Gueguen J, Kikic Z, Kozakowski N, Kraus E, Lefaucheur C, Liapis H, Mannon RB, Montgomery RA, Nankivell BJ, Nickeleit V, Nickerson P, Rabant M, Racusen L, Randhawa P, Robin B, Rosales IA, Sapir-Pichhadze R, Schinstock CA, Seron D, Singh HK, Smith RN, Stegall MD, Zeevi A, Solez K, Colvin RB, Mengel M. The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am J Transplant. 2020 Sep;20(9):2318-2331. doi: 10.1111/ajt.15898. Epub 2020 May 28. PMID: 32463180; PMCID: PMC7496245.
IV. AJKD Atlas of Renal Pathology: Chronic Antibody-Mediated Rejection Please summarise this article Chronic antibody-mediated rejection clinical features Progressive loss of graft function & proteinuria OR Subclinical (recognized through protocol biopsies). Pathologic features Banff 2013 diagnostic criteria include the presence of all of the following: 1. Histologic evidence of chronic tissue injury, defined by the presence of at =>1 of: a. TG (cg > 0) in the absence of chronic TMA b. Severe PTC BM multilayering by EM c. New-onset arterial intimal fibrosis with no other known cause 2. Current/recent histologic evidence of antibody interaction with vascular endothelium, defined by the presence of =>1 of: a. Linear C4d staining in peritubular capillaries (at least 10% by IF on frozen sections or any positivity by IHC on paraffin sections) b. At least moderate microvascular inflammation (g + ptc >2) c. Increased expression of tissue gene transcripts indicative of endothelial injury 3. Presence of DSA (HLA or non-HLA) in the serum Pathogenesis Endothelial injury results from interaction between DSA & mismatched HLA or non-HLA molecules. Formation of new basement membrane results from chronic & repetitive endothelial injury. This is manifested as: – GBM duplication(TG) & – Multilayring of PTC BM. Podocyte injury & effaced foot processes are common findings. Differential Diagnosis 1. Other causes of GBM duplication : – Chronic thrombotic microangiopathy: look for other clinical features. – MPGN due to immune complex depositions(must be ruled out by IF & EM): (i) Lupus nephritis (ii) IgAnephropathy (iii) Cryoglobulinemic GN 2. PTC BM multi-layering specially if not severe is not specific for CAMR. 3. Other causes of arterial intimal fibrosis: (i) Chronic hypertension (ii) Aging 4. Chronic TCMR: scattered T cells & foam cells may be seen as in chronic AMR. Please update the diagnostic criteria mentioned in this article based on the recent Banff classification According to the most recent BANFF IN 2017, the chronic AMR is classified under Category 2: Antibody-mediated changes as follows:
Chronic AMR Banff 2017 permits the use of this term for biopsy specimens showing TG & /or PTC BM multilayering in the absence of criterion of current/recent antibody interaction with the endothelium (Criteria Group 2) but with a prior documented diagnosis of Active or Chronic Active AMR or documented prior evidence of DSA Diagnostic Criteria Groups: Criteria Group 4 Histologic features of AMR chronicity
– Banff Lesion Score cg > 0 (by LM or EM, if available), excluding biopsies with evidence of chronic TMA. – =>7 layers in 1 cortical PTC &=> 5 in 2 additional capillaries, avoiding portions cut tangentially by EM, if available (Severe PTC BM Multilayering)
– Arterial Intimal Fibrosis Of New Onset, Excluding Other Causes; Leukocytes Within The Sclerotic Intima Favor Chronic AMR If There Is No Prior H/O Biopsy-Proven TCMR but are not required
☆ AJKD Atlas of Renal Pathology: Chronic Antibody-Mediated Rejection
▪︎Diagnostic criteria of Chronic ABMR
______________
▪︎Aaccording to the Banff 2013 include the presence of all of the following:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy in the absence of chronic TMA
b. Severe peritubular capillary basement
membrane(BM) multilayering by electron
microscopy
c. New-onset arterial intimal fibrosis with
no other known etiology
2. Current/recent histologic evidence of Ab interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in peritubular
capillaries (at least 10% by IF on frozen
sections or any positivity by IHC on
paraffin sections)
b. At least moderate microvascular
inflammation.
c. Increased expression of tissue gene
transcripts indicative of endothelial injury
3. Presence of donor-specific antibodies
(DSA; HLA or non-HLA) in the serum
Etiology/Pathogenesis:
_______________________€€
▪︎DSAs interact with primarily mismatched HLA or non-HLA molecules which result in endothelial injury with new BM formation (in glomeruli manifests as GBM duplication (transplant glomerulopathy)), often with resulting segmental sclerosis, and multilayering of the peritubular capillary BM.
▪︎Podocyte injury and foot process effacement are common findings.
Differential Diagnosis:
______________________
▪︎GBM duplication is seen in:
1. Chronic endothelial damage, causing a membranoproliferative pattern of injury.
2. Chronic TMA
3. Membranoproliferative glomerulonephritis due to immune complex processes (lupus nephritis, IgA nephropathy, cryoglobulinemic glomerulonephritis, etc)
▪︎The following are not is not specific to chronic ABMR:
1. Less severe peritubular capillary BM multilayering.
2. Arterial intimal fibrosis (often associated with chronic hypertension and aging).
3. Scattered T cells and foam cells present in the expanded intima (may also be seen in chronic T-cell–mediated rejection).
A. In Chronic active ABMR; all 3 criteria must be met for diagnosis
B. In Chronic (inactive) ABMR:
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSAC4d staining without evidence of rejection;
▪︎All 4 features must be present for diagnosis
1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
2. Criterion 1 for active or chronic active ABMR not met
3. No molecular evidence for ABMR as in criterion 2 for active and chronic active ABMR
4. No acute or chronic active TCMR, or borderline changes
______________
Ref:
Alexandre Loupy et al. Am J “The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection” Transplant. 2020
Chronic ABMR is devastating for both the phyiscian and the patient, and it ends up with progressive graft loss.
BANF is a city in canada where the pathologist meet every now and then to put giuidlines to recognize different types of kidney rejection over histological and to some extent immunological basis,
these guidlines are upadted every now and then.
In 2013 BANF commite put classification for cABMR,
Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
Transplant glomerulopathy (cg . 0) in the ab-
sence of chronic thrombotic microangiopathy
Severe peritubular capillary basement mem- brane multilayering by electron microscopy
New-onset arterial intimal fibrosis with no other
known etiology
Current/recent histologic evidence of antibody
interaction with vascular endothelium, defined by the presence of at least one of the following:
Linear C4d staining in peritubular capillaries (at
least 10% by immunofluorescence [IF] on frozen sections or any positivity by immuno- histochemistry on paraffin sections)
At least moderate microvascular inflammation (g 1 ptc.2)
Increased expression of tissue gene transcripts indicative of endothelial injury
Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
In 2019 the committe had made some changes to this classification
Chronic active ABMR; all 3 criteria must be met for diagnosis
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2. Identical to criterion 2 for active ABMR, above
3. Identical to criterion 3 for active ABMR, above, including strong recommendation for DSA testing whenever criteria 1 and 2 are met. Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA (posttransplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis of chronic active or active ABMR
Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
C4d staining without evidence of rejection; all 4 features must be present for diagnosisc
1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
2. Criterion 1 for active or chronic active ABMR not met
3. No molecular evidence for ABMR as in criterion 2 for active and chronic active ABMR
4. No acute or chronic active TCMR, or borderline changes
reference
1-Alexandre Loupy.The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection.American Journal of TransplantationVolume 20, Issue 9 p. 2318-2331.
Chronic Antibody mediated rejection represent a poor allograft prognosis .it’s usually present with gradually deteriorating allograft function with or without proteinuria.However, early stages might be subclinical and detected only by protocol biopsy.
In 2013 classification defined chronic AMR depending on 3 categories showcasing the evidences of chronic tissue injury, recent or current antibody endothelial interaction and lastly the presence of DSAs.
It was highlighted in details as follows:
1-:Histologic evidence of chronic tissue injury in the form of TG, severe PTC mutilayring by EM,and new onset arterial intimal fibrosis.
2-Evidence of recent /current Antibody endothelial interaction ,in the form of C4d deposition in PTC
Shown by IF or IHC.Or the presence of moderate MVI(g+ptc>2).And lastly increased expression of tissue gene transcripts.
3-DSA ,HLA and non HLA.
In 2019 the diagnosis of Chronic AMR was split into 2 category as follow;
1) Chronic active Antibody mediated rejection, C-aAMR, in which 3 diagnostic Criteria, including
a)histologic evidence of acute tissue injury,
b)evidence of recent or current antibody interaction with endothelium (usually C4d),however C4d stainig or validated transcripts may substitute for DSAs..
c)histologic evidence of chronic tissue injury,such as TG attributed to AMR.
Acute tissue injury involve MVI with g+ptc>2,acute tubular damage,thrombotic microangiopathy,and less commonly arterial lesion of endothelialitis,fibrinoid necrosis and transmutation inlammation..
2)Chronic inactive AMR: shows evidence of chronic tissue injury but without capillaritis and without C4d deposition.
One more category was added ,that is ptc staining for C4d without evidence of rejection.,referred to as accommodation related to ABO incompatible transplant with and without DSAs.
Reference:
1)Lynn D.Cornell.Histologic Features of Antibody Mediated Rejection:The Banff Classification and beyond.front.Immunol.sept 2021
AJKD Atlas of Renal Pathology: Chronic Antibody-Mediated Rejection.
Its mainly due to the same cause of ABMR which the HLA or Non-HLA antibodies interact with the endothelium and lead to chronic inflammatory process which lead to duplication of peritubular GBM. D.D of GBM duplication: its important as each one has specific treatment.
-Chronic TMD.
-MPGN due to immune complex processes (lupus nephritis, immunoglobulin A nephropathy, cryoglobulinemic glomerulonephritis, etc.) must be ruled out by IF and electron microscopy.
Chronic antibody-mediated rejection is commonly associated with progressive loss of kidney function and proteinuria, and its considered one of the common causes poor graft outcome. As per BANFF 2013 Ca-ABMR is diagnosed by three criteria:
1-Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following: (TG, BM multi-layering by E/M or . New-onset arterial intimal fibrosis).
2-Current/recent histologic evidence of antibody interaction with vascular endothelium e.g. (linear C4d staining in peritubular capillaries, moderate microvascular inflammation or expression of tissue gene transcripts).
3-Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum. Updates of 2019 Banff classification for chronic ABMR: (1).
1-Chronic active ABMR: same criteria as in BANFF 2013
2-Chronic (inactive) ABMR: 1. cg > 0 and/or severe ptcml (ptcml1) 2. Absence of criterion 2 of current/recent antibody interaction with the endothelium 3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA. C4d staining without evidence of rejection; all 4 features must be present for diagnosis
In this article publishes in 2015, chronic antibody-mediated rejection was defined according to BANFF 2013 criteria.
Chronic AMR which is always associated with graft loss in the long term should be differentiated from MPGN (membranoproliferative GN) and other immune complex related pathologies like SLE, IgA GN, and cryoglobulinemia some of which are differentiated by IF (immunofluorescence) staining. Multilayering of BM (basement membrane) is typically more than 7 layers in chronic rejection. In summary, the key features of Chronic AMBR are TG (transplant glomerulopathy), Peritubular BM multilayering and Peritubular capillary c4d staining.
In BANFF 2013 the chronic AMR is mandated by all three features:
1- Histologic evidence of chronic tissue injury
2- Current/recent evidence of interaction between antibodies and vascular epithelium
3- Presence of DSAs (either HLA or non-HLA)
The histologic features (1) are defined by at least one of :
a) TG (transplant glomerulopathy) cg>0 without chronic TMA.
B) severe BM multilayering.
C) new-onset arterial intimal fibrosis (w/o defined other cause)
Current/recent evidence of ab-endothelial interaction is defined as one of the below 3 :
a) Linear c4d staining in the PTCs
b) At least moderate microvascular inflammation (g+ptc >2)
c) İncreased expression of tissue gene transcripts
Category 2: Category 2: Antibody-mediated changes Active ABMR; all 3 criteria must be met for diagnosis 1. Histologic evidence of acute tissue injury, including 1 or more of the following:
Microvascular inflammation (g > 0 and/or ptc > 0), in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 1 alone is not sufficient and g must be ≥ 1
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 1 or more of the following:
Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
At least moderate microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated
3. Serologic evidence of circulating donor-specific antibodies (DSA to HLA or other antigens). C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA; however thorough DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised whenever criteria 1 and 2 are met Chronic active ABMR; all 3 criteria must be met for diagnosis 1. Morphologic evidence of chronic tissue injury, including 1 or more of the following: Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a) Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM) Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required 2. Identical to criterion 2 for active ABMR, above 3. Identical to criterion 3 for active ABMR, above, including strong recommendation for DSA testing whenever criteria 1 and 2 are met. Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA (posttransplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis of chronic active or active ABMR Chronic (inactive)ABMR 1. cg > 0 and/or severe ptcml (ptcml1) 2. Absence of criterion 2 of current/recent antibody interaction with the endothelium 3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA C4d staining without evidence of rejection; all 4 features must be present for diagnosisc 1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections) 2. Criterion 1 for active or chronic active ABMR not met 3. No molecular evidence for ABMR as in criterion 2 for active and chronic active ABMR 4. No acute or chronic active TCMR, or borderline changes
Reference The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am J Transplant. 2020 Sep;20(9):2318-2331. doi: 10.1111/ajt.15898. Epub 2020 May 28. PMID: 32463180; PMCID: PMC7496245.
AJKD Atlas of Renal Pathology: Chronic Antibody-Mediated Rejection
Chronic antibody-mediated rejection is associated with progressive loss of kidney function and proteinuria, early stages may be subclinical and recognizable only through protocol biopsies.
Diagnostic criteria according to the Banff 2013 classification :
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy (cg . 0) in the ab-
sence of chronic thrombotic microangiopathy
b. Severe peritubular capillary basement mem- brane multilayering by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
2. Current/recent histologic evidence of antibody
interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in peritubular capillaries (at least 10% by immunofluorescence [IF] on frozen sections or any positivity by immuno- histochemistry on paraffin sections)
b. At least moderate microvascular inflammation (g 1 ptc.2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
Etiology:
endothelial injury results from interaction between DSA with primarily mismatched HLA or non-HLA molecules.
Dear Asmaa
You need to explain better the difference between Banff 13 and 17 (19)
Mohamad Habli
3 years ago
Chronic Antibody-Mediated Rejection is diagnosed based on Banff 2013 classification:
1. Histologic evidence of chronic tissue injury
2. Current/recent histologic evidence of antibody interaction with vascular endothelium
3. Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
Chronic endothelial damage is manifested histologically with new basement membrane formation, GBM duplication (transplant glomerulopathy) associated with segmental sclerosis, and multilayering of the peritubular capillary basement membrane.
Glomerular basement membrane duplication is also found in other conditions associated with chronic endothelial damage, causing a membranoproliferative pattern of injury.
Chronic TMA may resemble transplant glomerulopathy on a morphologic basis unless features of concomitant acute thrombotic microangiopathy or vascular changes are present.
Peritubular capillary basement membrane multilayering, especially if not severe (<7 layers), is not specific to chronic antibody-mediated rejection.
1- Summary
Diagnostic criteria for chronic antibody mediated rejection according to the Banff 2013 classification include the presence of all of the following:
-Histologic evidence of chronic tissue injury, determined by occurrence of at least one of the following:
.Transplant glomerulopathy (cg . 0) in the absence of chronic thrombotic microangiopathy
. Severe peritubular capillary basement membrane multilayering by electron microscopy
. New-onset arterial intimal fibrosis with no other known etiology
-Current/recent histologic evidence of antibody interaction with vascular endothelium, detected by the ocuurnce of Linear C4d staining in peritubular capillaries ,at least moderate microvascular inflammation , Increased expression of tissue gene transcripts
-Presence of donor-specific antibodies Pathogenesis
DSA interaction with mismatched HLA or non-HLA molecules leads to endothelial injury, occurring repetitively causes glomerular basement membrane duplication (transplant glomerulopathy), with segmental sclerosis. DD
Glomerular basement membrane duplication can be associated with other conditions with membranoproliferative pattern .
So membranoproliferative glomerulonephritis need to be excluded with IF and EM.
Chronic thrombotic microangiopathy can resemble morphologically transplant glomerulopathy .
Peritubular capillary basement membrane multilayering, has to be severe to be diagnostic of chronic antibody mediated rejection.
Arterial intimal fibrosis and scattered T cells are non specific Diagnostic Features
Transplant glomerulopathy
Peritubular capillary basement membrane multilayering
Peritubular capillary C4d staining
2- Updated diagnostic criteria based on latest Banff classification
As of 2019, the Banff schema recognizes four diagnostic categories:
1. Active ABMR,
2. Chronic active ABMR,
3. Chronic (inactive) ABMR,
4. C4d staining without evidence of rejection,
§ The active ABMR, requires 3 diagnostic criteria:
Ø histologic evidence of acute tissue injury, microvascular inflammation (MVI), as capillaritis, glomerulitis (g) score + peritubular capillaritis (ptc) score of 2 or greater, thrombotic microangiopathy, and less commonly arterial lesions of endothelialitis, fibrinoid necrosis, or transmural inflammation.
Ø evidence of current or recent antibody interaction with the endothelium (usually C4d),
Ø serologic evidence of DSA (although C4d staining or validated transcripts may substitute for DSA).
§ Chronic active ABMR has a similar three criteria, but with
histologic evidence of chronic tissue injury, such as transplant glomerulopathy (TG) attributable to ABMR.
§ Chronic (inactive) ABMR shows histologic evidence of chronic tissue injury, but without capillaritis and without C4d deposition in peritubular capillaries.
§ PTC C4d staining without evidence of rejection, previously “accommodation” occurs in ABO blood group incompatible transplants, which show positive C4d staining in even 80% of protocol biopsies and the staining does not correlate with peritubular capillaritis.
Reference
Cornell L. D.Histopathologic Features of Antibody Mediated Rejection: The Banff Classification and Beyond .Front. Immunol., 27 September 2021.
AJKD Atlas of Renal Pathology: Chronic Antibody-Mediated Rejection
Please summarise this article
Chronic antibody mediated rejection (CABMR) a cause of proteinuria and loss of graft function. Diagnostic criteria (2013) Banff, all 3 below required for diagnosis of CABMR. 1.Histologic evidence of chronic tissue injury in form of one below; I. Transplant glomerulopathy (cg . 0) in the absence of chronic thrombotic microangiopathy I. Severe peritubular capillary basement membrane multilayering by electron microscopy II. New-onset arterial intimal fibrosis with no other known aetiology 2.Evidence of antibody interaction with vascular endothelium in form of one below; I. C4d staining of peritubular capillaries II. Moderate microvascular inflammation (g+ptc>2) 3. Presence of DSA in serum Pathogenesis Endothelial injury from DSA Glomerular duplication from repeated endothelial injury Podocytopathy Other causes of double contour appearance of GBM – chronic TMA and MPGN Intimal fibrosis can also be due – hypertension and aging
Please update the diagnostic criteria mentioned in this article based on the recent Banff classification
Banff 2019 now has two categories of chronic antibody mediated rejection(Loupy et al., 2020)
1. Chronic active ABMR; all 3 criteria must be met for diagnosis
I. Morphologic evidence of chronic tissue injury, any one of ;1 or more of the following:
Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favour chronic ABMR if there is no prior history of TCMR, but are not required
1. Chronic inactive ABMR
I. cg > 0 and/or severe peritubular capillary basement membrane multilayering
II. Absence of current/recent antibody interaction with the endothelium
III. 3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
LOUPY, A., HAAS, M., ROUFOSSE, C., NAESENS, M., ADAM, B., AFROUZIAN, M., AKALIN, E., ALACHKAR, N., BAGNASCO, S., BECKER, J. U., CORNELL, L. D., CLAHSEN-VAN GRONINGEN, M. C., DEMETRIS, A. J., DRAGUN, D., DUONG VAN HUYEN, J.-P., FARRIS, A. B., FOGO, A. B., GIBSON, I. W., GLOTZ, D., GUEGUEN, J., KIKIC, Z., KOZAKOWSKI, N., KRAUS, E., LEFAUCHEUR, C., LIAPIS, H., MANNON, R. B., MONTGOMERY, R. A., NANKIVELL, B. J., NICKELEIT, V., NICKERSON, P., RABANT, M., RACUSEN, L., RANDHAWA, P., ROBIN, B., ROSALES, I. A., SAPIR-PICHHADZE, R., SCHINSTOCK, C. A., SERON, D., SINGH, H. K., SMITH, R. N., STEGALL, M. D., ZEEVI, A., SOLEZ, K., COLVIN, R. B. & MENGEL, M. 2020. The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection. American Journal of Transplantation, 20, 2318-2331. II. Evidence of current/recent antibody interaction with vascular endothelium as Banff 2013;
III. Serologic evidence of circulating donor-specific antibodies (DSA to HLA or other antigens). C4d staining may substitute for this criterion
Chronic antibody mediated rejection is a common cause of late allograft loss , it presents with proteinuria ang decreased e GFR although in early stages it may have subclinical presentation .
(2) Evidence of antibody interaction with endothelial cells :
C4d +ve staining.
Moderate microvascular inflammation ( g + ptc > 2).
Endothelial associated transcripts / classifiers.
(3) DSA
In 2017 , The Banff group updated the criteria , it no longer require DSA , and diffuse C4d staining and endothelial associated transcripts / classifiers can replace the DSA criteria.
Chronic ABMR is associated with progressive loss of graft function and proteinuria, subclinical stages are diagnosed only in protocol biopsies.
Diagnostic criteria( Banff 2013):
Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following: a. Transplant glomerulopathy (cg . 0) in the absence of chronic thrombotic microangiopathy. b. Severe peritubular capillary basement membrane multilayering by electron microscopy. c. New-onset arterial intimal fibrosis with no other known etiology
Current/recent histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following: a. Linear C4d staining in peritubular capillaries (at least 10% by immunofluorescence [IF] on frozen sections or any positivity by immunohistochemistry on paraffin sections) b. At least moderate microvascular inflammation (g 1 ptc . 2) c. Increased expression of tissue gene transcripts indicative of endothelial injury.
Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
Pathogenesis:
Interaction between DSA with primary mismatched HLA or non-HLA molecules resulting in endothelial injury, repetitive damage will lead to double contour GBM formation with segmental sclerosis and multilayering of peritubular capillary basement membrane, podocyte injury and effacement.
Differential Diagnosis:
MPGN
Chronic thrombotic microangiopathy
Chronic hypertension and ageing. ( arterial intimal fibrosis).
Chronic TCMR. ( intimal T cells and foam cells infiltration).
Update: Banff 2019
Chronic active ABMR; all 3 criteria must be met for diagnosis 1. Morphologic evidence of chronic tissue injury, including 1 or more of the following: Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a) Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM). Arterial intimal fibrosis of new-onset, excluding other causes; leukocytes within the sclerotic intima favour chronic ABMR if there is no prior history of TCMR, but are not required
2. Identical to criterion 2 for active ABMR ( Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following: • Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections) • At least moderate microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1 • Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated).
3. Identical to criterion 3 for active ABMR, including a strong recommendation for DSA testing whenever criteria 1 and 2 are met. Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA (posttransplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for a diagnosis of chronic active or active ABMR Chronic (inactive) ABMR.
Chronic (inactive) ABMR: 1. cg > 0 and/or severe ptcml (ptcml1). 2. Absence of criterion 2 of current/recent antibody interaction with the endothelium. 3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA. C4d staining without evidence of rejection; all 4 features must be present for diagnosis: 1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections). 2. Criterion 1 for active or chronic active ABMR has not been met. 3. No molecular evidence for ABMR as in criterion 2 for active and chronic active ABMR. 4. No acute or chronic active TCMR, or borderline changes.
Chronic antibody mediated rejection is a progressive disease and is associated with graft loss and proteinuria. Early stages are only diagnosed by Protocol biopsies. Banf 2013 criteria for diagnosis includes:
1–Chronic tissue injury on biopsy and presence of at least one of the following.
· Transplant glomerulopathy in the absence of Thrombotic microangiopathy
· Severe peritubular capillary membrane multilayering
· New onset intimal fibrosis with no other cause
2- Histological evidence of interaction of antibody with vascular endothelium-defined by one of the following:
· Linear Cd4 staining in pertibullar capillaries- at least 10% by IF, on the frozen section or any positivity on immunohistochemistry or paraffin section.
· At least microvascular inflammation
· Increased expression of tissue gene transcript
3- Presence of DSA
Pathogenesis
Interaction of DSA with Mismatched HLA or Non HLA antigens leads to chronic an repetitive endothelial damage with new basement membrane formation manifesting as basement membrane duplication with resulting segmental sclerosis and multilayering.
Differential diagnosis
· Chronic Thrombotic microangiopathy
· Membranoproliferative glomerulonephritis due to immune complex processes
· Chronic hypertension and aging -Arterial intimal fibrosis can be seen
ABMR has wide variety of clinicopathological features which range from hyper acute rejection to early acute ABMR in patients with positive cross match to progressive graft dysfunction . Features of ABMR can be seen on routine protocol biopsies in patients who have history of pre transplant DSA with a stable graft function and proteinuria . The features can be different in patients who have history of denovo DSA and nonadherence to medications or those who have combined antibody mediated and cellular rejection. The challenge remains for any classification system to fit in variety of variable clinicopathologic findings.
In 2019 Banff Schema classified ABMR in to :
Active ABMR-
3 diagnostic criteria-
Evidence of acute tissue injury
Antibody interaction with Endothelium- C4d staining
Evidence of DSA
Histologically – Microvascular inflammation- Glomerulitis and Peritubular Capilliritis score of 2 or more. Other patterns are acute tubular injury, transplant microangiopathy and less commonly endothelitis, fibrinoid necrosis or transmural inflammation
Chronic Active ABMR
All three criteria must be met-
Evidence of chronic tissue injury including one or more of the following- Transplant glomerulopathy, Multilayering of PTC membrane , chronic arteriopathy without evidence of acute inflammation.
Evidence of antibody interaction with vascular endothelium.
Positive c4d staining in peritubular capillaries.
Evidence of Circulating DSA
Chronic inactive ABMR
If there is evidence of chronic tissue injury with one of the other two criteria’s
C4d staining without the evidence of rejection
Previously referred as accommodation. It is seen in ABO incompatible Transplants in which C4d staining is seen in 80% protocol biopsies and this staining does not co relate with peritubular capilliritis. In some protocol biopsies of patients with history of positive XM C4d staining is seen without evidence of tissue injury and this group qualifies for accommodation.
Reference :
D Cornell. Histopathologic Features of Antibody Mediated Rejection: The Banff Classification and Beyond. Front. Immunol., 27 September 2021
Dear All
Describe chronic AMR based on Banff (2017/19)
Chronic active ABMR;
The 3 criteria must be detected for diagnosis
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
§ Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
§ Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
§ Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favour chronic ABMR if there is no prior history of TCMR, but are not required.
2-Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following
• Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
• At least moderate microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis
• Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated
3-Serologic evidence of circulating donor-specific antibodies (DSA to HLA or other antigens). C4d staining or expression
Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA (posttransplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis of chronic active or active ABMR
Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA(Continues)C4d staining without evidence of rejection; all 4 features must be present for diagnosisc
1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
2. Criterion 1 for active or chronic active ABMR not met
3. No molecular evidence for ABMR as in criterion 2 for active and chronic active ABMR4. No acute or chronic active TCMR, or borderline changes
Reference
Loupy A et al.The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection. Am J Transplant. 2020;20:2318–2331.
Well done
3 components are required for the diagnosis of chronic active ABMR :
– If the patient has the first criteria and only one of the other 2 criteria, the patient is considered to have chronic active ABMR, this means C4d staining can replace DSA, and C4d negative chronic active ABMR exists
– But if the patient is lacking for both criteria and only have morphological criteria , diagnosis will be suspicious for chronic ABMR
Thank You
2019 Banff classification for ABMR:
Chronic active ABMR; all 3 criteria must be met for diagnosis
1. Morphologic evidence of chronic tissue injury, including 1 or more of the
following:
Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic
recurrent/de novo glomerulonephritis; includes changes evident by electron
microscopy (EM) alone (cg1a).
Severe peritubular capillary basement membrane multilayering (ptcml1;
requires EM) .
Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within
the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but
are not required.
2_ Evidence of current/recent antibody interaction with vascular endothelium,
including 1 or more of the following:
• Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or
C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
• At least moderate microvascular inflammation ([g + ptc] ≥2) in the absence of
recurrent or de novo glomerulonephritis, although in the presence of acute
TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g
must be ≥1
• Increased expression of gene transcripts/classifiers in the biopsy tissue
strongly associated with ABMR, if thoroughly validated .
3. Serologic evidence of circulating donor-specific antibodies (DSA to HLA or
other antigens).
C4d staining or expression of validated transcripts/classifiers as noted above in
criterion 2 may substitute for DSA; however thorough DSA testing, including
testing for non-HLA antibodies if HLA antibody testing is negative, is strongly
advised whenever criteria 1 and 2 are met.
recommendation for DSA testing whenever criteria 1 and 2 are met.
Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of
DSA (posttransplant) may be stated as showing chronic ABMR, however remote
DSA should not be considered for diagnosis of chronic active or active ABMR
Chronic (inactive) ABMR:
1. cg > 0 and/or severe ptcml (ptcml1).
2. Absence of criterion 2 of current/recent antibody interaction with the
endothelium.
3. Prior documented diagnosis of active or chronic active ABMR and/or
documented prior evidence of DSA.
Thank You
Update the diagnostic criteria(Banff 2019 for chronic ABMR)
Chronic active ABMR:
ALL 3 criteria to be met for the diagnosis
1) morphological evidence of chronic tissue injury include one or more of the following:
2) Evidence of current antibody interaction with vascular endothelial include one or more of the following:
3) Serological evidence of circulating DSA(to HLA and non-HLA antigens)
In renal biopsy meeting criteria 1 but not 2 with current or prior evidence of DSA (post transplant) may be stated as chronic ABMR but DSA should not be considered for diagnosis of chronic active ABMR or chronic inactive ABMR
Reference:
Loupy A et al.The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection. Am J Transplant. 2020;20:2318–2331
Thank You
Updates on Banff criteria 2019
Chronic active ABMR
All 3 criteria must be satisfied for making diagnosis :
A.Morphological evidence of chronic tissue injury including 1 or more of the following –
B. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following
C. Serological evidence of circulating DSA to HLA or other antigens. C4d staining or expression of validated transcripts/classifiers as noted in criterion 2 may substitute for DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised when criteria 1 and 2 are met.
Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA post transplant may be stated as showing chronic ABMR, but remote DSA should not be considered for diagnosis of chronic active or active ABMR.
Chronic inactive ABMR
A.cg>0 and/or severe ptcml (ptcml1)
B.Absence of current or recent antibody interaction with the endothelium
C.Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA.
References
It is nice to see your contribution Nandita
Chronic active ABMR; all 3 criteria must be met for diagnosis
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
2. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:
3. Serologic evidence of donor‐specific antibodies (DSA to HLA or other antigens). C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA; however thorough DSA testing, including testing for non‐HLA antibodies if HLA antibody testing is negative, is strongly advised whenever criteria 1 and 2 are met
M. Haas, C. Lefaucheur, C. Roufosse, D. Glotz, D. Seron, B. J. Nankivell, P. F. Halloran, R. B. Colvin, Enver Akalin, N. Alachkar, S. Bagnasco, Y. Bouatou, , J. U. Becker, L. D. Cornell, J. P. Duong van Huyen, I. W. Gibson, Edward S. Kraus, R. B. Mannon, M. Naesens, V. Nickeleit, P. Nickerson, D. L. Segev, H. K. Singh, M. Stegall, P. Randhawa, L. Racusen, K. Solez, M. Mengel. The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell–mediated rejection, antibody‐mediated rejection, and prospects for integrative endpoints for next‐generation clinical trials. Am J Transplant. 2018 Feb; 18(2): 293–307.
Thank You
Chronic ABMR is divided into 2 forms: chronic active ABMR and chronic inactive ABMR
Chronic active ABMR; all 3 criteria must be met for diagnosis (1)
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
a) Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
b) Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
c) Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:
a) Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
b) At least moderate MVI, microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
c) Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated
3. Serologic evidence of circulating donor-specific antibodies (DSA to HLA or other antigens). C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA; however thorough DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised whenever criteria 1 and 2 are met. Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA (posttransplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis of chronic active or active ABMR
Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
The differences between 2013 and 2019 classification:
1) Classifiying chronic (inactive) ABMR
2) TG in absence of chronic/recurrent de novo GN
3) leukocytes within intima not required
4) Linear C4d staining of medullary vasa recta
5) For MVI, in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
6) C4d staining or expression of validated transcripts/classifiers may substitute for DSA (criteria 3)
7) Biopsies meeting criterion 1 and 3 ( with current or prior evidence of DSA – posttransplant) without criterion 2 may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis.
Reference:
Loupy A, Haas M, Roufosse C, Naesens M, Adam B, Afrouzian M, Akalin E, Alachkar N, Bagnasco S, Becker JU, Cornell LD, Clahsen-van Groningen MC, Demetris AJ, Dragun D, Duong van Huyen JP, Farris AB, Fogo AB, Gibson IW, Glotz D, Gueguen J, Kikic Z, Kozakowski N, Kraus E, Lefaucheur C, Liapis H, Mannon RB, Montgomery RA, Nankivell BJ, Nickeleit V, Nickerson P, Rabant M, Racusen L, Randhawa P, Robin B, Rosales IA, Sapir-Pichhadze R, Schinstock CA, Seron D, Singh HK, Smith RN, Stegall MD, Zeevi A, Solez K, Colvin RB, Mengel M. The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am J Transplant. 2020 Sep;20(9):2318-2331. doi: 10.1111/ajt.15898. Epub 2020 May 28. PMID: 32463180; PMCID: PMC7496245.
Thank You
All three criteria must be met-
Evidence of chronic tissue injury including one or more of the following-
Transplant glomerulopathy By EM
Multilayering of PTC membrane BY EM
Chronic arteriopathy without evidence of acute inflammation.
Evidence of antibody interaction with vascular endothelium.
Linear Positive c4d staining in peritubular capillaries or medullary vasa recta- C4d2 or C4d3 by IF on frozen section or C4d >0 by IHC On paraffin section
·
Moderate Micro vascular inflammation in the absence of the recent or denovo glomerulonephritis.
Increased expression of gene transcripts in the biopsy
Evidence of Circulating DSA
If there is evidence of chronic tissue injury with one of the other two criteria’s it is labelled as Chronic ABMR
Thank You
Chronic active ABMR; all 3 criteria must be met for diagnosis
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
Arterial intimal fibrosis of new-onset, excluding other causes; leukocytes within the sclerotic intima favour chronic ABMR if there is no prior history of TCMR, but are not required .
2-Evidence of current/recent antibody interaction with vascular endothelium, which includes one or more of the factors listed below.
In peritubular capillaries or the medullary vasa recta, linear C4d staining was seen (C4d2 or C4d3 by immunofluorescence on frozen sections, or C4d > 0 by immunohistochemistry on paraffin sections).
• The presence of at least mild microvascular inflammation ([g + ptc] 2) in the absence of recurrent or de novo glomerulonephritis.
When adequately confirmed, increased expression of gene transcripts/classifiers in biopsy tissue has been shown to be significantly linked with ABMR.
3-Serologic evidence of donor-specific antibodies in circulation (DSA to HLA or other antigens). The presence or absence of C4d staining or expression
In the case of biopsies that fit criterion 1 but not criterion 2 and that have current or past evidence of DSA (posttransplant), the diagnosis of chronic ABMR may be made; however, distant DSA should not be considered for the diagnosis of chronic active or active ABMR, respectively.
Thank You
Chronic AMR was classified into 4 categories according to the Banff 2019 consensus,these are:
1) Chronic inactive AMR
2) Chronic active Antibody mediated rejectiAccommodations
3) Accomodation: where C4d staining is positive without evidence of rejection.
Diagnostic criteria for active AMR is consistant of 3 features:
a) Histologic evidence of acute tissue injury including :Capillaritis in the form of glomerulitis (g )and peritubular capillaritis( ptc) with g+ptc>2 score is qualifying for this , other acute tissue injury pattern are,acute tubular injury ,thrombotic microangiopathy,and less commonly, endothelitis ,fibrinoid necrosis or transmural inflammation.
b) evidence of recent or current antibody-endothelial interaction in the form of C4d staining or validated transcript .Microvascular inflammation MVI ,g +ptc score of >2 may substitute for C4d staining. C4d detected by IF or IHC.
C) Circulating Donor Specific Antibodies DSAs, however C4d staining or validated transcrip may substitute for it.
Diagnostic criteria of chronic AMR:
a)Transplant Glomerulopathy TG. (g>0).in the absence of thrombotic microangiopathy and recurrent /de novo Gn.
b) Peritubular Capillary basement membrane Multilayring PTCML(detected by EM).
c) Arterial intimal fibrosis of new onset. (Lukocytes within the sclerosis intima favor chronic AMR,if there is no prior history of CMR.
Chronic Active AMR:
Combined features of chronic features and active features.
Smoldering ,Accomodation : C4d deposition in ptc without features of chronic or active AMR. (no MVI)..
Reference:
Lynn D.Cornell.Histologic features of antibody mediated rejection:the Banff classification and beyond.fronties in immunology.2021
Thank You
Updates on Banff criteria 2019
Chronic active ABMR
All 3 criteria must be satisfied for making diagnosis:
1. Evidence of chronic tissue injury including 1 or more of the following –
2. Evidence antibody interaction with vascular endothelium, including 1 or more of the following
3. Serological evidence of circulating DSA to HLA or non HLA antigens.
· testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised when criteria 1 and 2 are met.
· C4d staining or expression of validated transcripts/classifiers substitute for DSA testing,
· Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA post-transplant considered as chronic inactive ABMR and remote DSA not considered for diagnosis of chronic active or active ABMR.
Chronic inactive ABMR
· criterion 1: include cg>0 and/or severe ptcml (ptcml1)
· Absence of criterion 2: current or recent antibody interaction with the endothelium
· Criterion 3: Prior diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA.Updates on Banff criteria 2019
Chronic active ABMR
All 3 criteria must be satisfied for making diagnosis:
1. Evidence of chronic tissue injury including 1 or more of the following –
2. Evidence antibody interaction with vascular endothelium, including 1 or more of the following
3. Serological evidence of circulating DSA to HLA or non HLA antigens.
· testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised when criteria 1 and 2 are met.
· C4d staining or expression of validated transcripts/classifiers substitute for DSA testing,
· Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA post-transplant considered as chronic inactive ABMR and remote DSA not considered for diagnosis of chronic active or active ABMR.
Chronic inactive ABMR
· criterion 1: include cg>0 and/or severe ptcml (ptcml1)
· Absence of criterion 2: current or recent antibody interaction with the endothelium
· Criterion 3: Prior diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA.
· Chronic active AMR diagnosis according to Banff 2017/19 depends on presence of :
o Histologic evidence of chronic tissue injury as transplant glomerulopathy (cg> 0)., peritubular capillary BM multilayering and arterial intimal fibrosis.,
o Evidence of antibody interaction with vascular endothelium (c4d) +ve staining by IHC or IF..
o Circulating DSA.
the 1st criterion plus either DSA or c4d is diagnostic for chronic active AMR.
Chronic active ABMR
3 criteria are required for diagnosis :
A.Morphological evidence of chronic tissue injury including 1 or more of the following –
· transplant glomerulopathy (cg>0) absence of TMA
· Severe peritubular capillary basement membrane multi layering
· Anew onset arterial intimal fibrosis
B. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following
· Linear C4d staining in peritubular capillaries deposition
· moderate microvascular inflammation
· Increased expression of gene transcripts.
C. Serological evidence of circulating DSA to HLA or other antigens. C4d staining or expression of validated transcripts/classifiers as noted in criterion 2 may substitute for DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised when criteria 1 and 2 are met.
Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA post transplant may be stated as showing chronic ABMR, but remote DSA should not be considered for diagnosis of chronic active or active ABMR.
Chronic inactive ABMR
A.cg>0 and/or severe ptcml (ptcml1)
B.Absence of current or recent antibody interaction with the endothelium
C.Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA.
Please summarise this article
Chronic antibody mediated rejection characterized by progressive renal graft dysfunction with worsening proteinuria.
Banff 2013 diagnostic criteria has three elements:
1-Histologically characterized by presence at least one of the following:
*Transplant glomerulopathy (cg . 0) in the absence of chronic thrombotic microangiopathy.
*Severe peritubular capillary basement membrane multilayering by electron microscopy.
2- Current/recent histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
*Linear C4d staining in peritubular capillaries (at least 10% by immunofluorescence [IF] on frozen sections or any positivity by immunohistochemistry on paraffin sections).
*At least moderate microvascular inflammation (g 1 ptc . 2)
*Increased expression of tissue gene transcripts indicative of endothelial injury.
3-Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
Differential Diagnosis:
Chronic ABMR is divided into 2 forms: chronic active ABMR and chronic inactive ABMR
Chronic active ABMR; all 3 criteria must be met for diagnosis (1)
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
a) Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
b) Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
c) Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:
a) Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
b) At least moderate MVI, microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
c) Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated
3. Serologic evidence of circulating donor-specific antibodies (DSA to HLA or other antigens). C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA; however thorough DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised whenever criteria 1 and 2 are met. Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA (posttransplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis of chronic active or active ABMR
Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
The differences between 2013 and 2019 classification:
1) Classifiying chronic (inactive) ABMR
2) TG in absence of chronic/recurrent de novo GN
3) leukocytes within intima not required
4) Linear C4d staining of medullary vasa recta
5) For MVI, in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
6) C4d staining or expression of validated transcripts/classifiers may substitute for DSA (criteria 3)
7) Biopsies meeting criterion 1 and 3 ( with current or prior evidence of DSA – posttransplant) without criterion 2 may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis.
Reference:
Loupy A, Haas M, Roufosse C, Naesens M, Adam B, Afrouzian M, Akalin E, Alachkar N, Bagnasco S, Becker JU, Cornell LD, Clahsen-van Groningen MC, Demetris AJ, Dragun D, Duong van Huyen JP, Farris AB, Fogo AB, Gibson IW, Glotz D, Gueguen J, Kikic Z, Kozakowski N, Kraus E, Lefaucheur C, Liapis H, Mannon RB, Montgomery RA, Nankivell BJ, Nickeleit V, Nickerson P, Rabant M, Racusen L, Randhawa P, Robin B, Rosales IA, Sapir-Pichhadze R, Schinstock CA, Seron D, Singh HK, Smith RN, Stegall MD, Zeevi A, Solez K, Colvin RB, Mengel M. The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am J Transplant. 2020 Sep;20(9):2318-2331. doi: 10.1111/ajt.15898. Epub 2020 May 28. PMID: 32463180; PMCID: PMC7496245.
update of 2019 Banff classification for chronic active ABMR :
All 3 criteria must be met for diagnosis.
Chronic inactive ABMR
Diagnostic criteria of Chronic antibody-mediated rejection according to the Banff 2013 classification.
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy.
b. Severe peritubular capillary basement membrane.
c. New-onset arterial intimal fibrosis without other etiology
2. Current/recent histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in peritubular capillaries
b. At least moderate microvascular inflammation
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Presence of donor-specific antibodies DSA.
Key Diagnostic Features
1. Transplant glomerulopathy.
2. Peritubular capillary basement membrane multilayering.
3. Peritubular capillary C4d staining.
Summary
Diagnostic criteria according to the Banff 2013 classification
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following: a. Transplant glomerulopathy (cg . 0) in the absence of chronic thrombotic microangiopathy b. Severe peritubular capillary basement membrane multilayering by electron microscopy c. New-onset arterial intimal fibrosis with no other known etiology 2. Current/recent histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following: a. Linear C4d staining in peritubular capillaries (at least 10% by immunofluorescence [IF] on frozen sections or any positivity by immunohistochemistry on paraffin sections) b. At least moderate microvascular inflammation (g 1 ptc .2) c. Increased expression of tissue gene transcripts indicative of endothelial injury 3. Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
Glomerular basement membrane duplication is also found in other conditions associated with chronic endothelial damage, causing a membranoproliferative pattern of injury
Peritubular capillary basement membrane multilayering, especially if not severe (,7 layers), is not specific to chronic antibody-mediated rejection.
Arterial intimal fibrosis is a common finding, often associated with chronic hypertension and aging. Scattered T cells and foam cells may be present in the expanded intima, but are not specific for chronic antibody-mediated rejection and may also be seen in chronic T-cell–mediated rejection.
Please summerize this article:
Chronic antibody mediated rejection (cAMR) is a condition characterized by graft dysfunction and proteinuria. It involves interaction of donor specific antibodies (DSA) with mismatched HLA or non-HLA molecules leading to repetitive endothelial injury causing GBM (glomerular basement membrane) duplication (transplant glomerulopathy, TG) with segmental sclerosis and peritubular capillary basement membrane multilayering (ptcml).
Diagnostic criteria for c-AMR according to Banff 2013 include presence of DSA with histological evidence of chronic tissue injury (either TG or ptcml or new onset arterial intimal fibrosis) and histological evidence of antibody interaction with vascular endothelium (either linear C4d staining or at least moderate microvascular inflammation or increased tissue gene transcript expression).
Differential diagnosis of cAMR include:
A) GBM duplication can be seen with:
1) Chronic endothelial damage (membranoproliferative type injury)
2) Chronic TMA (associated with acute TMA or vascular changes)
3) MPGN due to lupus nephritis, IgA nephropathy, cryoglobulinemic GN
B) Arterial intimal fibrosis seen with:
1) Chronic hypertension
2) Ageing
Chronic ABMR is divided into 2 forms: chronic active ABMR and chronic inactive ABMR
Chronic active ABMR; all 3 criteria must be met for diagnosis (1)
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
a) Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
b) Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
c) Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:
a) Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
b) At least moderate MVI, microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
c) Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated
3. Serologic evidence of circulating donor-specific antibodies (DSA to HLA or other antigens). C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA; however thorough DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised whenever criteria 1 and 2 are met. Biopsies meeting criterion 1 but not criterion 2 withcurrent or prior evidence of DSA (posttransplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis of chronic active or active ABMR
Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
The differences between 2013 and 2019 classification:
1) Classifiying chronic (inactive) ABMR
2) TG in absence of chronic/recurrent de novo GN
3) leukocytes within intima not required
4) Linear C4d staining of medullary vasa recta
5) For MVI, in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
6) C4d staining or expression of validated transcripts/classifiers may substitute for DSA (criteria 3)
7) Biopsies meeting criterion 1 and 3 ( with current or prior evidence of DSA – posttransplant) without criterion 2 may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis.
Reference:
Loupy A, Haas M, Roufosse C, Naesens M, Adam B, Afrouzian M, Akalin E, Alachkar N, Bagnasco S, Becker JU, Cornell LD, Clahsen-van Groningen MC, Demetris AJ, Dragun D, Duong van Huyen JP, Farris AB, Fogo AB, Gibson IW, Glotz D, Gueguen J, Kikic Z, Kozakowski N, Kraus E, Lefaucheur C, Liapis H, Mannon RB, Montgomery RA, Nankivell BJ, Nickeleit V, Nickerson P, Rabant M, Racusen L, Randhawa P, Robin B, Rosales IA, Sapir-Pichhadze R, Schinstock CA, Seron D, Singh HK, Smith RN, Stegall MD, Zeevi A, Solez K, Colvin RB, Mengel M. The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am J Transplant. 2020 Sep;20(9):2318-2331. doi: 10.1111/ajt.15898. Epub 2020 May 28. PMID: 32463180; PMCID: PMC7496245.
The above describe chronic active ABMR in the Banff 2019 criteria….Chronic ABMR is an ongoing process which is associated with graft injury and leads to irreversible graft injury…In chronic ABMR there is continuous activation of the endothelium by the antibody which leads to multi layering of the peritubular capillary wall… >7 layers are considered significant. The repetitive endothelial damage inside the glomerulus is seen as glomerular basement membrane duplication which later leads to podocyte injury….Differential diagnosis of chronic ABMR includes Chronic TMA, MPGN, Cryoglobulinemia…
The updated diagnostic criteria of chronic ABMR which was revised in the Banff 2019 meeting are
All the 3 criteria have to be present for chronic ABMR
1+3 – possible chronic ABMR
Reference:
Loupy A et al.The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection. Am J Transplant. 2020;20:2318–2331
Q1:
Diagnosis of chronic ABMR is important because it may lead to proteinuria and graft loss. Banff criteria (2013) for cABMR includes presence of all of three criteria.
1) Chronic injury defined by:
a. TG (cg > 0)
b. In EM: Sever multilayering of capillary BM.
c. Arterial intimal fibrosis without other etiology.
2) Evidence of Ab reaction in endothelium by:
a. C4d positive by IF or IHC
b. Moderate MVI (g + ptc > 2)
c. expression of gone transcripts of endothelial injury.
Chronic and repetitive endothelial injury leads to new GBM formation and TG with segmental Sclerosis and food process effacement.
Differential diagnosis for TG includes MPGN and chronic TMA. For example, if multilayering of peritubular capillary BM is not sever it is not specific for cABMR.
Q2:
Banff 2017: TG and / or PTCCBM multilayering in the absence of criteria for group 2 but with a prior diagnosis of active or c-aABMR or prior evidence of DSA.
histologic features of AMR chronicity:
– Banff lesion scone cg > 0 excluding cTMA
– 7 or more layers in cortical PTC and 5 or more in 2 additional capillaries
– GBM multilayering
– Arterial intimal fibrosis of new onset to rule out other causes. Absence of criteria for group 2 Ab interaction with tissue:
1- C4d positive
2- moderate MVI in the absence of GN
3- Expression of gene transcripts in the biopsy tissue
Roufosse, Candice MD, PhD1,2; Simmonds, Naomi MD3; Clahsen-van Groningen, Marian MD, PhD4; Haas, Mark MD, PhD5; Henriksen, Kammi J. MD6; Horsfield, Catherine MD3; Loupy, Alexandre MD7; Mengel, Michael MD8; Perkowska-Ptasińska, Agnieszka MD9; Rabant, Marion MD, PhD10; Racusen, Lorraine C. MD11; Solez, Kim MD8; Becker, Jan U. MD12 A 2018 Reference Guide to the Banff Classification of Renal Allograft Pathology, Transplantation: November 2018 – Volume 102 – Issue 11 – p 1795-1814
CHRONIC ANTIBODY MEDIATED REJECTION
It is one of the common cause of graft dysfunction.
It is diagnosed by presence of all of the following-
1.histologic evidence of chronic tissue injury (atleast one)
A.transplant glomerulopathy in absence of tma (d/d-chronic tma,ig mpgn)
B.severe peritubular capillary basement membrane multilayering in em.(If not severe that is 7 layered than not specific of abmr)
C.new-onset arterial intimal fibrosis (d/d-hypertension,aging)
2.current/recent histologic evidence of ab interaction with endothelium(atleast one)-
A.c4d staining c4d2,c4d3 in IF or any intensity in IHC .
B.at least moderate microvascular inflammation.(g+ptc>2)
C.increased expression of gene transcript of endothelial injury.
3.presence of DSA(HLA,nonHLA)
Chronic active ABMR from Banff 2019
All 3 criteria must be satisfied for making diagnosis :
Morphological evidence of chronic tissue injury including 1 or more of the following –
B. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following
C. Serological evidence of circulating DSA to HLA or other antigens. C4d staining or expression of validated transcripts/classifiers as noted in criterion 2 may substitute for DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised when criteria 1 and 2 are met.
Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA post transplant may be stated as showing chronic ABMR, but remote DSA should not be considered for diagnosis of chronic active or active ABMR.
Chronic inactive ABMR
A.cg>0 and/or severe ptcml (ptcml1)
B.Absence of current or recent antibody interaction with the endothelium
C.Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA.
how it differs from 2013
1) Classifiying chronic (inactive) ABMR
2) TG in absence of chronic/recurrent de novo GN
3) leukocytes within intima not required
4) Linear C4d staining of medullary vasa recta
5) For MVI, in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
6) C4d staining or expression of validated transcripts/classifiers may substitute for DSA (criteria 3)
7) Biopsies meeting criterion 1 and 3 ( with current or prior evidence of DSA – posttransplant) without criterion 2 may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis.
Reference
Loupy A et al.The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection. Am J Transplant. 2020;20:2318–2331.
Diagnostic criteria according to the Banff classification 2013 include the presence of all of the
following that must meet:
1- Histological evidence of chronic tissue injury, includes at least one of the following:
a- Transplant glomerulopathy (cg>0) in absence of chronic thrombotic microangiopathy, (or chronic recurrent/ de novo GN; including changes evident by electron microscopy (EM) alone {cg1a} 2019)
b- Severe peritubular capillary basement membrane multilayering by electron microscopy (ptcml1; require EM)
c- New-onset arterial intimal fibrosis with no other known cause.
2- Current/recent histologic evidence of antibody interaction with vascular endothelium, includes one or more of the following:
a- Linear C4d staining in peritubular capillaries (10% or more by IF or any positivity by IHC
2019; ptc or medullary vasa recta (C4d2 or C4d3 by IF or C4d > 0 by IHC)
b- At least moderate microvascular inflammation (g + ptc > 2)
(2019; {g+ ptc} ≥ 2)
c- An increased expression of tissue gene transcripts indicative of endothelial injury.
3- Presence of DSA in the serum (HLA or non-HLA DSA)
2019 Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA (posttransplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for the diagnosis of chronic active or active ABMR
Key features are:
· Transplant glomerulopathy (GBM duplication that can be present in membranoproliferative conditions like lupus nephritis)
· Peritubular capillary basement membrane multilayering which if not severe > 7 is not specific of c ABMR.
· Peritubular capillary C4d staining
Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
C4d staining without evidence of rejection; all 4 features must be present for diagnosis:
1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
2. Criterion 1 for active or chronic active ABMR not met
3. No molecular evidence for ABMR as in criterion 2 for active and chronic active ABMR
4. No acute or chronic active TCMR, or borderline changes
(1)
1. Loupy A, Haas M, Roufosse C, Naesens M, Adam B, Afrouzian M, et al. The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am J Transplant [Internet]. 2020/05/28. 2020 Sep;20(9):2318–31. Available from: https://pubmed.ncbi.nlm.nih.gov/32463180
The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection
How can we differentiated between thrombotic microangiopathy and Antibody mediated rejection ?
although it is histologically similar finding and difficult to differentiate so we should depend on clinical finding Ex thrombotic microangiopathy look for blood film shistocyte or fragmented RBC ,increase in LDH ,family HX ,primary disease ,CNS manifestation ,anaemia ,thrombocytopenia .
in antibody mediated rejection hx of previos sensitzation ,oligouria or inrease in DSA and decrease in GFR
Chronic Antibody-Mediated Rejection:
Diagnostic criteria according to the Banff 2013 classification include
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy (cg . 0) in the absence of chronic thrombotic microangiopathy
b. Severe peritubular capillary basement membrane multilayering by electron microscopy c. New-onset arterial intimal fibrosis with no other known etiology
2. Current/recent histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in peritubular capillaries (at least 10% by immunofluorescence [IF] on frozen sections or any positivity by immunohistochemistry on paraffin sections)
b. At least moderate microvascular inflammation (g 1 ptc . 2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
Glomerular basement membrane duplication is also found in a membranoproliferative pattern of injury.
Chronic thrombotic microangiopathy may be indistinguishable from transplant glomerulopathy on a morphologic basis unless features of concomitant acute thrombotic microangiopathy or vascular changes are present.
Peritubular capillary basement membrane multilayering, especially if not severe (less than 7 layers), is not specific to chronic antibody-mediated rejection.
Arterial intimal fibrosis is a common finding, often associated with chronic hypertension and aging.
Please update the diagnostic criteria mentioned in this article based on the recent Banff classification?
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Banff 2017 permits the use of this term for biopsy specimens showing TG and/or peritubular
capillary basement membrane multilayering in the absence of criterion of current/recent antibody
interaction with the endothelium (Criteria Group 2) but with a prior documented diagnosis of Active or
Chronic Active AMR or documented prior evidence of DSA
Criteria Group 4 Histologic features of AMR chronicity
Clinical and Pathologic Features
Chronic antibody-mediated rejection is commonly associated with progressive loss of kidney function and proteinuria, although early stages may be subclinical and recognizable only through protocol biopsies.
Diagnostic criteria according to the Banff 2013 classification include the presence of all of the following:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy (cg . 0) in the absence of chronic thrombotic microangiopathy
b. Severe peritubular capillary basement membrane multilayering by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
2. Current/recent histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in peritubular capillaries (at least 10% by immunofluorescence [IF] on frozen sections or any positivity by Immuno histochemistry on paraffin sections)
b. At least moderate microvascular inflammation (g 1 ptc . 2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
Etiology/Pathogenesis
Similar to acute antibody-mediated rejection, endothelial injury results from interaction between DSA with primarily mismatched HLA or non-HLA molecules. Repetitive and chronic endothelial damage is associated with new basement membrane formation, which in glomeruli manifests as glomerular basement membrane duplication (transplant glomerulopathy), often with resulting segmental sclerosis, and multilayering of the peritubular capillary basement membrane. Podocyte injury and foot process effacement are common findings.
Differential Diagnosis
Glomerular basement membrane duplication is also found in other conditions associated with chronic endothelial damage, causing a membranoproliferative pattern of injury. Chronic thrombotic microangiopathy may be indistinguishable from transplant glomerulopathy on a morphologic basis unless features of concomitant acute thrombotic microangiopathy or vascular changes are present. In such cases, correlation with clinical history will be important. Membranoproliferative glomerulonephritis due to immune complex processes (lupus nephritis, immunoglobulin A nephropathy, cryoglobulinemic glomerulonephritis, etc) must be ruled out by IF and electron microscopy. Peritubular capillary basement membrane multilayering, especially if not severe (,7 layers), is not specific to chronic antibody-mediated rejection. Arterial intimal fibrosis is a common finding, often associated with chronic hypertension and aging. Scattered T cells and foam cells may be present in the expanded intima, but are not specific for chronic antibody-mediated rejection and may also be seen in chronic T-cell–mediated rejection.
Revised Banff 2017 classification of antibody-mediated rejection (ABMR)
Chronic active ABMR:
All 3 criteria must be met for diagnosis:
1.Morphologic evidence of chronic tissue injury, including 1 or more of the following
– Transplant glomerulopathy (cg >0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
– Severe peritubular capillary basement membrane multilayering (requires EM)
– Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2.Identical to criterion 2 for active ABMR, above
3.Identical to criterion 3 for active ABMR, above, including strong recommendation for DSA testing whenever criteria 1 and 2 are met C4d Staining without Evidence of Rejection; all 4 features must be present for diagnosis:
– Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d>0 by IHC on paraffin sections)
– Criterion 1 for active or chronic, active ABMR not met
– No molecular evidence for ABMR as in criterion 2 for active and chronic, active ABMR
Diagnostic criteria for chronic antibody-mediated rejection according to the Banff 2013 classification include the presence of all of the
following:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy (cg . 0) in the absence of chronic thrombotic microangiopathy
b. Severe peritubular capillary basement membrane multilayering by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
2. Current/recent histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in peritubular capillaries .
b. At least moderate microvascular inflammation
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
– Repetitive and chronic endothelial damage is associated with new basement membrane formation, which in glomeruli manifests as glomerular
basement membrane duplication (transplant glomerulopathy),
often with resulting segmental sclerosis, and multilayering of the peritubular capillary basement membrane.
Differential Diagnosis
Glomerular basement membrane duplication is also found in:
1.Chronic thrombotic microangiopathy.
2. Membranoproliferative glomerulonephritis due to immune
complex processes (lupus nephritis, immunoglobulin A nephropathy, cryoglobulinemic glomerulonephritis, etc).
3. chronic hypertension and aging.
-Chronic active ABMR; all 3 criteria must be met for diagnosis:.Bannff 2017
1.Morphologic evidence of chronic tissue injury, including 1 or more of the following:
Transplant glomerulopathy (cg >0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
Severe peritubular capillary basement membranemultilayering (requires EM)
Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2.Strong recommendation for DSA testing .
3.C4d Staining .
This article explains the Banff 2013 diagnostic criteria for chronic antibody mediated rejection which is as follows
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy (cg . 0) in the ab-
sence of chronic thrombotic microangiopathy
b. Severe peritubular capillary basement mem- brane multilayering by electron microscopy
c. New-onset arterial intimal fibrosis with no other
known etiology
2. Current/recent histologic evidence of antibody
interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in peritubular capillaries (at
least 10% by immunofluorescence [IF] on frozen sections or any positivity by immuno- histochemistry on paraffin sections)
b. At least moderate microvascular inflammation (g 1 ptc.2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
According to Banff 2017
Patients with the first two criteria but no evidence of DSAs can be diagnosed with chronic active ABMR if there is C4d-positive staining of PTCs or expression of validated gene panels associated with ABMR . If neither is present, such patients are considered to be “suspicious” for chronic active ABMR.
Chronic AMR is associated with decline in kidney function and proteinuria. It may be subclinical and only be detected in protocol biopsy.
Based on Banff 2013 classification, it is defined by the presence of all three features consisting of histologic evidence of chronic tissue injury (presence of at least one of transplant glomerulopathy, severe peritubular BM multilayering, and new onset arterial intimal necrosis), histologic evidence of antibody interaction with endothelium (at least one of linear C4d staining in peritubular capillaries, moderate MVI, and increased tissue gene transcripts), and presence of DSA.
Chronic endothelial damage due to repetitive interaction between DSA with alloantigens leads to transplant glomerulopathy with duplication of GBM, IFTA, PTC basement membrane multilayering, and podocyte injury.
MPGN and chronic TMA are differential diagnosis of TG. MPGN due to immune complex processes such as SLE, IgA nephropathy, and cryoglobulinemic GN can be distinguished by IF. The PTC multilayering less than 7 layers is not specific for chronic AMR. Intimal fibrosis can be seen in chronic hypertension and aging. Scattered T cells and foamy cells in intima can be seen in chronic AMR and chronic TCMR.
Key diagnostic features are TG, PTC basement membrane multilayering, and PTC C4d staining.
Based on the Banff 2019 classification, chronic ABMR is categorized into two groups: chronic active ABMR and chronic inactive ABMR.
Chronic active ABMR; all 3 criteria must be met for diagnosis
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:
• Linear C4d staining in peritubular capillaries or medullary vasarecta (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
• At least moderate microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
• Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated
3. Identical to criterion 3 for active ABMR, above, including strong recommendation for DSA testing whenever criteria 1 and 2
are met. Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA (posttransplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis of chronic active or active ABMR
Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA C4d staining without evidence of rejection; all 4 features must be present for diagnosis
1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
2. Criterion 1 for active or chronic active ABMR not met
3. No molecular evidence for ABMR as in criterion 2 for active and chronic active ABMR
4. No acute or chronic active TCMR, or borderline changes
Chronic Antibody-Mediated Rejection
Chronic antibody-mediated rejection lead to progressive allograft loss and proteinuria.It can be subclinical and can be detected only by protocol biopsies in early stage.
Diagnostic criteria (Banff 2013) included the presence of all of the following:
1. Histologic evidence of chronic tissue injury (at least one of: Transplant glomerulopathy (no TMA), Severe PTC basement membrane multilayering by EM or New-onset arterial intimal fibrosis).
2. Current/recent histologic evidence of endothelial injury (at least one of: linear PTC C4d staining, moderate microvascular inflammation or increased expression of tissue gene transcripts.
3. Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the circulation .
Due to the chronicity of antibodies interaction with the endothelium, new glomeruli basement membrane formation occur (transplant glomerulopathy), resulting in segmental sclerosis, and multilayering of the PTC basement membrane with podocyte injury.
Glomerular basement membrane duplication can be found in cases with membranoproliferative histpathology (lupus nephritis, Ig A nephropathy, cryoglobulinemic glomerulonephritis)
Chronic TMA have similar morphology and can be distinguished by clinical history, concomitant acute thrombotic microangiopathy or vascular changes
Not severe PTC basement membrane multilayering (less than 7 layers), is not specific to chronic antibody-mediated rejection.
Arterial intimal fibrosis can occur in chronic hypertension and aging.
Scattered T cells and foam cells in expanded intima can occur in chronic T-cell–mediated rejection.
Chronic active AMR presents by slow decline of renal functions associated with proteinuria,
In order to diagnose chronic active ABMR : evidence of chronic tissue injury as Tx glomerulopathy or chronic arteriopathy with no evidence of acute injury.C4d +ve staining or capilliritis and Serologic evidence of circulating DSAs
All the above corners were needed for the diagnosis of chronic active AMR but in recent Banff classification diagnosis of chronic ABMR requires the presence of the chronic tissue injury and only one of the other 2 criteria.
Please summarise this article
Differential Diagnosis:
Chronic antibody-mediated rejection is commonly associated with progressive loss of kidney function and proteinuria, although early stages may be subclinical and recognizable only through protocol biopsies.
Diagnostic criteria according to the Banff 2013 classification (Haas et al, Am J Transplant 2014: 14(2):272-283) include the presence of all of the following:
1. Transplant glomerulopathy
2. Peritubular capillary basement membrane multilayering ,especially if not severe (7 layers), is not specific to chronic antibody-mediated rejection.
3.Peritubular capillary C4d staining
Etiology/Pathogenesis
DSA with primarily mismatched HLA or non-HLA molecules. Repetitive and chronic endothelial damage is associated with glomerular basement membrane duplication (TG), often with segmental sclerosis, and multilayering of the peritubular capillary basement membrane. Podocyte injury and foot process effacement are common findings.
Differential Diagnosis:
1. membranoproliferative pattern of injury.
2. Chronic thrombotic microangiopathy
Better to correlate with clinical history
. Arterial intimal fibrosis is a common finding, often associated with chronic hypertension and aging.
As of 2019, the Banff schema recognizes four diagnostic categories:
1. Active ABMR, requires 3 diagnostic criteria:1. histologic evidence of acute tissue injury (glomerulitis (g) score + peritubular capillaritis (ptc) score of 2 or greater), 2. evidence of current or recent antibody interaction with the endothelium (usually C4d),3. and serologic evidence of DSA (although C4d staining or validated transcripts may substitute for DSA).
2. Chronic active ABMR, has a similar three criteria, but with histologic evidence of chronic tissue injury, (TG) attributable to ABMR.
3. Chronic (inactive) ABMR, shows histologic evidence of chronic tissue injury, but without capillaritis and without C4d deposition in peritubular capillaries.
4. final category is peritubular capillary C4d staining without evidence of rejection, previously referred to as “accommodation”. This category primarily applies to ABO blood group incompatible transplants, which show positive C4d staining in even 80% of protocol biopsies and the staining does not correlate with peritubular capillaritis
the state of accommodation in patients with anti-HLA DSA is likely temporary and unstable
Ref: HYPOTHESIS AND THEORY articleFront. Immunol., 27 September 2021 | https://doi.org/10.3389/fimmu.2021.718122
Histopathologic Features of Antibody Mediated Rejection: The Banff Classification and Beyond
Chronic active ABMR; we need ALL 3 criteria
In the case of biopsies that fit criterion 1 but not criterion 2 and that have current or past evidence of DSA (posttransplant), the diagnosis of chronic ABMR may be made; however, distant DSA should not be considered for the diagnosis of chronic active or active ABMR, respectively.
But if the patient is lacking for both criteria and only have morphological criteria, the diagnosis will be suspicious for chronic ABMR
Chronic antibody-mediated rejection Banff 2013
Clinical and Pathologic Features is commonly associated with
1. progressive loss of kidney function
2. proteinuria,
3. subclinical and recognizable only by protocol biopsies.
Diagnostic criteria according to the Banff 2013 classification
the presence of all of the following:
1. Histologic evidence of chronic tissue injury, at least one of the following:
a. in the glomerulus: Transplant glomerulopathy (cg . 0) in the absence of chronic thrombotic microangiopathy
b. in the PTC: Severe peritubular capillary basement membrane multilayering by electron microscopy
c. in the blood vessels: New-onset arterial intimal fibrosis with no other etiology
2. histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. in the PTC: Linear C4d staining in peritubular capillaries (at least 10% by immunofluorescence [IF] on frozen sections or any positivity by immunohistochemistry on paraffin sections)
b. in the MV: At least moderate microvascular inflammation (g 1 ptc . 2)
c. gene transcripts: Increased expression of tissue gene transcripts indicative of endothelial injury
3. Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
Etiology/Pathogenesis
endothelial injury results from interaction between DSA with primarily mismatched HLA or non-HLA molecules. >>>> Repetitive and chronic endothelial damage is associated with new basement membrane formation, which
· in glomeruli manifests as glomerular basement membrane duplication (transplant glomerulopathy), often with resulting segmental sclerosis
· in PTC: multilayering of the peritubular capillary basement membrane. Podocyte injury and foot process effacement are common findings.
Differential Diagnosis (a membranoproliferative pattern of injury.)
· Chronic thrombotic microangiopathy may be indistinguishable from transplant glomerulopathy on a morphologic basis unless features of concomitant acute thrombotic microangiopathy or vascular changes are present. In such cases, correlation with clinical history will be important.
· Membranoproliferative glomerulonephritis due to immune complex processes (lupus nephritis, immunoglobulin A nephropathy, cryoglobulinemic glomerulonephritis, etc) must be ruled out by IF and electron microscopy.
Peritubular capillary basement membrane multilayering, especially if not severe (,7 layers), is not specific to chronic antibody-mediated rejection.
Arterial intimal fibrosis is a common finding, often associated with chronic hypertension and aging. Scattered T cells and foam cells may be present in the expanded intima, but are not specific for chronic antibody-mediated rejection and may also be seen in chronic T-cell–mediated rejection.
Key Diagnostic Features Transplant glomerulopathy +Peritubular capillary basement membrane multilayering + Peritubular capillary C4d staining
Updates on Banff criteria 2019
Chronic active ABMR
All 3 criteria must be satisfied for making diagnosis:
1. Evidence of chronic tissue injury including 1 or more of the following –
2. Evidence antibody interaction with vascular endothelium, including 1 or more of the following
3. Serological evidence of circulating DSA to HLA or non HLA antigens.
· testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised when criteria 1 and 2 are met.
· C4d staining or expression of validated transcripts/classifiers substitute for DSA testing,
· Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA post-transplant considered as chronic inactive ABMR and remote DSA not considered for diagnosis of chronic active or active ABMR.
Chronic inactive ABMR
· criterion 1: include cg>0 and/or severe ptcml (ptcml1)
· Absence of criterion 2: current or recent antibody interaction with the endothelium
· Criterion 3: Prior diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA.
References
Chronic active AMR is difficult to diagnose as it has several entities :
A: histological evidence of AMR:
1-TG>0 in absence of TMA
2-sever PTC multiplayering
3-new onset arterial intemal fibrosis
B:recent evidence of antibodies interaction with vascular endotheliam
1-positive C4d
2-moderate microvasular inflammation
3-increase expression of tissue gene transcripts
C:presence of DSA(HLA or non HLA)
Pathogenesis :the recurrent attack of antibodies to the vascular endotheliam lead to multilayered PTC basement membrane ,podocytes injury and effacement
New dignostic criteria due to banff 2019:
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2. Identical to criterion 2 for active ABMR, above
3. Identical to criterion 3 for active ABMR, above, including strong recommendation for DSA testing whenever criteria 1 and 2
are met.
Thank You
Despite the fact that early phases of chronic antibody-mediated rejection may be asymptomatic and only detectable by routine biopsies, chronic antibody-mediated rejection is frequently accompanied by increasing loss of kidney function and proteinuria.
According to the Banff 2013 categorization, diagnostic criteria include the presence of all of the following signs and symptoms:
a-Chronic tissue damage as evidenced by histologic examination.
b-Present histologic evidence of antibody interaction with the endothelium of the vascular system.
c-Presence of donor-specific antibodies (DSA) in the blood, whether they are HLA or non-HLA.
Indications of chronic tissue damage on histology are indicated by the presence of at least one of the following characteristics:
a. Chronic thrombotic microangiopathy in the absence of transplant glomerulopathy (cg. 0).
By electron microscopy, severe peritubular capillary basement membrane multilayering was seen in the capillary basement membrane.
c. New-onset arterial intimal fibrosis with no known etiological factor
Histologic evidence of antibody interaction with vascular endothelium that is current or recent in nature, as defined by the presence of at least one of the following:
a. C4d staining in peritubular capillaries with a linear pattern (at least 10 per cent by immunofluorescence [IF] on frozen sections or any positivity by immunohistochemistry on paraffin sections)
b. Microvascular inflammation that is at least mild (g 1 ptc . 2)
Inflammatory gene transcripts in the tissues are suggestive of endothelial damage.
Endothelial damage that occurs repeatedly and chronically is associated with the formation of new basement membranes, which manifests itself in the glomeruli as glomerular basement membrane duplication, which frequently results in segmental sclerosis and the multilayering of the peritubular capillary basement membrane. Podocyte damage and foot process effacement are two of the most often seen results.
Differential Diagnosis is a medical term that refers to the process of determining whether or not anything is wrong.
Chronic thrombotic microangiopathy is a condition in which the blood vessels get clogged with clots.
If electron microscopy is performed, it must be determined that the patient does not have immunological complex processes (lupus nephritis, immunoglobulin A nephropathy, cryoglobulinemic glomerulonephritis, etc).
Chronic hypertension and ageing are two issues that need to be addressed.
Thank You
Chronic antibody mediated rejection (cAMR) is characterized by graft dysfunction and proteinuria as a result of interaction of donor specific antibodies (DSA) with mismatched HLA or non-HLA molecules leading to endothelial injury causing GBM transplant glomerulopathy, (TG) with segmental sclerosis and peritubular capillary basement membrane multilayering (ptcml).
Diagnostic criteria for c-AMR according to Banff 2013 include presence of DSA with histological evidence of chronic tissue injury (either TG or ptcml or new onset arterial intimal fibrosis) and histological evidence of antibody interaction with vascular endothelium (either linear C4d staining or at least moderate microvascular inflammation or increased tissue gene transcript expression).
Differential diagnosis of cAMR include:
A) GBM duplication can be seen with:
1) Chronic endothelial damage (membranoproliferative type injury)
2) Chronic TMA (associated with acute TMA or vascular changes)
3) MPGN due to lupus nephritis, IgA nephropathy, cryoglobulinemic GN
B) Arterial intimal fibrosis seen with:
1) Chronic hypertension
2) Aging
Updates of Banff classification of chronic ABMR 2019
Chronic Active ABMR
ALL 3 criteria to be met for the diagnosis
1) morphological evidence of chronic tissue injury include one or more of the following:
Transplant glomerulopathy(cg>0) include evidence by EM(cg1a)
Severe PTC base membrane layering (require EM)
Arterial intimal fibrosis of new onset after exclusion of other causes
2) Evidence of current antibody interaction with vascular endothelial include one or more of the following:
linear c4d staining in the PTC or medullary vasa recta(c4d2 or c4d3) by IF or c4d>0 by IHC
At least moderate microvascular inflammation (Ig+ptc) 2 or more
Increase expression of gene transcript in tissue biopsy strongly associated with ABMR
3) Serological evidence of circulating DSA(to HLA and non-HLA antigens)
In renal biopsy meeting criteria 1 but not 2 with current or prior evidence of DSA (post transplant) may be stated as chronic ABMR but DSA should not be considered for diagnosis of chronic active ABMR or chronic inactive ABMR
Chronic (inactive) ABMR:
1. Chronic glomerulitis > 0 and/or severe peritubular capillaries multilayering (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
Excellent
IV. AJKD Atlas of Renal Pathology:
Chronic Antibody-Mediated Rejection
Please summarise this article
*Chronic antibody mediated rejection is associated with progressive loss of kidney function, proteinuria, early stages may be subclinical and recognizable only through protocol biopsies.
*Diagnostic criteria according to the Banff 2013 classification
1) Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a.Transplant glomerulopathy (cg . 0) in the absence of CTMA
b. Severe peritubular capillary basement membrane multilayering by EM
c. New onset arterial intimal fibrosis with no other known etiology
2) Current/recent histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a* Linear C4d staining in peritubular capillaries at least 10% by IF or any positivity by IHC
b* At least moderate microvascular inflammation (g 1 ptc . 2)
c* Increased expression of tissue gene transcripts indicative of endothelial injury
3) Presence of DSA HLA or non HLA in the serum
# Etiology
* Endothelial injury results from interaction between
DSA with primarily mismatched HLA or non HLA molecules.
* Repetitive and chronic endothelial damage result in transplant glomerulopathy and multilayring of PTCBM
*Podocyte injury and foot process effacement are common finding
# Differential Diagnosis
*Glomerular basement membrane duplication:
Chronic thrombotic microangiopathy
Membranoproliferative glomerulonephritis due to immune complex processes like:
lupus nephritisImmunoglobulin
A nephropathy
Cryoglobulinemic glomerulonephritis,
( must be ruled out by IF and EM)
*Peritubular capillary basement membrane multilayering, especially if not severe is not specific to CAMR
*Arterial intimal fibrosis is a common finding:
Chronic hypertension
Aging.
*Chronic T cell mediated rejection.
# Please update the diagnostic criteria mentioned in this article based on the recent Banff classification
An update of the diagnostic criteria according banff 2019 to:
https://pubmed.ncbi.nlm.nih.gov/32463180/
Chronic active ABMR; all 3 criteria must be met for diagnosis
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
** Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
** Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
** Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2.Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:
– Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
– At least moderate microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
– Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated
* *( Identical to criterion 2 for active ABMR)
3. Serologic evidence of circulating donor-specific antibodies (DSA to HLA or other antigens). C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA; however thorough DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised whenever criteria 1 and 2 are met
* * (Identical to criterion 3 for active ABM including strong recommendation for DSA testing whenever criteria 1 and 2 are met.)
* * Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA (posttransplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis of chronic active or active ABMR
Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSAC4d staining without evidence of rejection; all 4 features must be present for diagnosisc
1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
2. Criterion 1 for active or chronic active ABMR not met
3. No molecular evidence for ABMR as in criterion 2 for active and chronic active ABMR
4. No acute or chronic active TCMR, or borderline changes
Ref:
Alexandre Loupy et al. Am J “The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection” Transplant. 2020
Thank You
SUMMARY
This article is concerned with Chronic antibody mediated rejection and the response of the body to it in terms of pathological features.
CAMR is typically seen with progressive loss of kidney function along with proteinuria.
Banff 2013 diagnostic criteria :
A.Histological evidence of chronic tissue injury
B.Histological evidence of antibody interaction with vascular endothelium
C.Presence of serum DSA, HLA or non-HLA.
Chronic endothelial damage leads to formation of new layers of the basement membrane, which is seen as glomerular basement membrane duplication and peritubular capillaries multi layering, with segmental sclerosis. Common findings are podocyte injuries and foot process effacement.
Chronic Antibody-Mediated Rejectionc ABMR associated with graft loss and proteinurea,and in the early stage may be sub-clinical and only diagnosis by protocol biopsy
Diagnostic criteria according to the Banff13 classification:
1) histological evidence of chronic tissue injury defined by present of one of the following:
2) current histological evidence of Ab interaction,defined by the present at least one of the following:
3) presence of donor specific antibody (DSA,HLA or non-HLA) in the serum
Etiology-Pathogensis:
Differential diagnosis:
All can be ruled out by IF and EM
Key diagnosis features:
Update the diagnostic criteria(Banff 2019 for chronic ABMR)
Chronic active ABMR:
ALL 3 criteria to be met for the diagnosis
1) morphological evidence of chronic tissue injury include one or more of the following:
2) Evidence of current antibody interaction with vascular endothelial include one or more of the following:
3) Serological evidence of circulating DSA(to HLA and non-HLA antigens)
In renal biopsy meeting criteria 1 but not 2 with current or prior evidence of DSA (post transplant) may be stated as chronic ABMR but DSA should not be considered for diagnosis of chronic active ABMR or chronic inactive ABMR
Reference:
Loupy A et al.The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection. Am J Transplant. 2020;20:2318–2331.
Thank You
Chronic Antibody mediated Rejection
Defined as gradual progressive loss of kidney functions associated with proteinuria due to presence of antibodies directed against allograft kidney
according to Banff 2017
Chronic active ABMR;
A-Histological evidence one or more
1-Transplant glomerulopathy (if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis,)
2- EM doubling and multilayring of Peritubular capillaries glomerular basement membrane
3- fibrosis of arterial intima
B- Tissue evidence of antibody affection
C4d Linear staining C4d 2 or 3 by IF C4d > 0 by IHC
glomerulitis + Peritubular capiliritis ≥2
increased expression of gene transcripts/classifiers in the biopsy tissue strongly
C- DSA in serum ( HLA or NonHLA )
1st criteria in addition ton 2nd or 3rd needed for diagnosis
Chronic (inactive) ABMR
1. Chronic glomerulitis > 0 and/or severe peritubular capillaries multilayering (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
Pathogenesis :
Antibody against mismatches HLA and non HLA >> inflammation >> multilayering of GBM
Glomerular sclerosis and intimal fibrosis of arteries
Differential diagnosis :
Membranoproliferative GN ( due to IgA , Lupus and Cryoglobulinemia ) >> GBM doubling
Chronic Thrombotic microangiopathy >> Vascular affection
Chronic fibrosis of arterial intima >> Aging and hypertension
Well done Mohamed
Chronic AMR based on Banff (2017/19)
The introduction of ABMR into the Banff classification was in 2003,since then the criteria for diagnosis of ABMR have become more complex, with major modifications in 2013 and 2017 which have improved diagnostic sensitivity and predictive value for graft outcomes.
A major residual issue within the classification is that it still subclassifies ABMR into active or chronic active and chronic inactive.
Active ABMR; all 3 criteria must be met for diagnosis
1. Histologic evidence of acute tissue injury, including 1 or more of the following:
•Microvascular inflammation in the absence of recurrent or de novo glomerulonephritis,
• Intimal or transmural arteritis
• Acute thrombotic microangiopathy, in the absence of any other cause or
• Acute tubular injury, in the absence of any other apparent cause
2. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:
• Diffuse Linear C4d staining in peritubular capillaries or medullary vasa recta by IF on frozen sections, or by IHC on paraffin sections
• At least moderate microvascular inflammation in the absence of recurrent or de novo glomerulonephritis
• Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR.
3. Serologic evidence of circulating donor-specific antibodies (DSA to HLA or non-HLA antibodies if HLA antibody testing is negative)
Chronic active ABMR; based on 3 criteria must be met for diagnosis
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
-Transplant glomerulopathy if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis, Severe peritubular capillary basement membrane multilayering (requires EM) Arterial intimal fibrosis of new onset, excluding other causes.
2 and 3 Criteria same as active ABMR
Chronic (inactive) ABMR:
1. Chronic glomerulitis > 0 and/or severe peritubular capillaries multilayering (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
Referrences
-De Serres SA, Noël R, Côté I, et al. 2013 Banff criteria for chronic active antibody-mediated rejection: assessment in a real-life set[1]ting. Am J Transplant. 2016;16(5):1516-1525
Excellent
Chronic AMR associated with graft loss and diagnostic by progressive loss of kidney function and proteinuria.
Diagnostic criteria according to banff classification 2013:
1. TG in absence of chronic TMA
2. severe PTC basement membrane multilayering by electron microscopy
3. new onset of arterial intimal fibrosis
4. current or recent histological evidence
– [ ] linear c4d staining
– [ ] micro vascular inflammation
– [ ] increase expression of gene transcription indicates endothelial injury
– [ ] presence of Circulating DSA (HLA or non HLA).
Pathogenesis:
– [ ] transplant glomerulopathy due to react of circulating DSA on surface of endothelium leading to *multilayering basement membrane
– [ ] *segmental sclerosis *peritubular capillary basement membrane duplication
– [ ] *podocyte injury and foot process effacement
Differential diagnosis:
1. chronic TMA
2. membrano proliferative GN
– [ ] lupus nephritis
– [ ] IgA nephropathy
– [ ] cryoglobulinemia GN
Q2: Morphologic evidence of chronic tissue injury, including 1 or more of the following:
• 1. Transplant glomerulopathy (cg >O) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by EM alone (cgla)
• 2. Severe peritubular capillary basement membrane multilayering
• 3. Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR
2. Identical to criterion 2 for active ABMR,
3. Identical to criterion 3 for active ABMR, including strong recommendation for DSA testing whenever criteria 1 and 2 are met.
references:
Alexandre loupy et al. The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection: American Journal of TransplantationVolume 20, Issue 9 p. 2318-2331; First published: 28 May 2020
https://doi.org/10.1111/ajt.15898
Thank You
1- Please summarise this article?
Chronic antibody-mediated rejection is commonly associated with progressive loss of kidney function and proteinuria, although early stages may be subclinical and recognizable only through protocol biopsies.
Diagnostic criteria according to the Banff 2013 classification include the presence of all of the following:
1-Histologic evidence of chronic tissue injury .
2-Current histologic evidence of antibody interaction with vascular endothelium .
3-Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
Histologic evidence of chronic tissue injury; defined by the presence of at least one of the following:
a. Transplant glomerulopathy (cg . 0) in the absence of chronic thrombotic microangiopathy
b. Severe peritubular capillary basement membrane multilayering by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
Current/recent histologic evidence of antibody interaction with vascular endothelium ;
defined by the presence of at least one of the following:
a. Linear C4d staining in peritubular capillaries (at least 10% by immunofluorescence [IF] on frozen sections or any positivity by immunohistochemistry on paraffin sections)
b. At least moderate microvascular inflammation (g 1 ptc . 2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
Pathogenesis;
1-Endothelial injury results from interaction between DSA with primarily mismatched HLA or non-HLA molecules.
2-Repetitive and chronic endothelial dam- age is associated with new basement membrane formation, which in glomeruli manifests as glomerular basement membrane duplication.
3-often with resulting segmental sclerosis and multilayering of the peritubular capillary basement membrane.
4-Podocyte injury and foot process effacement are common findings.
Differential Diagnosis;
1- Glomerular basement membrane duplication is also found in;
a- Membranoproliferative glomerulonephritis due to immune complex processes
b-lupus nephritis
c-immunoglobulin A nephropathy
d-cryoglobulinemic glomerulonephritis .
2-Chronic thrombotic microangiopathy may be indistinguishable from transplant glomerulopathy on a morphologic basis unless features of concomitant acute thrombotic microangiopathy or vascular changes are present.
3-Arterial intimal fibrosis is a common finding in;
a-hypertension
b-aging.
2-Please update the diagnostic criteria mentioned in this article based on the recent Banff classification;
Updates of 2019 Banff classification for chronic ABMR ;
Chronic active ABMR; all 3 criteria must be met for diagnosis
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
a- Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
b- Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
c- Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:
a- Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
b- At least moderate microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
c- Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated
3. Serologic evidence of circulating donor-specific antibodies (DSA to HLA or other antigens). C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA; however thorough DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised whenever criteria 1 and 2 are met.
Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
Thank You
AJKD Atlas of Renal Pathology: Chronic Antibody-Mediated Rejection
Clinical and Pathologic Features
Diagnostic criteria according to the Banff 2013 classification include the presence of all of the
following:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the
following:
a. Transplant glomerulopathy (cg . 0) in the absence of chronic thrombotic microangiopathy
b. Severe peritubular capillary basement membrane multilayering by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
2. Current/recent histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in peritubular capillaries (at least 10% by immunofluorescence [IF] on frozen sections or any positivity by immunohistochemistry on paraffin sections)
b. At least moderate microvascular inflammation (g + ptc > 2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
Etiology/Pathogenesis
Repetitive and chronic endothelial damage is associated with new basement membrane formation, which in glomeruli manifests as glomerular basement membrane duplication often with resulting segmental sclerosis, and multilayering of the peritubular capillary basement membrane. Podocyte injury and foot process effacement are common findings
Differential Diagnosis
Chronic thrombotic microangiopathy
Membranoproliferative glomerulonephritis due to immune complex processes (lupus nephritis, immunoglobulin A nephropathy, cryoglobulinemic glomerulonephritis, etc) must be ruled out by IF and electron microscopy.
chronic hypertension and aging.
Key Diagnostic Features
Transplant glomerulopathy
Peritubular capillary basement membrane
multilayering
Peritubular capillary C4d staining
Updates of Banff classification of chronic ABMR 2019
Chronic active ABMR; all 3 criteria must be met for diagnosis
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
– Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
– Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
– Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:
3. Serologic evidence of circulating donor-specific antibodies (DSA to HLA or other antigens). C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA; however thorough DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised whenever criteria 1 and 2 are met.
Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA (posttransplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis of chronic active or active ABMR
Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
C4d staining without evidence of rejection; all 4 features must be present for diagnosisc
1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
2. Criterion 1 for active or chronic active ABMR not met
3. No molecular evidence for ABMR as in criterion 2 for active and chronic active ABMR
4. No acute or chronic active TCMR, or borderline changes
Thanks Mike
Summary:
CHRONIC ABMR:
Chronic Antibody-Mediated Rejection is characterised by gradual onset Proteinuric Renal Allograft Dysfunction.
Diagnostic criteria for Chronic ABMR is according to the Banff 2013 and should include ALL the below mentioned Broad Criteria:
1.Histologic evidence of chronic tissue injury
2. Evidence of histologic evidence of Antibody interaction with the Vascular Endothelium
3.Presence of DSAs in the Serum
Criteria 1.Histologic evidence of chronic tissue injury: Glomerulus: Presence of Transplant Glomerulopathy (>G0) in the absence of Chronic TMA / Severe PTC multilayering by EM/ New onset arterial intimal fibrosis / New onset intimal arterial fibrosis in the absence of other aetiologies
Criteria 2. Evidence of histologic evidence of Antibody interaction with the Vascular Endothelium:
Criteria 3.Presence of DSAs in the Serum:
ETIO PATHOGENESIS:
Repetitive interaction of DSA with unmatched HLA/Non HLA antigens leads to chronic and cumulative injury.
Chronic and cumulative injury is manifested as multilayering of glomeruli and PTC, which ultimately culminate as glomerulosclerosis. On Electron Microscopy, podocyte injury and foot process effacement would be evident
DIFFERENTIAL DIAGNOSIS:
GBM DUPLICATION: Any chronic and repetitive injury can result in this such as chronic TMA / Chronic MPGN due to any cause 9especially due to Hepatitis C)
It is worth noting that PTC BM multiplication of < 7 years is not characteristic of Chronic ABMR
UPDATES ABOUT CHRONIC ABMR:
ABMR is classified as Acute ABMR, Chronic Active ABMR and Chronic Inactive ABMR.
After the introduction of the word ABMR in 2003, major modification were brought in 2013 and 2017.
The Updates in Banff 2017 revision include:
Ref:
Well done
Chronic antibody-mediated rejection
CABMR in early stages could be subclinical and diagnosed through renal biopsy,
Mean features is progressive loss of graft funcation plus proteinuria.
Diagnostic criteria according to the Banff 2013
1. Histologic evidence of chronic tissue injury,defined by the presence of at least one of the following:
a. Transplant glomerulopathy (cg . 0) in the absence of chronicthrombotic microangiopathy
b. Severe peritubular capillary basement membrane multilayering by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
2. Current/recent histologic evidence of antibody interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in peritubular capillaries (at least 10% by immunofluorescence [IF] on frozen sections or any positivity by immuno- histochemistry on paraffin sections)
b. At least moderate microvascular inflammation (g 1 ptc . 2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum.
Etiology and pathogenesis
Interaction between DSA and primarily mismatched HLA or non-HLA molecules leading to chronic endothelial damage and transplant glomerulopathy which result in segmental sclerosis and multilayering of the peritubular capillary basement membrane, Podocyte injury and foot process effacement are common findings.
Differential diagnosis of cAMR include:
A) GBM duplication can be seen with:
Chronic endothelial damage (membranoproliferative type injury), Chronic TMA (associated with acute TMA or vascular changes), MPGN due to lupus nephritis, IgA nephropathy, cryoglobulinemic GN.
B) Arterial intimal fibrosis seen with:
Chronic hypertension, Ageing
update of the diagnostic criteria according banff 2019 to:
all 3 criteria must be met for diagnosis
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
Severe peri-tubular capillary basement membrane multi-layering (ptcml1; requires EM)
Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2. Identical to criterion 2 for active ABMR, above
3. Identical to criterion 3 for active ABMR, above, including strong recommendation for DSA testing whenever criteria 1 and 2 are met. Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA (post transplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis of chronic active or active ABMR
Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
C4d staining without evidence of rejection; all 4 features must be present for diagnosis.
1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
2. Criterion 1 for active or chronic active ABMR not met
3. No molecular evidence for ABMR as in criterion 2 for active and chronic active ABMR
4. No acute or chronic active TCMR, or borderline changes
https://pubmed.ncbi.nlm.nih.gov/32463180/
Thanks
Chronic antibody mediated rejection
presents with progressive deterioration of kidney function and proteinuria while early stages may be subclinical and are recognized in protocol biopsies.
Diagnostic criteria according to Banff 2013 classification:
All of the following criteria should be present:
Histologic evidence of chronic tissue injury:
transplant glomerulopathy in absence of TMA.
peritubular capillary basement membrane by electron microscopy
New onset arterial intimal fibrosis with no other cause.
Current/recent histologic evidence of antibody interaction with vascular endothelium:
linear C4d staining in peritubular capillaries
moderate microvascular inflammation
increased expression of tissue gene transcripts indicating endothelial injury
Presence of DSA (HLA or non-HLA) in serum.
Pathogenesis:
DSA interact with primarily mismatched HLA or non-HLA molecules leading to chronic endothelial damage and transplant glomerulopathy which result in segmental sclerosis and multilayering of the peritubular capillary basement membrane.
Differential diagnosis
Glomerular basement membrane duplication: may occur with chronic endothelial damage causing membranoproliferative pattern of injury due to immune complex process, ruled out by immunofluorescence and electron microscopy
transplant glomerulopathy: differentiated from Chronic TMA if features of concomitant acute TMA and vascular changes are present.
Peritubular capillary basement membrane multilayering not specific to chronic antibody mediated rejection.
Arterial intimal fibrosis may occur in chronic hypertension and with ageing.
Recent update of Banff classification (Banff 2017)
It stated that both C4d staining and validated molecular assays could be considered as potential alternatives to DSAs in the diagnosis of ABMR.
Haas M, Loupy A, Lefaucheur C, Roufosse C, Glotz D, Seron D, et al. The Banff 2017 kidney meeting report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant 2018;18:293-307
Thanks Heba for the update, but it is more than this
IV. AJKD Atlas of Renal Pathology: Chronic Antibody-Mediated Rejection
Chronic antibody mediated rejection (cAMR) is a condition characterized by graft dysfunction and proteinuria. It involves interaction of donor specific antibodies (DSA) with mismatched HLA or non-HLA molecules leading to repetitive endothelial injury causing GBM (glomerular basement membrane) duplication (transplant glomerulopathy, TG) with segmental sclerosis and peritubular capillary basement membrane multilayering (ptcml).
Diagnostic criteria for c-AMR according to Banff 2013 include presence of DSA with histological evidence of chronic tissue injury (either TG or ptcml or new onset arterial intimal fibrosis) and histological evidence of antibody interaction with vascular endothelium (either linear C4d staining or at least moderate microvascular inflammation or increased tissue gene transcript expression).
Differential diagnosis of cAMR include:
A) GBM duplication can be seen with:
1) Chronic endothelial damage (membranoproliferative type injury)
2) Chronic TMA (associated with acute TMA or vascular changes)
3) MPGN due to lupus nephritis, IgA nephropathy, cryoglobulinemic GN
B) Arterial intimal fibrosis seen with:
1) Chronic hypertension
2) Ageing
Chronic ABMR is divided into 2 forms: chronic active ABMR and chronic inactive ABMR
Chronic active ABMR; all 3 criteria must be met for diagnosis (1)
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
a) Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
b) Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
c) Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:
a) Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
b) At least moderate MVI, microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
c) Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated
3. Serologic evidence of circulating donor-specific antibodies (DSA to HLA or other antigens). C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA; however thorough DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised whenever criteria 1 and 2 are met. Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA (posttransplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis of chronic active or active ABMR
Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
The differences between 2013 and 2019 classification:
1) Classifiying chronic (inactive) ABMR
2) TG in absence of chronic/recurrent de novo GN
3) leukocytes within intima not required
4) Linear C4d staining of medullary vasa recta
5) For MVI, in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
6) C4d staining or expression of validated transcripts/classifiers may substitute for DSA (criteria 3)
7) Biopsies meeting criterion 1 and 3 ( with current or prior evidence of DSA – posttransplant) without criterion 2 may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis.
Reference:
Loupy A, Haas M, Roufosse C, Naesens M, Adam B, Afrouzian M, Akalin E, Alachkar N, Bagnasco S, Becker JU, Cornell LD, Clahsen-van Groningen MC, Demetris AJ, Dragun D, Duong van Huyen JP, Farris AB, Fogo AB, Gibson IW, Glotz D, Gueguen J, Kikic Z, Kozakowski N, Kraus E, Lefaucheur C, Liapis H, Mannon RB, Montgomery RA, Nankivell BJ, Nickeleit V, Nickerson P, Rabant M, Racusen L, Randhawa P, Robin B, Rosales IA, Sapir-Pichhadze R, Schinstock CA, Seron D, Singh HK, Smith RN, Stegall MD, Zeevi A, Solez K, Colvin RB, Mengel M. The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am J Transplant. 2020 Sep;20(9):2318-2331. doi: 10.1111/ajt.15898. Epub 2020 May 28. PMID: 32463180; PMCID: PMC7496245.
Excellent Amit, thank you for the update
IV. AJKD Atlas of Renal Pathology: Chronic Antibody-Mediated Rejection
Please summarise this article
Chronic antibody-mediated rejection
clinical features
Progressive loss of graft function & proteinuria
OR
Subclinical (recognized through protocol biopsies).
Pathologic features
Banff 2013 diagnostic criteria include the presence of all of the
following:
1. Histologic evidence of chronic tissue injury, defined by the presence of at =>1 of:
a. TG (cg > 0) in the absence of chronic TMA
b. Severe PTC BM multilayering by EM
c. New-onset arterial intimal fibrosis with no other known cause
2. Current/recent histologic evidence of antibody interaction with vascular endothelium, defined by the presence of =>1 of:
a. Linear C4d staining in peritubular capillaries (at least 10% by IF on frozen sections or any positivity by IHC on paraffin sections)
b. At least moderate microvascular inflammation (g + ptc >2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Presence of DSA (HLA or non-HLA) in the serum
Pathogenesis
Endothelial injury results from interaction between
DSA & mismatched HLA or non-HLA molecules.
Formation of new basement membrane results from chronic & repetitive endothelial injury. This is manifested as:
– GBM duplication(TG) &
– Multilayring of PTC BM.
Podocyte injury & effaced foot processes are common findings.
Differential Diagnosis
1. Other causes of GBM duplication :
– Chronic thrombotic microangiopathy: look for other clinical features.
– MPGN due to immune complex depositions(must be ruled out by IF & EM):
(i) Lupus nephritis
(ii) IgAnephropathy
(iii) Cryoglobulinemic GN
2. PTC BM multi-layering specially if not severe is not specific for CAMR.
3. Other causes of arterial intimal fibrosis:
(i) Chronic hypertension
(ii) Aging
4. Chronic TCMR: scattered T cells & foam cells may be seen as in chronic AMR.
Please update the diagnostic criteria mentioned in this article based on the recent Banff classification
According to the most recent BANFF IN 2017, the chronic AMR is classified under Category 2: Antibody-mediated changes as follows:
Chronic AMR
Banff 2017 permits the use of this term for biopsy specimens showing TG & /or PTC BM multilayering in the absence of criterion of current/recent antibody interaction with the endothelium (Criteria Group 2) but with a prior documented diagnosis of Active or Chronic Active AMR or documented prior evidence of DSA
Diagnostic Criteria Groups:
Criteria Group 4 Histologic features of AMR chronicity
– Banff Lesion Score cg > 0 (by LM or EM, if available), excluding biopsies with evidence of chronic TMA.
– =>7 layers in 1 cortical PTC &=> 5 in 2 additional capillaries, avoiding portions cut tangentially by EM, if available (Severe PTC BM Multilayering)
– Arterial Intimal Fibrosis Of New Onset, Excluding Other Causes; Leukocytes Within The Sclerotic Intima Favor Chronic AMR If There Is No Prior H/O Biopsy-Proven TCMR but are not required
Excellent
☆ AJKD Atlas of Renal Pathology: Chronic Antibody-Mediated Rejection
▪︎Diagnostic criteria of Chronic ABMR
______________
▪︎Aaccording to the Banff 2013 include the presence of all of the following:
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy in the absence of chronic TMA
b. Severe peritubular capillary basement
membrane(BM) multilayering by electron
microscopy
c. New-onset arterial intimal fibrosis with
no other known etiology
2. Current/recent histologic evidence of Ab interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in peritubular
capillaries (at least 10% by IF on frozen
sections or any positivity by IHC on
paraffin sections)
b. At least moderate microvascular
inflammation.
c. Increased expression of tissue gene
transcripts indicative of endothelial injury
3. Presence of donor-specific antibodies
(DSA; HLA or non-HLA) in the serum
Etiology/Pathogenesis:
_______________________€€
▪︎DSAs interact with primarily mismatched HLA or non-HLA molecules which result in endothelial injury with new BM formation (in glomeruli manifests as GBM duplication (transplant glomerulopathy)), often with resulting segmental sclerosis, and multilayering of the peritubular capillary BM.
▪︎Podocyte injury and foot process effacement are common findings.
Differential Diagnosis:
______________________
▪︎GBM duplication is seen in:
1. Chronic endothelial damage, causing a membranoproliferative pattern of injury.
2. Chronic TMA
3. Membranoproliferative glomerulonephritis due to immune complex processes (lupus nephritis, IgA nephropathy, cryoglobulinemic glomerulonephritis, etc)
▪︎The following are not is not specific to chronic ABMR:
1. Less severe peritubular capillary BM multilayering.
2. Arterial intimal fibrosis (often associated with chronic hypertension and aging).
3. Scattered T cells and foam cells present in the expanded intima (may also be seen in chronic T-cell–mediated rejection).
☆An update of the diagnostic criteria according banff 2019 to:
https://pubmed.ncbi.nlm.nih.gov/32463180/
A. In Chronic active ABMR; all 3 criteria must be met for diagnosis
B. In Chronic (inactive) ABMR:
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSAC4d staining without evidence of rejection;
▪︎All 4 features must be present for diagnosis
1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
2. Criterion 1 for active or chronic active ABMR not met
3. No molecular evidence for ABMR as in criterion 2 for active and chronic active ABMR
4. No acute or chronic active TCMR, or borderline changes
______________
Ref:
Alexandre Loupy et al. Am J “The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection” Transplant. 2020
Excellent
In 2013 BANF commite put classification for cABMR,
In 2019 the committe had made some changes to this classification
Chronic active ABMR; all 3 criteria must be met for diagnosis
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2. Identical to criterion 2 for active ABMR, above
3. Identical to criterion 3 for active ABMR, above, including strong recommendation for DSA testing whenever criteria 1 and 2 are met. Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA (posttransplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis of chronic active or active ABMR
Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
C4d staining without evidence of rejection; all 4 features must be present for diagnosisc
1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
2. Criterion 1 for active or chronic active ABMR not met
3. No molecular evidence for ABMR as in criterion 2 for active and chronic active ABMR
4. No acute or chronic active TCMR, or borderline changes
reference
1-Alexandre Loupy.The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection.American Journal of TransplantationVolume 20, Issue 9 p. 2318-2331.
Excellent
Chronic Antibody mediated rejection represent a poor allograft prognosis .it’s usually present with gradually deteriorating allograft function with or without proteinuria.However, early stages might be subclinical and detected only by protocol biopsy.
In 2013 classification defined chronic AMR depending on 3 categories showcasing the evidences of chronic tissue injury, recent or current antibody endothelial interaction and lastly the presence of DSAs.
It was highlighted in details as follows:
1-:Histologic evidence of chronic tissue injury in the form of TG, severe PTC mutilayring by EM,and new onset arterial intimal fibrosis.
2-Evidence of recent /current Antibody endothelial interaction ,in the form of C4d deposition in PTC
Shown by IF or IHC.Or the presence of moderate MVI(g+ptc>2).And lastly increased expression of tissue gene transcripts.
3-DSA ,HLA and non HLA.
In 2019 the diagnosis of Chronic AMR was split into 2 category as follow;
1) Chronic active Antibody mediated rejection, C-aAMR, in which 3 diagnostic Criteria, including
a)histologic evidence of acute tissue injury,
b)evidence of recent or current antibody interaction with endothelium (usually C4d),however C4d stainig or validated transcripts may substitute for DSAs..
c)histologic evidence of chronic tissue injury,such as TG attributed to AMR.
Acute tissue injury involve MVI with g+ptc>2,acute tubular damage,thrombotic microangiopathy,and less commonly arterial lesion of endothelialitis,fibrinoid necrosis and transmutation inlammation..
2)Chronic inactive AMR: shows evidence of chronic tissue injury but without capillaritis and without C4d deposition.
One more category was added ,that is ptc staining for C4d without evidence of rejection.,referred to as accommodation related to ABO incompatible transplant with and without DSAs.
Reference:
1)Lynn D.Cornell.Histologic Features of Antibody Mediated Rejection:The Banff Classification and beyond.front.Immunol.sept 2021
Well done. Very impressed
AJKD Atlas of Renal Pathology: Chronic Antibody-Mediated Rejection.
Its mainly due to the same cause of ABMR which the HLA or Non-HLA antibodies interact with the endothelium and lead to chronic inflammatory process which lead to duplication of peritubular GBM.
D.D of GBM duplication: its important as each one has specific treatment.
-Chronic TMD.
-MPGN due to immune complex processes (lupus nephritis, immunoglobulin A nephropathy, cryoglobulinemic glomerulonephritis, etc.) must be ruled out by IF and electron microscopy.
Chronic antibody-mediated rejection is commonly associated with progressive loss of kidney function and proteinuria, and its considered one of the common causes poor graft outcome.
As per BANFF 2013 Ca-ABMR is diagnosed by three criteria:
1-Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following: (TG, BM multi-layering by E/M or . New-onset arterial intimal fibrosis).
2-Current/recent histologic evidence of antibody interaction with vascular endothelium e.g. (linear C4d staining in peritubular capillaries, moderate microvascular inflammation or expression of tissue gene transcripts).
3-Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum.
Updates of 2019 Banff classification for chronic ABMR: (1).
1-Chronic active ABMR: same criteria as in BANFF 2013
2-Chronic (inactive) ABMR:
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA.
C4d staining without evidence of rejection; all 4 features must be present for diagnosis
Reference:
1-Alexandre Loupy,Mark Haas,et al.( The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection) 28 May 2020.https://doi.org/10.1111/ajt.15898
Well done
In this article publishes in 2015, chronic antibody-mediated rejection was defined according to BANFF 2013 criteria.
Chronic AMR which is always associated with graft loss in the long term should be differentiated from MPGN (membranoproliferative GN) and other immune complex related pathologies like SLE, IgA GN, and cryoglobulinemia some of which are differentiated by IF (immunofluorescence) staining. Multilayering of BM (basement membrane) is typically more than 7 layers in chronic rejection. In summary, the key features of Chronic AMBR are TG (transplant glomerulopathy), Peritubular BM multilayering and Peritubular capillary c4d staining.
In BANFF 2013 the chronic AMR is mandated by all three features:
1- Histologic evidence of chronic tissue injury
2- Current/recent evidence of interaction between antibodies and vascular epithelium
3- Presence of DSAs (either HLA or non-HLA)
The histologic features (1) are defined by at least one of :
a) TG (transplant glomerulopathy) cg>0 without chronic TMA.
B) severe BM multilayering.
C) new-onset arterial intimal fibrosis (w/o defined other cause)
Current/recent evidence of ab-endothelial interaction is defined as one of the below 3 :
a) Linear c4d staining in the PTCs
b) At least moderate microvascular inflammation (g+ptc >2)
c) İncreased expression of tissue gene transcripts
In the latest BANFFupdate in 2019 we observe that catergory 2 defining AMBR is much detailed and classified as active, chronic active, chronic (inactive) (reference: The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection)
Category 2:
Category 2: Antibody-mediated changes
Active ABMR; all 3 criteria must be met for diagnosis
1. Histologic evidence of acute tissue injury, including 1 or more of the following:
2. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:
3. Serologic evidence of circulating donor-specific antibodies (DSA to HLA or other antigens). C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA; however thorough DSA testing, including testing for non-HLA antibodies if HLA antibody testing is negative, is strongly advised whenever criteria 1 and 2 are met
Chronic active ABMR; all 3 criteria must be met for diagnosis
1. Morphologic evidence of chronic tissue injury, including 1 or more of the following:
Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favor chronic ABMR if there is no prior history of TCMR, but are not required
2. Identical to criterion 2 for active ABMR, above
3. Identical to criterion 3 for active ABMR, above, including strong recommendation for DSA testing whenever criteria 1 and 2 are met. Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA (posttransplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for diagnosis of chronic active or active ABMR
Chronic (inactive) ABMR
1. cg > 0 and/or severe ptcml (ptcml1)
2. Absence of criterion 2 of current/recent antibody interaction with the endothelium
3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
C4d staining without evidence of rejection; all 4 features must be present for diagnosisc
1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
2. Criterion 1 for active or chronic active ABMR not met
3. No molecular evidence for ABMR as in criterion 2 for active and chronic active ABMR
4. No acute or chronic active TCMR, or borderline changes
Reference
The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am J Transplant. 2020 Sep;20(9):2318-2331. doi: 10.1111/ajt.15898. Epub 2020 May 28. PMID: 32463180; PMCID: PMC7496245.
Excellent
AJKD Atlas of Renal Pathology: Chronic Antibody-Mediated Rejection
Chronic antibody-mediated rejection is associated with progressive loss of kidney function and proteinuria, early stages may be subclinical and recognizable only through protocol biopsies.
Diagnostic criteria according to the Banff 2013 classification :
1. Histologic evidence of chronic tissue injury, defined by the presence of at least one of the following:
a. Transplant glomerulopathy (cg . 0) in the ab-
sence of chronic thrombotic microangiopathy
b. Severe peritubular capillary basement mem- brane multilayering by electron microscopy
c. New-onset arterial intimal fibrosis with no other known etiology
2. Current/recent histologic evidence of antibody
interaction with vascular endothelium, defined by the presence of at least one of the following:
a. Linear C4d staining in peritubular capillaries (at least 10% by immunofluorescence [IF] on frozen sections or any positivity by immuno- histochemistry on paraffin sections)
b. At least moderate microvascular inflammation (g 1 ptc.2)
c. Increased expression of tissue gene transcripts indicative of endothelial injury
3. Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
Etiology:
endothelial injury results from interaction between DSA with primarily mismatched HLA or non-HLA molecules.
Differential Diagnosis:
1-Chronic thrombotic microangiopathy.
2- Membranoproliferative glomerulonephritis .
3-lupus nephritis
4- immunoglobulin A nephropathy.
5-cryoglobulinemic glomerulo- nephritis.
The update Banff criteria 2019 :
Include (1) plus either (2) or (3)
Dear Asmaa
You need to explain better the difference between Banff 13 and 17 (19)
Chronic Antibody-Mediated Rejection is diagnosed based on Banff 2013 classification:
1. Histologic evidence of chronic tissue injury
2. Current/recent histologic evidence of antibody interaction with vascular endothelium
3. Presence of donor-specific antibodies (DSA; HLA or non-HLA) in the serum
Chronic endothelial damage is manifested histologically with new basement membrane formation, GBM duplication (transplant glomerulopathy) associated with segmental sclerosis, and multilayering of the peritubular capillary basement membrane.
Glomerular basement membrane duplication is also found in other conditions associated with chronic endothelial damage, causing a membranoproliferative pattern of injury.
Chronic TMA may resemble transplant glomerulopathy on a morphologic basis unless features of concomitant acute thrombotic microangiopathy or vascular changes are present.
Peritubular capillary basement membrane multilayering, especially if not severe (<7 layers), is not specific to chronic antibody-mediated rejection.
Can you focus better on the update?
1- Summary
Diagnostic criteria for chronic antibody mediated rejection according to the Banff 2013 classification include the presence of all of the following:
-Histologic evidence of chronic tissue injury, determined by occurrence of at least one of the following:
.Transplant glomerulopathy (cg . 0) in the absence of chronic thrombotic microangiopathy
. Severe peritubular capillary basement membrane multilayering by electron microscopy
. New-onset arterial intimal fibrosis with no other known etiology
-Current/recent histologic evidence of antibody interaction with vascular endothelium, detected by the ocuurnce of Linear C4d staining in peritubular capillaries ,at least moderate microvascular inflammation , Increased expression of tissue gene transcripts
-Presence of donor-specific antibodies
Pathogenesis
DSA interaction with mismatched HLA or non-HLA molecules leads to endothelial injury, occurring repetitively causes glomerular basement membrane duplication (transplant glomerulopathy), with segmental sclerosis.
DD
Glomerular basement membrane duplication can be associated with other conditions with membranoproliferative pattern .
So membranoproliferative glomerulonephritis need to be excluded with IF and EM.
Chronic thrombotic microangiopathy can resemble morphologically transplant glomerulopathy .
Peritubular capillary basement membrane multilayering, has to be severe to be diagnostic of chronic antibody mediated rejection.
Arterial intimal fibrosis and scattered T cells are non specific
Diagnostic Features
Transplant glomerulopathy
Peritubular capillary basement membrane multilayering
Peritubular capillary C4d staining
2- Updated diagnostic criteria based on latest Banff classification
As of 2019, the Banff schema recognizes four diagnostic categories:
1. Active ABMR,
2. Chronic active ABMR,
3. Chronic (inactive) ABMR,
4. C4d staining without evidence of rejection,
§ The active ABMR, requires 3 diagnostic criteria:
Ø histologic evidence of acute tissue injury, microvascular inflammation (MVI), as capillaritis, glomerulitis (g) score + peritubular capillaritis (ptc) score of 2 or greater, thrombotic microangiopathy, and less commonly arterial lesions of endothelialitis, fibrinoid necrosis, or transmural inflammation.
Ø evidence of current or recent antibody interaction with the endothelium (usually C4d),
Ø serologic evidence of DSA (although C4d staining or validated transcripts may substitute for DSA).
§ Chronic active ABMR has a similar three criteria, but with
histologic evidence of chronic tissue injury, such as transplant glomerulopathy (TG) attributable to ABMR.
§ Chronic (inactive) ABMR shows histologic evidence of chronic tissue injury, but without capillaritis and without C4d deposition in peritubular capillaries.
§ PTC C4d staining without evidence of rejection, previously “accommodation” occurs in ABO blood group incompatible transplants, which show positive C4d staining in even 80% of protocol biopsies and the staining does not correlate with peritubular capillaritis.
Reference
Cornell L. D. Histopathologic Features of Antibody Mediated Rejection: The Banff Classification and Beyond .Front. Immunol., 27 September 2021.
Excellent
AJKD Atlas of Renal Pathology: Chronic Antibody-Mediated Rejection
Chronic antibody mediated rejection (CABMR) a cause of proteinuria and loss of graft function.
Diagnostic criteria (2013) Banff, all 3 below required for diagnosis of CABMR.
1.Histologic evidence of chronic tissue injury in form of one below;
I. Transplant glomerulopathy (cg . 0) in the absence of chronic thrombotic microangiopathy
I. Severe peritubular capillary basement membrane multilayering by electron microscopy
II. New-onset arterial intimal fibrosis with no other known aetiology
2.Evidence of antibody interaction with vascular endothelium in form of one below;
I. C4d staining of peritubular capillaries
II. Moderate microvascular inflammation (g+ptc>2)
3. Presence of DSA in serum
Pathogenesis
Endothelial injury from DSA
Glomerular duplication from repeated endothelial injury
Podocytopathy
Other causes of double contour appearance of GBM – chronic TMA and MPGN
Intimal fibrosis can also be due – hypertension and aging
Banff 2019 now has two categories of chronic antibody mediated rejection(Loupy et al., 2020)
1. Chronic active ABMR; all 3 criteria must be met for diagnosis
I. Morphologic evidence of chronic tissue injury, any one of ;1 or more of the following:
Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)
Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM)
Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima favour chronic ABMR if there is no prior history of TCMR, but are not required
1. Chronic inactive ABMR
I. cg > 0 and/or severe peritubular capillary basement membrane multilayering
II. Absence of current/recent antibody interaction with the endothelium
III. 3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA
LOUPY, A., HAAS, M., ROUFOSSE, C., NAESENS, M., ADAM, B., AFROUZIAN, M., AKALIN, E., ALACHKAR, N., BAGNASCO, S., BECKER, J. U., CORNELL, L. D., CLAHSEN-VAN GRONINGEN, M. C., DEMETRIS, A. J., DRAGUN, D., DUONG VAN HUYEN, J.-P., FARRIS, A. B., FOGO, A. B., GIBSON, I. W., GLOTZ, D., GUEGUEN, J., KIKIC, Z., KOZAKOWSKI, N., KRAUS, E., LEFAUCHEUR, C., LIAPIS, H., MANNON, R. B., MONTGOMERY, R. A., NANKIVELL, B. J., NICKELEIT, V., NICKERSON, P., RABANT, M., RACUSEN, L., RANDHAWA, P., ROBIN, B., ROSALES, I. A., SAPIR-PICHHADZE, R., SCHINSTOCK, C. A., SERON, D., SINGH, H. K., SMITH, R. N., STEGALL, M. D., ZEEVI, A., SOLEZ, K., COLVIN, R. B. & MENGEL, M. 2020. The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection. American Journal of Transplantation, 20, 2318-2331.
II. Evidence of current/recent antibody interaction with vascular endothelium as Banff 2013;
III. Serologic evidence of circulating donor-specific antibodies (DSA to HLA or other antigens).
C4d staining may substitute for this criterion
Well done Innocent
Chronic antibody mediated rejection is a common cause of late allograft loss , it presents with proteinuria ang decreased e GFR although in early stages it may have subclinical presentation .
Diagnostic criteria :
(1) Evidence of tissue damage :
(2) Evidence of antibody interaction with endothelial cells :
(3) DSA
In 2017 , The Banff group updated the criteria , it no longer require DSA , and diffuse C4d staining and endothelial associated transcripts / classifiers can replace the DSA criteria.
Thanks Mujtaba
Can you expand more on 2017 update
Summary:
Chronic ABMR is associated with progressive loss of graft function and proteinuria, subclinical stages are diagnosed only in protocol biopsies.
Diagnostic criteria( Banff 2013):
Pathogenesis:
Interaction between DSA with primary mismatched HLA or non-HLA molecules resulting in endothelial injury, repetitive damage will lead to double contour GBM formation with segmental sclerosis and multilayering of peritubular capillary basement membrane, podocyte injury and effacement.
Differential Diagnosis:
Update: Banff 2019
Chronic active ABMR; all 3 criteria must be met for diagnosis 1. Morphologic evidence of chronic tissue injury, including 1 or more of the following: Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a) Severe peritubular capillary basement membrane multilayering (ptcml1; requires EM). Arterial intimal fibrosis of new-onset, excluding other causes; leukocytes within the sclerotic intima favour chronic ABMR if there is no prior history of TCMR, but are not required
2. Identical to criterion 2 for active ABMR ( Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following: • Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections) • At least moderate microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1 • Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated).
3. Identical to criterion 3 for active ABMR, including a strong recommendation for DSA testing whenever criteria 1 and 2 are met. Biopsies meeting criterion 1 but not criterion 2 with current or prior evidence of DSA (posttransplant) may be stated as showing chronic ABMR, however remote DSA should not be considered for a diagnosis of chronic active or active ABMR Chronic (inactive) ABMR.
Chronic (inactive) ABMR: 1. cg > 0 and/or severe ptcml (ptcml1). 2. Absence of criterion 2 of current/recent antibody interaction with the endothelium. 3. Prior documented diagnosis of active or chronic active ABMR and/or documented prior evidence of DSA. C4d staining without evidence of rejection; all 4 features must be present for diagnosis: 1. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections). 2. Criterion 1 for active or chronic active ABMR has not been met. 3. No molecular evidence for ABMR as in criterion 2 for active and chronic active ABMR. 4. No acute or chronic active TCMR, or borderline changes.
Excellent
Chronic antibody mediated rejection is a progressive disease and is associated with graft loss and proteinuria. Early stages are only diagnosed by Protocol biopsies. Banf 2013 criteria for diagnosis includes:
1–Chronic tissue injury on biopsy and presence of at least one of the following.
· Transplant glomerulopathy in the absence of Thrombotic microangiopathy
· Severe peritubular capillary membrane multilayering
· New onset intimal fibrosis with no other cause
2- Histological evidence of interaction of antibody with vascular endothelium-defined by one of the following:
· Linear Cd4 staining in pertibullar capillaries- at least 10% by IF, on the frozen section or any positivity on immunohistochemistry or paraffin section.
· At least microvascular inflammation
· Increased expression of tissue gene transcript
3- Presence of DSA
Pathogenesis
Interaction of DSA with Mismatched HLA or Non HLA antigens leads to chronic an repetitive endothelial damage with new basement membrane formation manifesting as basement membrane duplication with resulting segmental sclerosis and multilayering.
Differential diagnosis
· Chronic Thrombotic microangiopathy
· Membranoproliferative glomerulonephritis due to immune complex processes
· Chronic hypertension and aging -Arterial intimal fibrosis can be seen
· Chronic T cell mediated Rejection
What about the update Dr Khan?
ABMR has wide variety of clinicopathological features which range from hyper acute rejection to early acute ABMR in patients with positive cross match to progressive graft dysfunction . Features of ABMR can be seen on routine protocol biopsies in patients who have history of pre transplant DSA with a stable graft function and proteinuria . The features can be different in patients who have history of denovo DSA and nonadherence to medications or those who have combined antibody mediated and cellular rejection. The challenge remains for any classification system to fit in variety of variable clinicopathologic findings.
In 2019 Banff Schema classified ABMR in to :
Active ABMR-
3 diagnostic criteria-
Evidence of acute tissue injury
Antibody interaction with Endothelium- C4d staining
Evidence of DSA
Histologically – Microvascular inflammation- Glomerulitis and Peritubular Capilliritis score of 2 or more. Other patterns are acute tubular injury, transplant microangiopathy and less commonly endothelitis, fibrinoid necrosis or transmural inflammation
Chronic Active ABMR
All three criteria must be met-
Evidence of chronic tissue injury including one or more of the following- Transplant glomerulopathy, Multilayering of PTC membrane , chronic arteriopathy without evidence of acute inflammation.
Evidence of antibody interaction with vascular endothelium.
Positive c4d staining in peritubular capillaries.
Evidence of Circulating DSA
Chronic inactive ABMR
If there is evidence of chronic tissue injury with one of the other two criteria’s
C4d staining without the evidence of rejection
Previously referred as accommodation. It is seen in ABO incompatible Transplants in which C4d staining is seen in 80% protocol biopsies and this staining does not co relate with peritubular capilliritis. In some protocol biopsies of patients with history of positive XM C4d staining is seen without evidence of tissue injury and this group qualifies for accommodation.
Reference :
D Cornell. Histopathologic Features of Antibody Mediated Rejection: The Banff Classification and Beyond. Front. Immunol., 27 September 2021