II. Chronic-active antibody-mediated rejection with or without donor-specific antibodies has similar histomorphology and clinical outcome – a retrospective study
- Please summarise this article
- What is the kind of this study?
- What is the level of evidence?
– Chronic active antibody mediated rejection is diagnosed as histological evidence of transplant glomerulopathy with one of ( microvascular inflammation or C4d staining positive). However, DSA is uncommonly found in patients with allograft dysfunction with ongoing tissue injury.
– Patients with transplant glomerulopathy and feature of microvascular inflammation or c4d staining in absence of DSA are considered as highly suspicious for cABMR
– This is a retrospective study aimed to investigate weather the histomprphological criteria and graft survival differ between patient with definite cABMR (DSA positive) and patients with suspicion for cABMR (DSA negative). It included 41patients, 17 patient with DSA, and 24 patients with negative DSA.
– Both groups were studied for histomorphological, allograft function, and long term survival.
Results: Both groups showed a loss of their function.
DSA criteria:
Mostly anti-HLA II (anti-HLA-DQ abs)
No difference between both groups regarding the allograft survival and decline in graft function.
the need for DSAs to be present for the diagnosis of c-aABMR.
What is the kind of this study?
retrospective study
What is the level of evidence?
III
This is a s retrospective single center study in Netherlands between January 2007 and November 2014 with level III evidence. The objective is to study whether cases suspicious for c-aABMR (DSA negative ) differ from cases of c-aABMR (DSA positive ) with respect to renal histology, allograft function and long-term graft survival. A total of 24 patients with the diagnosis of suspicious for c-aABMR (DSA negative ) and 17 with c-aABMR (DSA positive) were recruited. Baseline characteristics, decline in allograft function and renal allograft survival did not differ significantly between the two groups. Limitation, retrospective study which allow unknown bias and small sample size. In conclusion, renal allograft biopsy histology and clinical outcome of transplant recipients with c-aABMR do not significantly differ from those suspicious for c-aABMR. However, further trial involve larger sample size is needed.
retrospective cohort study.
Level 3 evidence
Summary:
C4 is cleaved by C1s into C4a and C4b, exposing a sulfhydryl group. The active sulfhydryl group of C4b rapidly forms an amide or ester bond with nearby molecules containing hydroxyl or amino groups and forms C4d
C4d positive:
a. Acute AMR
b. Chronic antibody‑mediated rejection
c. A, B, O blood group ABO incompatible grafts
d. Accommodation.
complement 4d is negative :
a. T‑cell‑mediated rejection (TCMR)
b. A technical error like a type of fixatives, immunofluorescence (IF) versus immunohistochemistry (IHC)
c. Fc receptor (FCR) on NK cells (FcRIIA) mediated rejection
d. Antibodies unable to fix the complement
e. Complement independent pathways of endothelial activation
f. C4d deposition is a very low in quantity for the identification limits of IF/IHC
g. Alloantibodies can direct endothelium injury to interact with major histocompatibility complex (MHC)
h. Increased expression of endothelial transcripts causing endothelium injury.
Two techniques are mostly used for identification of C4d IHC and IF in allograft biopsies of the kidney.
The scoring of C4d is significant by IF on frozen section ie C4d2 or C4d3 and by IHC C4d >0 on paraffin sections
The C4d‑positive staining in PTC is a diagnostic marker as well as a prognostic marker for allograft.
PROS (1) provoked an enormous amount of insight in the diagnosis of allograft rejection, (2) core diagnostic tool to identify AMR, and (3) used for vast amount of research into the deposition patterns of C4d in different clinical settings such as pregnancy, thrombotic complications
CONS as follows: (1) difficulties of interpreting focal staining patterns, (2) relatively low sensitivity of C4d as a marker for AMR in late renal allograft biopsies, and (3) its lack of utility as a marker for antibody‑mediated injury in biopsies of ABO‑incompatible allografts)
Complement pathway
-Level of evidence III
– retrospective cohort study.
-Cases in which renal histology show chronic endothelial activation as evidenced by glomerular basement membrane duplication, known as transplant glomerulopathy (TG), and C4d-positive staining and/or significant microvascular inflammation (MVI) with no detectable DSA are considered suspicious for c-aABMR.
-whether allograft
outcome and renal histomorphology differed between cases suspicious for c-aABMR (DSAneg) and cases with c-a-ABMR (DSApos).
-performed with antibodies against IgG, IgM, IgA, C3c,
. C1q, kappa and lambda on snap frozen material according to standard diagnostic procedure in our hospital.
Several individual Banff lesions were combined to assess microvascular inflammation and chronicity of the renal parenchyma and vessels. The microvascular
inflammation (MVI) score was calculated by combining the glomerulitis and peritubular capillaritis score. MVI score ≥2 was considered moderate to severe and a
diagnostic criterion for c-aABMR. The chronic inflammation score was calculated as (interstitial fibrosis (ci) + tubular atrophy (ct) + total inflammation (ti)) as previously described .
-estimated glomerular filtration rate (eGFR, MDRD) measurements 1 year prior to diagnosis and 1 year after diagnosis for both patient groups . A minimum of five measurements per year at regular intervals was required to give a reliable estimate over time of the decrease in renal allograft function. eGFR measurements influenced by antibiotic treatment, i.v. fluids or other potential factors were excluded from the
analysis due to misleading representation of allograft function. Return to dialysis or retransplantation was considered allograft failure.
-The Banff ’15 criteria do not allow for the classifying diagnosis of c-aABMR if there
are no DSA present. Instead, these cases are diagnosed as suspicious for c-aABMR. Therefore, the significance of DSA and their contribution to the loss of allograft
function and relation to renal histomorphology have not yet been fully explored. We found that there are no
. histological or clinical differences between cases with c-aABMR and cases suspicious for c-aABMR. Most studies have used transplant glomerulopathy (with or without DSA) as the histopathological diagnosis and have not described the level of microvascular inflammation and chronic tissue damage between cases
with or without DSAs. the presence of DSA is not a conditio sine qua non to establish the diagnosis of c-aABMR when other criteria indicative of chronic tissue injury
and current/recent antibody interaction with vascular endothelium are met.
SUMMARY
Chronic active antibody mediates rejection or c aABMR is usually recognized and confirmed by the presence of DSAs. When DSAs are not present, we tend to think that the patient is not facing ABMR. However, this is far from the truth.
Even a suspicion of ABMR, in the absence of DSA, can lead to the same histological and clinical outcomes as a patient with ABMR with recognized DSAs.
In the absence of DSA, the following criteria, if present, increases suspicion of ABMR :
This study highlights the concept that long term graft survival as well as histomorphological aspects of ABMR are similar in patients with DSA or without.
Irrespective of DSA status, substantial chronic histomorphological damage is manifested by glomerular basement membrane double contours (layering), chronic inflammation and microvascular inflammation.
This study is a retrospective study with level III evidence.
Chronic active ABMR (c-aABMR) define as GBM duplication (TG) + MVI or C4 d +.
This is a retrospective study conducted on 41 cases suspicion for c-aABMR. There patients are divided in tow groups regarding DSA presence: positive or negative. There two groups are compared for variables such as: pathology, graft function and survival. All patients with evidence for c-aABMR were included between 2007 to 2014. They were excluded if biopsy was done within the first – year or they didn’t have 5 measurements for eGFR per year. All of them received Treatment with 3 doses methylprednisolone + 1 g / kg IVIG without plasmapheresis. IHC for C4d and IF for antibodies were done, too. MVI ³ 2 and chronic inflammation were considered as suspicious for c-aABMR. CDC–XM was negative at TX in all patient: seventeen patients were DSA positive (de novo DSA) against HLA–DQ.
There was non-significant difference between two groups regrading histo-morphological characteristics.
All patients had declined GFR (average 31 ml / min) at the time of biopsy. With treatment both groups had significant less allograft function reduction comparing before treatment. Two groups had no significant difference regarding graft survival. C4d staining was not associated with graft survival difference. They concluded that in presence of high cg and MVI score, C4d and DSA are not necessary for diagnosis of c-aABMR. This is a retrospective study. It’s level of evidence is 3.
Introduction
Chronic-active antibody-mediated rejection (c-aABMR) is currently defined by the Banff classification by
(i) histologic evidence of chronic tissue injury,
(ii) evidence of current or recent antibody interaction with vascular endothelium and
(iii) serologic evidence of donor-specific antibodies (DSA)
Cases in which renal histology show chronic endothelial activation as evidenced by glomerular basement membrane duplication, known as transplant glomerulopathy (TG), and C4d-positive staining and/or significant microvascular inflammation (MVI) with no detectable DSA are considered suspicious for c-aABMR.
In this study, we investigated whether allograft outcome and renal histomorphology differed between cases suspicious for c-aABMR (DSAneg) and cases with c-a-ABMR (DSApos).
Patients and methods
Study population
All patients with the histomorphological biopsy diagnosed of chronic-active antibody-mediated rejection after a progressive decline in renal allograft function, are studied retrospectively. Patients were identified from the pathology database at our center between January 2007 and November 2014.
Exclusion:
– if the biopsy was within the first-year post-transplantation (inaccurate information
about renal allograft function) or the requirement of a minimum of 5 eGFR measurements per year was not met.
– Alternative diagnoses for the histomorphological changes compatible with c-aABMR such as hepatitis C virus infection, membranoproliferative glomerulonephritis (MPGN) or
(chronic) thrombotic microangiopathy (cTMA) were excluded, by immunofluorescence and clinical analysis
– eGFR measurements influenced by antibiotic treatment, i.v. fluids or other potential factors were excluded from the analysis due to misleading representation of allograft
function.
Patients were divided into two groups based on the presence of detectable DSA in their serum at time of biopsy.
Upon diagnosis, all patients, regardless of DSA status (which was unavailable at time of diagnosis), received similar treatment with three doses of 1 g intravenous methylprednisolone (MP) over a 3-day period combined with a single dose of intravenous immunoglobulins (IVIG) (1 g/kg body weight) on the second day of treatment. None of the patients had plasmapheresis.
Renal biopsies were re-evaluated and the individual lesions were scored according to the Banff classification by two independent pathologists.
Renal allograft function
Change in renal allograft function in time was evaluated by including all estimated glomerular filtration rate (eGFR, MDRD) measurements 1 year prior to diagnosis and 1 year after diagnosis for both patient groups.
A minimum of five measurements per year at regular intervals was required to give a reliable estimate over time of the decrease in renal allograft function.
Return to dialysis or retransplantation was considered allograft failure.
Characterization of anti-HLA antibodies
All patients were transplanted with a CDC-negative cross-match. To determine the definite diagnosis of each patient, serum samples at the time of biopsy were reevaluated and tested for the presence of donor-specific antibodies against HLA (DSA). If DSA were found to be present, it was determined whether this concerned de novo DSA.
If samples were found to be negative, additional screening was performed by analyzing serum
samples for DSA in the 2 years prior to diagnosis.
Patient serum samples were screened for the presence or absence of HLA antibodies using the Luminex Screening Assay.
Discussion and conclusion
The Banff ’15 criteria do not allow for the classifying diagnosis of c-aABMR if there are no DSA present. Instead, these cases are diagnosed as suspicious for c-aABMR. Therefore, the significance of DSA and their contribution to the loss of allograft function and relation to renal histomorphology have not yet been fully explored. We found that there are no histological or clinical differences between cases with caABMR and cases suspicious for c-aABMR
What is the kind of this study?
Retrospective study
What is the level of evidence?
Level III
Chronic-active antibody-mediated rejection with or without donor-specific antibodies has similar histomorphology and clinical outcome – a retrospective study
This Retrospective study investigated differences in allograft outcome and renal histomorphology between cases of DSA positive chronic ABMR & DSA negative chronic ABMR. It recruited All patients with a histomorphology diagnosis of chronic active ABMR between Jan 2007 and Nov 2014.
The patients are grouped into 2 groups according to their DSA status at the time of biopsy. All of the patients received similar treatment: 3 doses of MP (1 gm), with single dose of IVIG (1 g/kg) on the second day of treatment, no PE was done. Renal biopsies were revaluated and scored according to Banff 2015 by 2 independent pathologists.
C4d was evaluated using IHC. IF staining for IgG, IgA, IgM, C3, C1q, kappa and lambda.
Luminex screening was used to detect the presence of anti-HLA antibodies, further analysis was done by SAB-Luminex testing.
The study showed:
Number of DSA positive patients 17/41
Number of DSA negative patients 24/41
78% of the detected DSA was against HLA-DQ, with an average MFI of 13477.
All renal Tx biopsies had double contours of GBM.
The majority had severe capillary loop involvement.
For DSA positive patients, 8 patients had positive C4d staining, and 9 of the DSA patients were C4d positive. Among them, 4 had tubulitis.
A comparison between histomorphology characteristics of the 2 groups showed no significant differences in the individual Banff lesions, nor between C4d positive and C4d negative groups. The groups showed no significant differences in the chronic inflammation score of MVI.
All patients had a progressive decline in renal allograft function at the time of renal biopsy. After treatment, there was more loss of graft function for both groups. No significant difference in graft survival between the 2 groups was found and decreased graft survival was seen in all cases with high IFTA and total inflammation.
The study concluded that renal histology and clinical outcomes of DSA negative c-aABMR do not significantly differ from DSA positive c-aABMR
What is the kind of this study?
Retrospective study
What is the level of evidence?
Level III
The presence of DSA is part of diagnosis of C-aABMR besides histologic evidence of chronic tissue injury and evidence of recent antibody interaction with endothelium. DSA cannot be detected in high number of patients.
Patients with histologic evidence of transplant glomerulopathy (GBM duplication) and positive C4d staining and/or significant MVI without detectable DSA was considered suspicious for C-aABMR in previous Banff classification.
This study is a retrospective study that evaluated kidney allograft outcomes and histopathologic features between DSA-neg and DSA-pos C-ABMR in 41 patients with C-aABMR.
This study found that there are no histological and clinical differences between DSA positive and DSA negative C-aABMR who are suspicious for C-aABMR. The presence of DSA was not related to difference in response to therapy or graft survival. Irrespective of DSA, there was a substantial chronic histomorphology damage including transplant glomerulopthy.
In this study, in 24 patients with C-aABMR, all DSAs were de novo, and the majority of them directed against HLA_DQ. These findings were in line with previous reports that found dominance of de novo DSA, especially anti HLA-DQ antibodies.
Chronic histologic damage is the most important factor that attributed to graft survival. In transplant glomerulopathy, IFTA and total inflammation irrespective of DSA are associated with graft survival. The absence of DSA does not reject involvement of antibody mediated process.
Both non-HLA antibodies and fixing of DSA to the transplanted kidney tissue should be considered for the cause of DSA negativity. Although about the latter one, there is some uncertainly, because a similar percentage of DSA positivity was reported in both kidney allograft and serum samples. There is a weak possibility of fluctuation in DSA level. In one report, the patient was DSA negative at the time of the biopsy but DSA positive 1-2 year prior to the biopsy.
The presence of MVI ≥2 is also considered as current or recent antibody rejection and is associated with graft survival. Independent of DSA, TG in combination with MVI was considered as ABMR.
Conclusion: The presence of DSA is not essential to establish the diagnosis of c-aABMR when other criteria indicative of chronic tissue injury and current/recent antibody interaction with vascular endothelium are met.
Limitations of this study:
It is retrospective study
Data was extracted from only for cause biopsies, not protocol biopsies.
It includes relatively small samples.
Retrospective observational (cohort) study, level 3 of evidence.
1- Please summarise this article
SUMMARY
Chronic-active antibody-mediated rejection (c-aABMR) is defined as histological evidence of chronic endothelial injury (cg), also known as transplant glomerulopathy, and either microvascular inflammation (MVI) or positivity for C4d.
Importantly, the presence of donor-specific antibodies (DSA) is currently still mandatory for the diagnosis of c-aABMR.
This retrospective study of 41 c-aABMR patients investigates whether cases suspicious for c-aABMR (DSA negative, n = 24) differ from cases of c-aABMR (DSA positive, n = 17) with respect to renal histology, allograft function and long-term graft survival.
In all DSApos cases, DSA were de novo and the majority was directed against HLA-II being mostly anti-HLA-DQ antibodies.
Renal histology and clinical outcome of patients suspicious for c-aABMR (DSAneg) do not significantly differ from patients with a diagnosis of c-aABMR (DSApos).
Introduction
Chronic-active antibody-mediated rejection (c-aABMR) is currently defined by the Banff classification by
(i) histologic evidence of chronic tissue injury,
(ii) evidence of current or recent antibody interaction with vascular endothelium and
(iii) serologic evidence of donor-specific antibodies (DSA)
In the clinical setting, however, it is not uncommon for these diagnostic criteria to appear as an incomplete combination. This is largely due to the requirement of DSA positivity as DSA cannot be detected in a substantial number of patients .
Cases in which renal histology show chronic endothe lial activation as evidenced by glomerular basementmembrane duplication, known as transplant glomerulopathy (TG), and C4d-positive staining and/or significan microvascular inflammation (MVI) with no detectable DSA are considered suspicious for c-aABMR .
According to this study ,alternative diagnoses for the histomorphological changes compatible with c-aABMR are
· hepatitis C virus infection,
· Membranoproliferative glomerulonephritis (MPGN)
· (chronic) thrombotic microangiopathy (cTMA) .
In this study there was a 24 patients with the diagnosis of suspicious for c-aABMR (DSAneg) and 17 with c-aABMR (DSApos). The diagnosis was made on average 77 months after transplantation (80 months = DSApos vs. 75 months DSAneg .
The vast majority of the circulating DSA detected were directed against HLA-DQ (78%). Except for one patient who had both HLA-DQ and HLA-A antibodies, all other patients only had one specificity of circulating DSA. All circulating DSA were found to be de novo DSA.
A comparison between the histomorphological char acteristics of the DSApos and DSAneg cases showed no significant differences in the individual Banff lesions score. Neither was there a difference in histo morphology
between DSAneg C4d+ and DSAneg C4d –ve patients.
Both the DSApos and DSAneg cases showed a sub stantial
‘chronic inflammation score’ of 5( 1–8) and 6 (1–9), respectively. Furthermore, there was considerable presence of MVI. The groups showed no significant dif ferences in the ‘chronic inflammation score’ or MVI.
The response to treatment was similar regardless of DSA status.
There was no significant difference in overall graft survival between DSApos and DSAneg cases.
A decrease in graft survival was seen in all cases with high tubular atrophy, interstitial fibrosis and total inflammation.
This study found that, regardless of DSA status, cases with moderate to severe interstitial fibrosis, tubular atrophy and total inflammation showed significantly worse allograft survival.
The absence of detectable DSA should not discard the involvement of an antibody-mediated process . The evolving knowledge regarding DSA in combination with the complexity of HLA antibody assessment should prompt cautious interpretation and diagnostic decisions based on DSA in a chronic-active antibody-mediated rejection process .
Now, in addition to C4d-positive staining, a MVI score =2 is regarded as evidence of current or recent antibody interaction with the vascular endothelium.
One study ,demonstrated a strong association between pathogenesis-based transcript sets related to ABMR and a MVI score ≥2. These changes in the Banff diagnostic criteria gave newfound importance to microvascular inflammation in the diagnosis of ABMR.
Another study, recently provided supporting evidence for the importance of microcirculation lesions, rather than DSA, in the classification of ABMR cases.
The findings of this study, suggest that patients with a biopsy classified as ‘suspicious’ for c-aABMR according to the Banff 2015 classification also represent c-aABMR.
We believe that including these cases in the current study illustrates that C4d and DSA are not necessary in the diagnosis of c-aABMR and subsequent graft outcomewhen cg and MVI are present.
In conclusion, we show that renal histology and clinical outcome of patients with c-aABMR do not significantly differ from patients suspicious for c aABMR. We believe that the data we presented adds to the growing body of evidence that the presence of DSA is not a condition sine qua non to establish the diagnosis of c-aABMR when other criteria indicative of chronic tissue injury and current/recent antibody interaction with vascular endothelium are met.
1- What is the kind of this study?
Retrospective study .
2- What is the level of evidence?
Level three
In this study they use immunohistochemistry for C4d detection but immunofluorescence more accurate .
In this study they use pulse steroid for 3 day but I don’t know if there is evidence base for use of pulse steroid in chronic Ab mediated rejection ??
Please summarise this article:
Introduction
Chronic-active antibody-mediated rejection (c-aABMR) is currently defined by the Banff classification by (i) histologic evidence of chronic tissue injury, (ii) evidence of current or recent antibody interaction with vascular endothelium and (iii) serologic evidence of donor-specific antibodies (DSA).
Patients and methods:
all patients with the histomorphological diagnosis of chronic-active antibody-mediated rejection retrospectively included in study between January 2007 and November 2014 biopsy was performed after a progressive decline in renal allograft function, Patients were divided into two groups based on the presence of detectable DSA in their serum at time of biopsy, C4d was evaluated using immunohistochemical staining of 4 l m slides of formalin fixed paraffin embedded tissue. Immunofluorescent staining was performed with antibodies against IgG, IgM, IgA, C3c, C1q, kappa and lambda.
Results
Baseline characteristics did not differ significantly between the two groups. The diagnosis was made on average 77 months after transplantation (80 months DSA pos vs. 75 months DSA neg, P = 0.76), The vast majority of the circulating DSA detected were directed against HLA-DQ (78%) ,All renal biopsies were re-evaluated and the individual lesions were scored according to the Banff 2015 classification.
A comparison between the histomorphological characteristics of the DSA pos and DSA neg cases showed no significant differences in the individual Banff lesions score . Neither was there a difference in histomorphology between DSA neg C4d+ and DSAneg C4d patients. Both the DSA pos and DSA neg cases showed a substantial ‘chronic inflammation score’ of 5 (1–8) and 6 (1–9), respectively. Furthermore, there was considerable presence of MVI. The groups showed no significant differences in the ‘chronic inflammation score’ or MVI,The average eGFR at baseline, approx. 31 ml/min/1.732 was similar in both patient groups (P = 0.44),The response to treatment was similar regardless of DSA status (change in renal allograft loss: DSA neg: 5.5 ml/min/1.73 m2 /year vs. DSA pos: 5.4 ml/min/1.73 m2 /year (P = 0.93) (Fig. 1).
There was no significant difference ( P = 0.93) in overall graft survival between DSA pos and DSA neg cases (12.2 vs. 13 years, respectively).
Discussion :
The Banff ’15 criteria do not allow for the classifying diagnosis of c-aABMR if there are no DSA present. but the study found that there are no histological or clinical differences between cases with ca ABMR and cases suspicious for c-a ABMR.
The presence of DSA was not associated with a difference in response to therapy or graft survival. The latter finding is in accordance with previous studies that did not show a significant impact of DSA on renal allograft survival in transplant patients with evidence for antibody-mediated rejection either acute or chronic, in this study found that, regardless of DSA status, cases with moderate to severe interstitial fibrosis, tubular atrophy and total inflammation showed significantly worse allograft survival.
Limitations:
This study has some obvious limitations. As it is of retrospective nature, it allows for unknown bias and includes a selection of patients with (suspicious for) ca ABMR related to progressive loss of allograft function. Our data describe a the severity in capillary loop alterations might differ from a population of c-a ABMR patients diagnosed based on a protocol biopsy without clinical observable graft deterioration. This difference may explain why the vast majority of our patients has severe glomerular basement membrane double contours (cg3.
Secondly, it includes a relatively small sample size.
In conclusion: we show that renal histology and clinical outcome of patients with c-a ABMR do not significantly differ from patients suspicious for c-aABMR.
What is the kind of this study?
Retrospective study.
What is the level of evidence?
level 3
Chronic-active antibody-mediated rejection (c-aABMR) is currently defined by the Banff classification by (i) histologic evidence of chronic tissue injury, (ii) evidence of current or recent antibody interaction with vascular endothelium and (iii) serologic evidence of donor-specific antibodies (DSA)
. This retrospective study of 41 c-aABMR patients investigates whether cases suspicious for c-aABMR (DSA negative, n = 24) differ from cases of c-aABMR (DSA positive, n = 17) with respect to renal histology, allograft function and long-term graft survival.
Patients were identified from the pathology database at there centre between January 2007 and November 2014.
Patients were excluded if the biopsy was within the first-year post-transplantation (inaccurate information about renal allograft function) or the requirement of a minimum of 5 eGFR measurements per year was not met.
Patients were divided into two groups based on the presence of detectable DSA in their serum at time of biopsy. Upon diagnosis, all patients, regardless of DSA status (which was unavailable at time of diagnosis), received similar treatment with three doses of 1 g intra- venous methylprednisolone (MP) over a 3-day period combined with a single dose of intravenous immunoglobulins (IVIG) (1 g/kg body weight) on the second day of treatment. None of the patients had plasmapheresis. Renal biopsies were re-evaluated and the individual lesions were scored according to the Banff ’15 classification by two independent pathologists.
All patients were transplanted with a CDC-negative cross-match. To determine the definite diagnosis of each patient, serum samples at the time of biopsy were re- evaluated and tested for the presence of donor-specific antibodies against HLA (DSA). If DSA were found to be present, it was determined whether this concerned de novo DSA. If samples were found to be negative, addi- tional screening was performed by analyzing serum samples for DSA in the 2 years prior to diagnosis.
24 patients were identified with the diagnosis of suspicious for c-aABMR (DSAneg) and 17 with c-aABMR (DSApos).
Seventeen of the 41 patients were tested positive for cir- culating DSA at time of biopsy, these cases are included in the c-aABMR (DSApos) . Majority of DSA was against HLADQ(78%)
. All circulating DSA were found to be de novo DSA. Mean fluorescent intensity (MFI) ranged between 2336 and 25 588 with an average MFI of 13 477.
A comparison between the histomorphological characteristics of the DSApos and DSAneg cases showed no significant differences in the individual Banff lesions score .
There was no significant difference ( P = 0.93) in overall graft survival between DSApos and DSAneg cases (12.2 vs. 13 years, respectively)
The presence of DSA was not associated with a difference in response to therapy or graft survival.
This retrospective study having a small sample size and a definitive bias showed that renal histology and clinical outcome of patients with c-aABMR do not significantly differ from patients suspicious for c-aABMR.
Chronic-active antibody-mediated rejection (c-aABMR) is currently defined by the Banff classification by (i) histologic evidence of chronic tissue injury
(ii) evidence of current or recent antibody interaction with vascular endothelium
(iii) serologic evidence of donor-specific antibodies (DSA). In the clinical setting, however, it is not uncommon for these diagnostic criteria to appear as an incomplete combination. This is largely due to the requirement of DSA positivity as DSA cannot be detected in a substantial number of patients. Cases in which renal histology shows chronic endothelial activation as evidenced by glomerular basement membrane duplication, known as transplant glomerulopathy (TG), and C4d-positive staining and/or significant microvascular inflammation (MVI) with no detectable DSA are considered suspicious for c-aABMR . This diagnosis leaves clinicians uncertain about the accuracy of the diagnosis and treatment options for these DSA-negative cases. Furthermore, those cases classified as suspicious for c-aABMR are frequently excluded from clinical trials, resulting in scarce data about the clinical significance of DSA seropositivity. In this study, we investigated whether allograft outcome and renal histomorphology differed between cases suspicious for c-aABMR (DSAneg) and cases with c-a-ABMR (DSApos).
retrospective study of 41 c-aABMR patients biopsy and scored according to the Banff ’15 criteria.24 of which were suspicious for c-aABMR (DSA negative) and 17 were cases of c-aABMR (DSA positive) with respect to renal histology,
the question of the research was (are DSA really make difference regarding diagnosis and prognosis of graft survival when pathology shows suspicion for c-aABMR??)
study design has multiple positive points :
This study has some obvious limitations
most important points covered in this topic
In conclusion, we show that renal histology and clinical outcome of patients with c-aABMR do not significantly differ from patients suspicious of c-aABMR. We believe that the data we presented adds to the growing body of evidence that the presence of DSA will not be necessary to establish the diagnosis of c-aABMR when other criteria indicative of chronic tissue injury and current/recent antibody interaction with vascular endothelium are met
retrospective observational study level 3
The definition of chronic active antibody-mediated rejection (c-a ABMR) according to Banff classification depends on:
1- Histological evidence of chronic tissue injury
2- Evidence of antibody interaction with vascular endothelium
3- Serologic evidence of DSA
It is unlikely to find all this evidence together in clinical practice because DSA positivity cannot be detected in a large number of patients.
on the other hand; if there is no DSA positivity, the diagnosis of c-a ABMR is considered suspicious. This put clinicians in doubt about the exact diagnosis and the right treatment for these cases. As well, these suspicious cases are largely excluded from clinical trials, leading to fewer data about the relevance DSA seropositivity.
methodology
According to certain criteria, patients enrolled in this retrospective study. Upon diagnosis, all patients regardless of DSA status received the same treatment with three doses of 1 g IV methylprednisolone over 3 day period plus a single dose of IVIG 1 g/kg body weight on the second day of treatment.
Patients were divided into DSA positive group and a negative one and comparatively studied
Results:
Patient characteristics
The baseline characteristics did not differ significantly between the two groups. The is difference of almost 1 g/l more proteinuria in the DSA positive patient but it was not significant. DSA neg group, show no significant differences between those tested positive for C4d and those who tested negative.
Anti-HLA antibody
The study found that most of DSAs Were anti-DQ antibodies 78%. And most were against single HLA class either HLA class I or II except one patient has DSAs to both classes.
All circulating DSA were found to be de novo DSA. MFI range between 2336 and 25588.
Histopathological comparison of DSApos and DSAneg cases
A median of 21 glomeruli (18—32) was available per biopsy for DSApos group of which 13% (5%—20%) were globally sclerotic. For the DSAneg group, a median of 13 (10—21) glomeruli was available of which 8% (2—17%) was globally sclerotic. Although the total number of glomeruli was significantly different (P=0.2) between the groups, the difference was not significant for the percentage of global glomerulosclerosis (P=0.22). GMB show double contour in all graft biopsies. The majority had severe (cg3) capillary loop involvement. All biopsies had a MVI score of more than 2. The biopsies show vast glomerulitis and peritubular capillaritis.
A comparison between the histomorphological characteristics of the DSApos and DSAneg cases showed no significant differences in the individual Banff lesions
score. Neither was there a difference in histomorphology between DSAneg C4d+ and DSAneg C4d patients. The groups showed no significant differences in the ‘chronic inflammation score’ or MVI.
Graft function:
The DSAneg cases showed a slightly larger average decrease in allograft
function before diagnosis compared to the DSApos cases. After diagnosis and treatment with IVIG/MP both groups showed a more loss of allograft function than before diagnosis (p= < 0.001). the response to treatment was similar regardless of DSA status. As well upon a comparison of C4d pos and negative one.
in regard to graft survival, there was no significant difference between DSApos and DSAneg cases. The graft survival decrease with high tubular atrophy, interstitial fibrosis and total inflammation. The correlation between the cg score and graft survival was not possible to be assessed due to a small number of patients 3 out of 41. The presence or absence of C4d did not make a difference in graft survival.
Discussion:
o The study found that there are no histological or clinical differences between cases with caABMR and cases suspicious for c-aABMR.
o All DSA were de novo and the vast majority of them DSA detected were directed against HLA-DQ. Which was in line with other studies.
o DSApostivity was not associated with a difference in response to therapy or graft survival, in concordance with other studies.
o There are GBM double contours, chronic inflammation and microvascular inflammation in both DSApos and DSAneg group.
o The study found that regardless of DSA status moderate to severe interstitial fibrosis, tubular atrophy, and total inflammation showed significantly worse allograft survival.
o The absence of detectable DSA should not discard the involvement of an antibody-mediated process.
o In consideration of increasing information about DSA and the complexity of HLA antibody assessment, the diagnosis of c-a ABMR based on DSA should be decided cautiously. The ability to detect non-HLA antibodies and possible fixing of DSA to the graft should be considered in DSA negative test.
o Testing time of DSA is of significant importance possibly due to the transient nature of detectable DSA. Fluctuation in DSA positivity may lead to false-negative results at a single moment. This is supported by one patient that shows DSA negative at biopsy time but, positive test 1 and 2 years prior to biopsy.
o Clinical manifestation often of late presentation comes after histomorphological changes.
o Newly, MVI score ≥2 is regarded as evidence to antibody interaction with vascular endothelium and it has a strong association with ABMR. MVI adds to C4d positivity staining, leading to changes in Banff diagnostic criteria of ABMR.
o TG lesions in combination with MVI were molecularly confirmed as ABMR cases even when DSA was not detected via current methods according to Halloran et al.
Limitation of the study:
1- Its retrospective nature allows for unknown bias
2- Small sample size
Retrospective . level III evidence
Chronic-active antibody-mediated rejection with or without donor-specific antibodies has similar histomorphology and clinical outcome.
☆☆☆☆☆☆☆☆☆☆☆
▪︎This a retrospective study, investigated whether allograft outcome and renal histomorphology differed between cases suspicious for c-aABMR (DSA negative) and cases with c-a-ABMR (DSA positive).
☆Introduction:
_________________
▪︎Chronic-active antibody-mediated rejection (c-aABMR) is currently defined by the Banff classification by:
1) Histologic evidence of chronic tissue injury
2) Evidence of current or recent antibody interaction with vascular endothelium
3) Serologic evidence of donor-specific antibodies (DSA)
▪︎Suspisious of c-aABMR is diagnosed by:
1) Chronic endothelial activation as evidenced by glomerular basement membrane duplication, known as transplant glomerulopathy (TG)
2) C4d-positive staining and/or
3) Significant microvascular inflammation (MVI) with no detectable DSA
☆Result & Discussion:
_________ _________________
▪︎41 patients were included in this study and all had progressive loss of allograft function and were diagnosed by for cause biopsy and scored according to the Banff ’15 criteria.
▪︎The pts were devided into two groups:
i. Cases suspicious for c-aABMR (DSA negative, n = 24)
ii. Cases of c-aABMR (DSA positive, n = 17)
▪︎In all DSA pos cases, DSA were de novo and the majority was directed against HLA II being mostly anti-HLA-DQ antibodies.
▪︎ There were no statistically significant differences in clinical characteristics, decline in allograft function and renal allograft survival in cases with or without DSAs.
▪︎ All cases showed chronic histomorphological damage and inflammation, irrespective of the presence of DSA.
▪︎ Renal histology and clinical outcome of patients suspicious for c-aABMR (DSAneg) do not significantly differ from patients with a diagnosis of c-aABMR
(DSApos).
▪︎The presence of DSA was not associated with a difference in response to therapy or graft survival.
▪︎ Irrespective of DSA status, there was substantial chronic histomorphological damage as manifested by glomerular basement membrane double contours, chronic inflammation in addition to microvascular inflammation.
▪︎ This study found that :regardless of DSA status, cases with moderate to severe interstitial fibrosis, tubular atrophy and total inflammation showed significantly worse allograft survival.
▪︎ The absence of detectable DSA should not discard the involvement of an antibody-mediated process.
▪︎Both the current (in-)ability to detect non-HLA antibodies and the possible fixing of DSA to the kidney transplant should be taken into consideration when testing negative for DSA.
▪︎ The time of DSA assessment is of significant importance due to the possible transient nature of detectable DSA.
▪︎The fluctuating nature of C4d-positive staining lead to the development of the C4d-negative category of ABMR.
▪︎In addition to C4d-positive staining, a MVI score ≥2 is regarded as evidence of current or recent antibody interaction with the vascular endothelium.
▪︎Microcirculation lesions is important than DSA, in the classification of ABMR cases.
☆ Limitations of the study:
____________________________
▪︎Allowed for unknown bias.
▪︎ It’s data described a patient group that has had a for cause biopsy and not included a patient group with protocol biopsy and the severity in capillary loop alterations might differ in both groups.
▪︎ Small sample size.
▪︎Doesnot include data on non-HLA Abs.
▪︎Used the previous Banff classification (2015), and the use of the most updated version of the Banff classification (2017) would have led to the exclusion of a total of 15 patients as they would not meet the updated criteria for c-aABMR.
☆Interesting points in this study:
______________________
▪︎ Patients with a biopsy classified as ‘suspicious’ for c-aABMR according to the Banff 2015 classification also represent c-aABMR.
▪︎C4d and DSA are not necessary in the diagnosis of c-aABMR and subsequent graft outcome when cg and MVI are present.
☆Conclusion:
_______________
▪︎Renal histology and clinical outcome of patients with c-aABMR do not significantly differ from patients suspicious for c-aABMR.
▪︎The diagnosis of c-a ABMR can be established without the presence of DSA when other criteria indicative of chronic tissue injury and current/recent antibody interaction with vascular endothelium are met.
■ What kind of this study? Retrospective study
■Level of evidence : III
Introduction:
Chronic active ABMR is defined as :
1- Histological evidence of chronic tissue damage in the form of
*Transplant glomeulopathy in the form of GBM duplication
*Microvascular inflammation (glomerulitis and peritubular capillaritis)
*TMA
2- Presence of C4d deposits
3- Presence of DSA
inclusion criteria
patient 1-year post-transplant with gradual progression of kidney function with chronic antibody-mediated rejection
Exclusion criteria
Early in the first year of kidney transplantation
HCV
MPGN
Chronic TMA
Method:
41 patient were included after they were diagnosed to have chronic ABMR.
All included patient received the same regime in form of three doses of 1 gram IV methylprednisolone for 3 days and single dose if IVIG on the second treatment day. None of them received plasmapheresis.
C4d deposition was tested using IHC.
All patients were tested for presence of DSA at time of the biopsy using SAB Luminex.
Patients were divided into DSA negative and DSA positive groups :
In this study we found a 24 of the patient were negative for DSA and the ruminant 17 were DSA positive.
most of DSAs were Denovo and were directed against HLA DQ ( 78%)
Discussion:
No difference in graft survival in cABMR with DSA positive or DSA negative groups
No difference in histopathology in both groups make doubt of role of DSA in cABMR
Limitations :
Retrospective study
a small sample size of patients
Conclusion
No difference on renal allograft outcome and survival in both group diagnosed cABMR and suspected cABMR
no role of DSA or C4d in the diagnosis of cABMR if cg and MVI were present
What is the kind of this study?
Retrospective Cohort Study.
What is the level of evidence?
Level III.
Introduction:
Chronic active ABMR is defined as a gradual endothelial injury associated with chronic glomerulopathy in presence of active microvascular inflammation or positive C4d
and according to Banff, it depends on :
-chronic tissue affection in Biopsy
-evidence of recent antibody affection
– DSA
Patients and methods
inclusion criteria
patient 1-year post-transplant with gradual progression of kidney function with chronic antibody-mediated rejection
Exclusion criteria
patient in the first year of kidney transplantation
HCV
MPGN
Chronic TMA
The patients were divided into groups DSA positive patients and DSA negative patients during allograft biopsy
renal allograft biopsy histology studied
follow up of kidney functions
DSA done 1and 2 years before renal biopsy
Results :
24 patients were DSA negative
17 patients were DSA positive
most of DSA was directed against HLA DQ ( 78%)
all DSA were Denovo
Renal Biopsy :
All renal biopsies had double contour of GBM , capillary loop involvement and MVI score >2
C4d positive in 8 DSA positive patients and in 9 DSA negative patients
with no histopathological difference between DSA positive and DSA negative patients
Renal transplant kidney functions :
Deterioration of kidney functions by 11ml/min/ 1.73 in DSA negative patients and 8.9ml/min decline in DSA positive patients
With no difference of allograft survival in both groups
With more decrease of graft survival with marked interstitial fibrosis and tubular atrophy and marked inflammation.
Discussion:
No difference in graft survival in cABMR with DSA positive or DSA negative groups
No difference in histopathology in both groups make doubt of role of DSA in cABMR
Most of DSA were against HLA DQ
The presence or absence of DSA made no difference on response to medical treatment
NonHLA DSA and fixing of DSA all over Allograft may be considered in DSA negative group ( need to be studied )
fluctuating DSA positivity made false-negative results of DSA to be considered
MVI ≥2 is now considered as evidence of new or current antibody affection of endothelial tissue
Limitations :
Retrospective study
Known patients with suspected cABMR
a small sample size of patients
Conclusion
No difference on renal allograft outcome and survival in both group diagnosed cABMR and suspected cABMR
no role of DSA or C4d in the diagnosis of cABMR if cg and MVI were present
What is the kind of this study?
Retrospective Cohort Study.
What is the level of evidence?
Level III.
. Chronic-active antibody-mediated rejection (c-aABMR) is currently defined by the Banff classification by (i) histologic evidence of chronic tissue injury, (ii) evidence of current or recent antibody interaction with vascular endothelium and
(iii) serologic evidence of donor-specific antibodies (DSA)
-It is a retrospective study between January 2007 and November 2014.
– 17 cases of c-aABMR (DSApos). and 24 cases suspicious for c-aABMR(DSAneg).
-It investigated whether allograft outcome and renal histomorphology differed between cases suspicious for c-aABMR (DSAneg) and cases with c-a-ABMR (DSApos).
-All patients, regardless of DSA status received similar treatment with three doses of 1 g intravenous methylprednisolone (MP) over 3 days combined with a single dose of intravenous immunoglobulins (IVIG) (1 g/kg body weight) on the
second day of treatment. None of the patients had plasmapheresis.
-Change in renal allograft function in time was evaluated by including all estimated glomerular filtration rate (eGFR, MDRD) measurements 1 year before diagnosis and 1 year after diagnosis for both patient groups.
-All patients were transplanted with a CDC-negative cross-match.
-Patient serum samples were screened for the presence or absence of HLA antibodies using the Luminex Screening Assay .
-We found that there are no histological or clinical differences between cases with caABMR and cases suspicious for c-AMR.
-The presence of DSA was not associated with a difference in response to therapy or graft survival.
-Similar clinical characteristics and no differences in the renal allograft histomorphology were observed between the DSApos and DSAneg cases.
-Regardless of DSA status, cases with moderate to severe interstitial
fibrosis, tubular atrophy, and total inflammation showed significantly worse allograft survival.
–Conclusion: renal histology and clinical outcome of patients with c-aABMR do not significantly differ from patients suspicious of c-aABMR .The presence of DSA is not essential to establish the diagnosis of c-aABMR when other criteria indicative of chronic tissue injury and current/recent antibody interaction with vascular endothelium are met.
What is the kind of this study?
A retrospective study
What is the level of evidence?
III
Any role for plasma exchange in patient with chronic Ab mediated rejection ??
Please summarise this article
What is the kind of this study?
What is the level of evidence?
This is a retrospective study; level 3 evidence.
This study included 41 recipients who had evidence of graft dysfunction and were diagnosed as a chronic-active ABMR according to biopsy. Patients who had graft biopsy in the 1st year post transplant were excluded. All recipients’ cross matches pre-transplant were negative by CDC and all of them received methylprednisolone followed by single dose of IVIG.
Results:
-de novo DSA in chronic-active ABMR were mainly directed against HLA class-II mainly DQ.
-presence of DSA against HLA-DQ didn’t affect response to treatment or graft survival.
-No histopathological differences were found between +ve DSA & negative DSA in chronic-active ABMR.
Limitation:
-small sized study.
Conclusion:
-C4d and DSA are not necessary for diagnosis of chronic-active ABMR.
-Outcome of both suspected and chronic active and ABMR is similar.
1- Type of study : retrospective case –control
2- Level of evidence : 3
C AMR is defined by 3 chriteria :
1- Histological evidence of chronic tissue damage in the form of
– GBM duplication ( transplant glomerulopathy)
– Microvascular inflammation (glomerulitit and peritubular capillaritis)
– TMA
2- Presence of C4d deposits in PCT
3- Presence of DSA
In this study the investigators included all patients presented with graft dysfunction except patients transplanted less than 1 year , patients with MCGN , HCV or TMA . The enrolled patients were classified into confirmed cases of CAMR (DSA +) and suspectious CAMB (DSA –ve)
Both groups received the same treatment ( 3 doses of MPN and 1 dose IVIG) and they were followed up and compared regarding graft function and survival , improvement of renal histology . The out come in the three parameters was comparable and no significant difference between the two groups.
Explainnations :
The investigators assumed that the suspecuios CAMR group could had DSA that couldnot be detected due to
– False negative results
– Fluctuating nature of DSA
– Non HLA DSA
Conclusion
Both DSA =ve and – ve CAMR have coparable outcome regarding e GFR , severity or renal histology and graft survival
This is a retrospective case-control study (evidence level is III)
In this article 17 cases of chronic active AMBR (c-aAMBR) cases were compared with 24 c-aAMBR suspicious cases (a total of 31). all patients had biopsies because of deteriorating renal function. all had steroid and IVIG (no plasmapheresis). most cases had resembling histologic features of chronic (active ?) rejection but only 17 cases had proven DSA (so definite; 24 accordingly suspicious) . only one case in the suspicious group had historical DSA detected in the previous year’s serum. because of biopsies being taken after the elevation of renal function tests the findings were near to chronic. the authors advocate the inclusion of suspicious cases not relying on the presence of DSAs in case of suggestive features of chronic active ABMR. limitations are the nature of study being retrospective which in term limits reaching some clinical information. another limitation could be unavailability of non -HLA DSAs
Please summarise this article
It is a single-center study where he questions the mandatory presence of DSA to close the diagnosis of ABMR. Data were collected from January 2007 to November 2014, where the biopsy was performed on those who had worsening renal function, excluding biopsies performed in the first year of transplantation.
All patients were transplanted with CDC-negative-crossmatch. Standard treatment was methylprednisolone with IVIg without plasma exchange.
All circulating DSA were found to be de novo DSA. with an average MFI of 13,477.
A comparison between the histomorphological characteristics of the DSA-positive and DSA-negative cases showed no significant differences in the individual Banff lesions
score. Neither was there a difference in histomorphology between DSA-negative-C4d and DSA-negative C4d patients.
The groups showed no significant differences in the chronic inflammation score or MVI
All patients had a progressive decline in renal allograft function at the time of renal biopsy.
The response to treatment was similar regardless of DSA status.
The presence or absence of C4d did not associate with a difference in graft survival.
Progressive graft dysfunction was similar in two groups with similar poor responses to the PMP and IVIG, in both groups in fact in the DSA-negative group the progression to allograft failure was even faster with an annual reduction in e GFR of 11 ml/min compared to 8ml/min in DSA pos group. Overall graft survival was similar in both groups and even the C4D staining +ve or -ve did not affect the overall prognosis and graft survival. so, the presence of DSA did not affect the response to treatment or impact the graft survival, and these findings similar to what has been reported in many studies.
What is the kind of this study?
Single-center retrospective cohort study
What is the level of evidence?
3
All cases with positive DSA are denovo most of them directed against class II specifically DQ
Chronic-active antibody-mediated rejection (c-a ABMR) also known as transplant glomerulopathy is defined according to Banff 15 by (i) histologic evidence of chronic tissue injury, (ii) evidence of current or recent antibody interaction with vascular endothelium and (iii) serologic evidence of donor-specific antibodies (DSA).
Importantly, the presence of donor-specific antibodies (DSA) is currently still mandatory for the diagnosis of c-a ABMR.
A retrospective study of 41 c-a ABMR patients investigates whether cases suspicious for c-a ABMR (DSA negative, n = 24) differ from cases of c-a ABMR (DSA positive, n = 17) with respect to renal histology, allograft function and long-term graft survival.
Duration of study: between January 2007 and November 2014.
Inclusion criteria: All patients had progressive loss of allograft function and were diagnosed by for cause biopsy and scored according to the Banff ’15 criteria.
Exclusion criteria: 1. if the biopsy was within the first-year post-transplantation (inaccurate information about renal allograft function).
2. the requirement of a minimum of 5 eGFR measurements per year was not met. Patients were divided into two groups based on the presence of detectable DSA in their serum at time of biopsy.
Patients were divided into two groups (DSA positive) and (DSA negative) at time of biopsy.
Upon diagnosis, all patients received similar treatment with three doses of 1 g intravenous methylprednisolone (MP) over a 3-day period combined with a single dose of intravenous immunoglobulins (IVIG) (1 g/kg body weight) on the second day of treatment. None of the patients had plasmapheresis.
Renal biopsies were re-evaluated the individual lesions were scored according to the Banff ’15
In this study four parameters looked for to make the comparison
1.Histological changes after the treatment (Several individual Banff lesions were combined to assess microvascular inflammation and chronicity of the renal parenchyma and vessels.
All renal transplant biopsies (n = 41) had glomerular basement membrane double contours. The majority of patients in both and DSA neg cases had severe (cg3) capillary loop involvement. The DSA pos and DSA neg cases showed vast glomerulitis (g3; 86% vs. 95%) in combination with moderate to severe peritubular capillaritis (ptc2-3; 93% vs. 86%).
2.Decline in the graft function (estimated glomerular filtration rate 1 year prior to diagnosis and 1 year after diagnosis for both patient groups at regular intervals was required to give a reliable estimate over time of the decrease in renal allograft function. The average eGFR at baseline, approx. 31 ml/min/1.732, was similar in both patient groups (P = 0.44).
4. Presence or absence of DSA (All patients were transplanted with a CDC-negative cross-match. To determine the definite diagnosis of each patient, serum samples at the time of biopsy were reevaluated and tested for the presence of donor-specific antibodies against HLA (DSA).
Conclusion: The contribution of donor-specific antibodies to the diagnosis of c-a ABMR has become an important topic of discussion . The Banff ’15 criteria do not allow for the classifying diagnosis of c-a ABMR if there are no DSA present. Instead, these cases are diagnosed as suspicious for c-a ABMR. Therefore, the significance of DSA and their contribution to the loss of allograft function and relation to renal histomorphology have not yet been fully explored. We found that there are no histological or clinical differences between cases with c- a ABMR and cases suspicious for c-a ABMR.
Retrospective cohort study
Level III
Introduction
Chronic active antibody mediated rejection (CaABMR ) criteria for the definition or classification is not yet complete . according to the histological Banff diagnostic criteria CaABMR refer to the state of chronic tissue injury with microvascular inflammation which indicate the antibody mediated endothelial damage in the presence of circulatory DSA , although its not always the case ,as not all patients have positive DSA and still have the classical histological changes with transplant glomerulopathy and double counter microvascular inflammation such cases they categorized as suspicious for Ca ABMR so this leave us with uncertainty about the diagnosis and the affect the clinical decision about the treatment options , in addition such cases with DSA negative suspected Ca ABMR were excluded from many trails.
Aim of the study:
To assess renal histology and clinical allograft outcome in suspected DSA negative Ca ABMR and compared with the DSA positive Ca ABMR .
Methods and materials
Retrospective study included all patients with the histological diagnosis of chronic active ABMR upon indicated biopsy when progressive graft deterioration , study period from 2007-2014 from single center in Netherlands , the exclude patients with graft biopsy done with in first year or those with less than 5 eGFR reading per year, they divided the patients in two groups depend on presence of DSA at time of biopsy , all patients received same antirejection therapy including PMP 1gm for 3 days followed by IVIG 1gm/kg without plasmapheresis , graft biopsies where reevaluated and reported according to the Banff diagnostic score 2015, by two independent pathologists,they excluded cases with similar pathological morphology like chronic TM A, ,HCV infection related MPGN by doing IF in addition to other clinical features , C4D testing by using IHC staining in paraffin block plus IF test was done for antibodies against IgG,IgM,IgA,C3c,c1q , kappa and lambda .
combined glomerulitis and PTC was referred to the calculated MVI score of ≥ 2 which considered diagnostic criteria of moderate to severe Type of Ca-AMBR, chronic inflammation score referred to the (tubular atrophy ct, + interstitial fibrosis ci+ total inflammation ti) (24).
For assessment of graft function, they used the eGFR BY MDRD with minimum of 5 readings per year over fu period, transplant failure considered when any patient back to dialysis or re-transplanted.
All patients included in this study have CDCXM negative and DSA screen done by using Luminex SAB for class1, class11 DSA with FU DSA screening after two years from the diagnosis.
Patients follow up minimum of 1 year and till graft failure.
Banff classification they divided in two groups; Banff score range from 0-1 indicated mild inflammation while 2-3 score indicate moderate to severe inflammation with exemption for V lesion and C4D staining + or -ve .
Results:
In this study total numbers was 41 and they found 24 cases with the diagnosis of suspected Ca-ABMR , DSA neg , and another 17 with confirmed Ca ABMR , DSA-pos, with the average time of the diagnosis of 80 months for suspected Ca ABMR and 75 months for the Ca-ABMR , DSA-pos , all patients demographic s and clinical characteristic are similar between the two groups except more proteinuria in DSA-pos Ca ABMR , denovo DSA positive with predominate of anti-HLA class11 DQ ( 78%).
Histopathological comparison of DSA-pos and DSA-neg case:
Both groups have similar chronicity index in term of cg score and MVI Score (g, PTC) was in the range of 5-6 in both DSA-pos and DSA neg groups
Both had similar Chronic inflammation score ( Ci,ct ti) also in the range for 5-6
Discussion:
Progressive graft dysfunction was similar in two groups with similar poor response to the PMP and IVIG, in both groups in fact in the DSA neg group the progression to allograft failure even faster with annul reduction in e GFR of 11 ml/min compared to 8ml/min in DSA pos group. Over all graft survival was similar in both groups and even the C4D staining +ve or -ve did not affect the overall prognosis and graft survival. so, presence of DSA did not affect the response to treatment or impact the graft survival and these finding similar to what have been reported in many studies (14.15,18.24).
To conclude from this limited study that C4d and DSA are not necessary in the diagnosis of c-a-ABMR due to the fluctuation nature of the CD4 staining and the current limitation of the use of DSA as part of the diagnostic criteria of Ca ABMR due to the in ability to detect non-HLA DSA and the possible fixing of DSA with its transient nature of DSA expression in kidney tissues can give false negative DSA or variation in DSA positivity , currently the updated Banff 17 score including the microcirculation injury score ( MVI) for the classification of ABMR regardless to the DSA status .
Limitation of this study:
1- retrospective design
2- small sample size with risk of many bias
3- DSA monitoring very infrequent with long interval no data about non -HLA DSA
4-15 Cases left undiagnosed with C4D -VE, DSA -ve
5-Follow up period not clearly identified 12- till the time of graft failure ( median ??)
What is the kind of this study?
Retrospective from single center and small sample size
What is the level of evidence?
level of evidence 111
Well done
II. Chronic-active antibody-mediated rejection with or without donor-specific antibodies has similar histomorphology and clinical outcome – a retrospective study
# Please summarise this article
# Introduction
The Banff classification (2015) of Chronic active antibody mediated rejection (c-aABMR) is by:
(i) Histologic evidence of chronic tissue injury
(ii) Evidence of current or recent antibody interaction with vascular endothelium
(iii) Serologic evidence of donor-specific antibodies (DSA)
# In the clinical setting the diagnosis and treatment options for these DSA negative cases remain uncertain about the accuracy
inaddition to that, those cases classified as suspicious for c-aABMR are frequently excluded from clinical trials.
# The aim of this study to investigated allograft outcome and renal histomorphology differed between
cases suspicious for c-aABMR (DSAneg) and cases with c-a-ABMR (DSApos).
#Patients and methods
* This retrospectively study included all patients with the histomorphological diagnosis of chronic active antibody mediated rejection from biopsy after a progressive decline in renal allograft function between January 2007 and November 2014.
*Patients were divided into two groups according to detectable DSA in their serum at time of biopsy, all patients Received three doses of 1 g intravenous methylprednisolone (MP) for 3days and single dose of (IVIG) (1 g/kg body weight) on the second day of treatment without plasmapheresis, renal biopsies were re-evaluated.
*Alternative diagnoses for the histomorphological changes compatible
with c-aABMR such as HCV, MPGN or cTMA were excluded.
*The microvascular inflammation (MVI) score was calculated by combining the glomerulitis and peritubular capillaritis score. AMVI score ≥2 was considered moderate to severe and a diagnostic criterion for c-aABMR.
*The chronic inflammation score was calculated as (interstitial fibrosis
(ci) + tubular atrophy (ct) + total inflammation (ti).
*Change in renal allograft function was estimated 1 year before and 1 year after diagnosis.
*Serum samples at the time of biopsy were tested for the presence of DSA using the Luminex Screening Assay.
If DSA present, it was concerned denovo DSA, If samples were negative additional screening in the 2 years prior to diagnosis.
#Results
* All circulating DSA were found to be de novo DSA. with an average MFI of 13 477.
*A comparison between the histomorphological characteristics
of the DSApos and DSAneg cases showed no significant differences in the individual Banff lesions
score . Neither was there a difference in histomorphology
between DSAneg C4d+ and DSAneg C4dpatients.
* The groups showed no significant differences in the chronic inflammation score or MVI
*All patients had a progressive decline in renal allograft function at the time of renal biopsy.
*The response to treatment was similar regardless of DSA status.
*The presence or absence of C4d did not associate witha difference in graft survival .
# Discussion
* The Banff ’15 criteria do not allow for the classifying diagnosis of c-aABMR if there are no DSA present diagnosed as suspicious for c-aABMR.
*The study found that there are no histological or clinical differences between caABMR and suspicious for c-aABMR.
* In the c-aABMR all DSA were de novo and directed mainly against HLA-DQ .
*The presence of DSA was not associated with a difference in response to therapy or graft survival.
*Regardless of DSA status, cases with moderate to severe interstitial
fibrosis, tubular atrophy and total inflammation showed
significantly worse allograft survival.
*The absence of DSA not exclude antibody mediated process because fluctuation in DSA positivity, DSA testing might lead to a false-negative result when tested at a single moment in time.
*For the current study the have chosen to use the previous Banff classification (2015), as this classificationallows for the use of the Banff category 2 suspicious for’ c-aABMR. The use of the most updated version of the Banff classification (2017) would have led to the exclusion of a total of 15 patients as they would not meet the updated criteria for c-aABMR
# In conclusion:
*There is no renal histology and clinical outcome differences between patients with c-aABMR and patients suspicious for c-aABMR.
* The presence of DSA is not necessary to diagnosis c-aABMD when other criteria indicative of chronic tissue injury and current antibody interaction with vascular endothelium established
# What is the kind of this study?
This study is a retrospective cohort study
#What is the level of evidence?
Level of evidence 3
Well done
Chronic-active antibody-mediated rejection (c-aABMR) is defined as histological evidence of chronic endothelial injury (cg), which defined histologically as transplant glomerulopathy, and either microvascular inflammation (MVI) or positivity for C4d. Importantly, the presence of donor-specific antibodies (DSA) is currently still mandatory for the diagnosis of c-aABMR.
This is the This retrospective study of level III recruits of 41 c-aABMR patients studied the difference between DSA negative c-aABMR (DSA negative, n = 24) and DSA positive c-aABMR (DSA positive, n = 17) in regards of renal histology, allograft function and long-term graft survival.
In all DSA positive cases, DSA were de novo and the majority was directed against HLA-II ,mostly anti-HLA-DQ antibodies.
Study design:
-Inclusion criteria: all patients with the histopathological diagnosis of chronic-active antibody-mediated rejection with indicated graft biopsy after a progressive decline in renal allograft function using Banff classification (2015).
-Exclusion criteria: Patients were excluded if the biopsy was within the first-year post-transplantation or there is no available minimum of 5 eGFR measurements per year. Alternative diagnoses with histopathological changes compatible with c-aABMR such as hepatitis C virus infection, membranoproliferative glomerulonephritis (MPGN) or (chronic) thrombotic microangiopathy (cTMA) were excluded
-Patients were divided into two groups: group 1 with positive DSA and group 2 with negative DSA in their serum at time of biopsy.
-All patients received similar treatment with three doses of 1 g intravenous methylprednisolone combined with a single dose of intravenous immunoglobulins (IVIG) (1 g/kg body weight) on the second day of treatment. Patients did not receive plasmapheresis.
Result: There were no statistically significant differences in clinical characteristics, decline in allograft function and renal allograft survival in cases with or without DSAs.
Well done
Chronic-active antibody-mediated rejection is defined as histological evidence of chronic endothelial injury , also known as transplant glomerulopathy, and either microvascular inflammation or positive C4d in biopsy.
Still DSA is mandatory for the diagnosis of c-aABMR.
41patients with c-aABMR had biopsy and level of DSA
c-aABMR (DSA negative, n = 24) , (DSA positive, n = 17). All included patients had progressive loss of allograft function and were diagnosed based on biopsy and scored according to the Banff ’15 criteria. In all cases DSA were de novo most of them were directed against HLA-II mainly anti-HLA-DQ antibodies with a mean MFI of 13477,. There were no differences in renal allograft outcome in patients with or without DSAs. All cases revealed chronic histological damage and inflammation, independent of the presence of circulating DSA.
What is the kind of this study?
Cohort retrospective study
What is the level of evidence?
Level 3
Well done
Using a retrospective investigation, we discovered that chronically active antibody-mediated rejection with or without donor-specific antibodies had identical histomorphology and clinical prognosis.
Antibody-mediated rejection (c-aABMR) is characterized by the Banff classification as I histologic evidence of chronic tissue harm, (ii) evidence of current or recent antibody interaction with vascular endothelium, and (iii) evidence of donor-specific antibodies in the bloodstream (DSA). Nevertheless, in the clinical world, it is not unusual for these diagnostic criteria to be used in an insufficiently comprehensive manner. A significant portion of this is related to the necessity of DSA positive, which cannot be diagnosed in a significant proportion of patients. Clinical suspicion for c-aABMR is raised in cases where renal histology reveals chronic endothelial activation as evidenced by the presence of transplant glomerulopathy (TG), as well as C4d-positive staining and/or significant microvascular inflammation (MVI) with no detectable DSA, which is known as chronic endothelial activation.
This retrospective investigation, which took place between January 2007 and November 2014, covered all patients with a histological diagnosis of c-aABMR, with the exception of those who were in their first year after transplantation and those who had poor follow-up (less than 5 eGFR measurements per year). A kidney biopsy was performed, and DSA levels were measured.
Patients were separated into two groups based on the presence or absence of DSA c-aABMR (DSApos) or c-aABMR (DSAneg) in their blood samples. MVI, which was derived by combining the glomerulitis and peritubular capillaritis scores, was a diagnostic criterion for c-aABMR. A score of 2 indicated microvascular inflammation. It was possible to determine the Chronic Inflammation Score by combining interstitial fibrosis, tubular atrophy, and the overall inflammation score together.
Patients were treated with intravenous immunoglobulin and injectable methylprednisolone. Patients were monitored for a minimum of one year or until graft failure was observed (return to dialysis or re-transplant).
The study comprised a total of 41 patients, 24 of who had c-aABMR (DSAneg) and 17 of whom had c-aABMR (DSApos). The diagnosis was established around six and a half years after the transplantation procedure was completed.
Proteinuria was found to be more prevalent in the DSA positive group. All of the DSA were de novo, with a mean MFI of 13477, and the vast majority of them were anti-HLA-DQ antibodies (see table). One patient had a history of DSA, although at the time of the biopsy, there was no DSA present in the patient.
The role played by donor-specific antibodies in the diagnosis of c-aABMR has risen to the top of the list of hot topics in medical research. If there is no DSA present, the Banff ’15 criteria do not permit the classification of c-aABMR as a classifying diagnostic. Instead, these instances are classified as “suspicious for c-aABMR” by the medical community. So yet, nothing is known about the relevance of DSA and their contribution to the loss of allograft function, much alone their relationship to renal histomorphology. Instances with caABMR and cases suspected of having c-aABMR were found to have no histological or clinical changes, according to our findings.
A retrospective cohort analysis was conducted.
What is the quality of the evidence?
The level of evidence is at the third level.
Well done
Retrospective study to investigate whether allograft outcome and renal histomorphology differed between cases of DSA positive chronic ABMR & DSA negative chronic ABMR.
Study population:
All patients with a histomorphological diagnosis of chronic active ABMR between Jan 2007 and Nov 2014 are involved.
Exclusion criteria:
The patients are grouped into 2 groups according to their DSA status at the time of biopsy. All of the patients received similar treatment: 3 doses of MP (1 gm ), with single dose of IVIG ( 1 g/kg) on the second day of treatment, no PE was done. Renal biopsies were reevaluated and scored according to Banff 2015 by 2 independent pathologists.
C4d was evaluated using IHC. IF staining for IgG, IgA, IgM, C3, C1q, kappa and lambda.
Renal function was evaluated using eGFR, MDRD measurement 1 year prior to the diagnosis and 1 year after the diagnosis.
Luminex screening was used to detect the presence of anti-HLA antibodies, further analysis was done by SAB-Luminex testing.
Results:
Number of DSA positive patients 17/41
Number of DSA negative patients 24/41
Most of the detected DSA was against HLA-DQ,( All are de novo), with an average MFI of 13477.
All renal Tx biopsies had double contours of GBM.
The majority had severe capillary loop involvement.
For DSA positive patients, 8 patients had positive C4d staining, and 9 of the DSA patients were C4d positive.
Of the total no of patients, 4 had tubulitis.
A comparison between histomorphological characteristics of the 2 groups showed no significant differences in the individual Banff lesions, nor between C4d positive and C4d negative groups. The groups showed no significant differences in the chronic inflammation score of MVI.
All patients had a progressive decline in renal allograft function at the time of renal biopsy. After treatment, there was more loss of graft function for both groups. No significant difference in graft survival between the 2 groups was found and decreased graft survival was seen in all cases with high IFTA and total inflammation.
Conclusion:
Renal histology and clinical outcomes of DSA negative c-aABMR do not significantly differ from DSA positive c-aABMR, so this study adds to the debate regarding the need for DSA presence to diagnose c-aABMR.
Retrospective study
Level III
Well done
SUMMARY:
STUDY OBJECTIVE:
To study differences the Histomorphology & Clinical Outcomes in patients with Chronic Active ABMR who had DSAs and in those who lacked DSAs
STUDY METHODS:
1. Retrospective Study from Jan 2007 to Nov 2014 and included 41 patients
2. Exclusion Criteria: Those who underwent Graft Biopsy with in an year of Transplant / In those minimum 5 eGFR measurements were not available
3. Divided into Two groups basing on DSA negativity (n=24) Vs Positivity (n=17)
4. Intervention was same in both the groups: three doses of 1 gm IV Methyl Predinolone followed by a single dose of IV Ig on Day 2 of Treatment (1 gm/Kg). None received Plasmapheresis
5. Graft Biopsy Scoring: Banff 2015 classification by Two independent Pathologists
6. C4d Detection Method: IHC on Paraffin Embedded Sections
7. eGFR measurements (MDRD) one year prior to Diagnosis and One year after Diagnosis ( A Minimum of Five Measurements)
8. DSA Measurements: Screened by Luminex Screening Assay. If found positive, further analysed with the aid of Luminex Single Antigen Assay. DSA screening was done at the time of Renal Biopsy. If negative, then historical samples in the prior two years were analysed.
RESULTS:
1. In those who had DSA positivity, DSA were of denovo in nature and were of Class II in nature. Vast majority of them were directed against HLA DQ . The mean MFI ranged between 2336 and 25588.
2. The Histomorphological characteristics of the DSApos and DSAneg cases demonstrated no significant differences in the individual Banff lesions score
3. The response to treatment was same regardless of DSA status (change in renal allograft loss: DSAneg: 5.5 ml/min/1.73 m2/year vs. DSApos: 5.4 ml/min/1.73 m2/year (P = 0.93)
4. There was no significant difference (log rank; P = 0.93) in overall graft survival between DSApos and DSAneg cases (12.2 vs. 13 years, respectively)
LIMITATIONS OF THE STUDY:
1. Retrospective study and hence allows for the creeping of unknown Bias
2. Small Sample Size
CONCLUSION:
There were no statistically significant differences in clinical characteristics, decline in allograft function and renal allograft survival in cases with or without DSAs. All cases showed chronic histomorphological damage and inflammation, irrespective of the presence of DSA.
KIND OF THE STUDY:
Retrospective Study ( Case control Study / Non Experimental Observational Studies)
LEVEL OF EVIDENCE:
Level-3
Well done
• Please summarise this article
Chronic-active antibody-mediated rejection (c-aABMR) is defined by combination of ;
1-histological evidence of chronic endothelial injury (cg), transplant glomerulopathy,
2- either microvascular inflammation (MVI) or positivity for C4d.
3- presence of DSA which still mandatory for the diagnosis of c-aABMR.
It was found that in Some cases biopsy showed chronic endothelial activation as evidenced by glomerular basement membrane duplication, and C4d-positive staining and/or MVI but
DSA can’t be detected and the diagnostic criteria become incomplete .
Cases in which no detectable DSA are considered suspicious for c-aABMR.
* Patients and methods
This is a retrospective study of 41 c-aABMR patients investigates whether cases suspicious for c-aABMR with neg DSA differ from cases of c-aABMR with pos DSA with respect to renal histology, allograft function and long-term graft survival.
Patients were divided into 2 groups
-DSA negative, n = 24.
-DSA positive, n = 17.
-All patients were transplanted with a CDC-negative cross-match.
-All included patients had progressive loss of allograft function, Patients were excluded if the biopsy was within the first-year post-transplantation.
-DSA level was done at time of biposy and patients were divided to 2 groups accordingly.
-All patients received the same ttt methyleprednisolone with IVIG no plasmapheresis.
-24 patients with the diagnosis of suspicious for c-aABMR (DSAneg) and 17 with c-aABMR (DSApos) most of them had DSA against HLA-DQ (78%) .
-All circulating DSA were found to be de novo DSA.
-All renal transplant biopsies had glomerular basement membrane double contours,and MVI score of more than 2.
-all biopsies had a MVI score of more than 2.
-all cases showed vast glomerulitis (g3; 86% vs. 95%) in combination with moderate to severe peritubular capillaritis (ptc2-3; 93% vs. 86%).
-8 patients had C4d+ staining in the DSA pos patients , only 9 of 24 DSA neg patients were positive for C4d staining .
Conclusion
They found that there are no histological or clinical differences between cases with c-aABMR and cases suspicious for c-aABMR and the presence or absence of DSA was not associated with a difference in response to therapy or graft survival.
Limitations of the study
-Small number of patients .
– It’s a retrospective study , with unknown bias
-all includesd patients with had progressive loss of allograft function.
What is the kind of this study?
retrospective study , level of evidence III
Well done
The contribution of DSA to the diagnosis of chronic active antibody mediated rejection (c-a-ABMR) is controversial.
c-a-ABMR is defined according to Banff’15 classification by
Patients with transplant glomerulopathy (chronic endothelial activation with glomerular basement membrane duplication), C4d positive staining and/or microvascular inflammation without DSA detection are categorized as suspicious for c-a-ABMR.
Treatment options for DSA negative cases and accuracy of diagnosis is not well determined.
Also the clinical significance of DSA and their effect on graft outcome is not well studied.
This study aimed to investigate the differences between cases suspicious for c-a-ABMR and cases with c-a-ABMR regarding renal histology, allograft function and long term graft survival.
It is a retrospective study, included 41 cases with histological diagnosis of c-a-ABMR with progressive decline in graft function.
Patients were divided according to presence or absence of DSA at time of biopsy
All patients received the same treatment and serum samples with HLA class I or II antibodies were analyzed.
The study showed no histological or clinical differences between the two groups.
In DSA positive group, DSA were de novo in most patients and mostly were against HLA-DQ
Presence of DSA had no significant impact on response to therapy or graft survival.
They suggested that C4d and DSA are not necessary for diagnosis of c-a-ABMR.
DSA testing may be false negative due to the possible transient nature of detectable DSA
Regardless of the DSA status, moderate to severe interstitial fibrosis , tubular atrophy and total inflammation are significantly associated with worse graft survival.
Conclusion:
DSA is not mandatory for the diagnosis of c-a-ABMR when criteria of chronic tissue injury and antibody interaction with vascular endothelium are present.
Limitations:
Retrospective study with small sample size.
Non-HLA antibodies were not tested
Didn’t include c-a-ABMR detected in protocol biopsy (all patients were with deteriorating graft function and performed for cause biopsy)
Type of study: Retrospective
Level of evidence: 3
Thank You
SUMMARY OFChronic-active antibody-mediated rejection with or without donor-specific antibodies has similar histomorphology and clinical outcome .Chronic-active antibody mediated rejection ,critria of diagnosis by Banff(2015) classification:
1-histological evidence of chronic tissue injury
2-Evidence of recent antibody interaction with vascular endothelium
3-serological evidence of DSA
The study is design to evaluate renal histomorphology and allograft outcome different between case suspicious for c-a ABMR (DSA neg) and cases with c-a ABMR (DSA pos)
Patients and methods:
The study was carried between Jan 2007-and Nov 2014 include all patients of chronic active antibody mediated rejection is progressive decline of renal allograft function
Patient excluded from study :
All patients receive 1g methyl prednisone single dose of IV IG
Banff15 classification used to reevaluate renal biopsy
All alternative diagnosis was excluded by IF
Use of IHC staining to detect c4d deposition
Micro vascular inflammation (MVI) score 2 or more considered moderate to severe for c-a ABMR
Score of chronic inflammation calculated as (interstitium ci+tubular atrophy ct+tubular inflammation)
Renal allograft function evaluate at least 5 measurements per year by eGFR(MDRD)
All patients with CDC -ve cross matching at the time of transplant and all patients screen for HLA Ab using lemunix screening assay
Result:
The study showed that there is no significant different in both DSA po and DSA neg cases in the following:
Discussion:
A cording to Banff15 criteria, presence of DSAs is crucial in diagnosis c-a ABMR although their contribution to graft function and renal histomorphology have not yet been fully explore so this study found there was no difference clinically and histologically between cases aABMR and cases suspicious for c-aABMR
The finding of this study as the same as previous publication that DSA+ve in TG cases with de novo anti HLA-DQ Abs is 20-80%
The absence of DSA showed not discard the involve of antibody mediated process
DSA testing can lead to false -ve result when tested at single moment in time which is already avoided in this study
Limitation of this study as it is retrospective, it allow for unknown bias include selection of patients with suspicious for cABMR related to progressive loss of graft function but this bias not related to presence od DSA as this information was unavialable for both clinician and pathologist at time of diagnosis
Conclusion:
The outcome of patients with c-a ABMR histological and clinical outcome not significant different
The presence of DSA is not necessary to establish diagnosis of c-aABMR when other criteria of chronic tissue injury and recent antibody interaction with vascular endothelium are met
2) Retrospective study
3) level 3
Thank You
Chronic-active antibody-mediated rejection with or without donor-specific antibodies has similar histomorphology and clinical outcome – a retrospective study:
c-aABMR) is defined:
A chronic endothelial injury (cg), also known as transplant
glomerulopathy.
Either microvascular inflammation (MVI)
Or positivity for C4d.
The presence of DSA is currently still mandatory for the diagnosis of
c-aABMR.
This retrospective study of 41 c-aABMR patients investigates
whether cases suspicious for c-aABMR (DSA negative, n = 24) differ
from cases of c-aABMR (DSA positive, n = 17) with respect to renal
histology, allograft function and long-term graft survival.
Study population:
All patients with the histomorphological diagnosis of chronic-active
antibody-mediated rejection upon for cause biopsy which was
performed after a progressive decline in renal allograft function.
Study time:
Between January 2007 and November 2014.
Patients were divided into two groups based on the presence of
detectable DSA in their serum at time of biopsy.
DSA negative, n = 24) differ from cases of c-aABMR (DSA positive, n
= 17).
Methods:
C4d was evaluated using immunohistochemically.
Several individual Banff lesions were combined to
Assess microvascular inflammation and chronicity of the
Renal parenchyma and vessels.
Renal allograft function:
Change in renal allograft function in time was evaluated
By including all estimated glomerular filtration rate
(eGFR, MDRD) measurements 1 year prior to diagnosis
And 1 year after diagnosis for both patient groups.
A minimum of five measurements per year at regular
Intervals was required to give a reliable estimate over
Time of the decrease in renal allograft function.
Characterization of anti-HLA antibodies:
Patient serum samples were screened for the presence
Or absence of HLA antibodies using the Luminex Screening Assay.
Statistical analysis:
Characteristics between the DSApos and DSAneg
Groups unpaired t test for continuous variables, Mann–Whitney U test
for ordinal variables and chi-square or Fisher exact test for
categorical variables.
Allograft survival was assessed using censored Kaplan–Meiercurves
and log rank test.
Patient follow-up was a mini-mum of 12 months or until allograft
failure.
Results:
The diagnosis was made on average 77 months after transplantation
(80 monthsDSApos vs. 75 months DSAneg, P = 0.76).
There was, a noteworthy difference of almost 1 g/l more proteinuria in
the DSApos patients, although this was not statistically significant (P
= 0.15).
Of interest, no significant differences were found between DSAneg
C4d+ andDSAneg C4d patients.
Anti-HLA antibodies:
Vast majority of circulating DSA detected were directed against HLA-
DQ (78%).
All circulating DSA were found to be de novo DSA.
Histopathological comparison of DSApos and DSAneg cases:
All renal biopsies were re-evaluated and the individual lesions were
scored according to the Banff 2015 classification.
A comparison between the histomorphological characteristics of the
DSApos and DSAneg cases showed no significant differences in the
individual Banff lesions score. Neither was there a difference in
histo-morphology between DSAneg C4d+ and DSAneg C4dpatients.
Both the DSApos and DSAneg cases showed a substantial ‘chronic
inflammation score’ of respectively.
The groups showed no significant differences in the ‘chronic
inflammation score’ or MVI.
Renal allograft function:
All patients had a progressive decline in renal allograft function at the
time of renal biopsy.
Was no significant difference (log rank = 0.93) in overall graft survival
between DSApos and DSAneg cases (12.2 vs. 13 years,
respectively).
Discussion:
There are no histological or clinical differences between cases with
caABMR and cases suspicious for c-aABMR.
In this study, we report of 17 cases of c-aABMR and 24 cases
suspicious for c-aABMR.
In the c-aABMR group.
All DSA were de novo and the vast majority of the circulating DSA
detected were directed against HLA-DQ (78 %).
This in lined with previous publications showing a range of 20–80%
DSA positivity in TG cases with de novo anti-HLA-DQ antibodies
most frequently found.
DSA was not associated with a difference in response to therapy or
graft survival. The latter finding is in accordance with previous
studies that did not show a significant impact of DSA on renal
allograft survival in transplant patients with evidence for antibody-
mediated rejection either acute or chronic.
IrrespectiveofDSAstatus,therewassubstantialchronichistomorphologic
al damage as manifested by GBM double contours, chronic
inflammation in addition to microvascular inflammation.
Found that, regardless of DSA status, cases with moderate to severe
interstitial fibrosis, tubular atrophy and total inflammation showed
significantly worse allograft survival.
limitations:
As it is of retrospective nature, it allows for unknown bias.
Secondly, it includes a relatively small sample size.
Retrospective study.
Level of evidence 111.
Thanks
II. Chronic-active antibody-mediated rejection with or without donor-specific antibodies has similar histomorphology and clinical outcome – a retrospective study
Please summarise this article
The c-aABMR is defined by Banff as:
(i) Histological evidence of chronic endothelial injury (cg), also known as TG. & either
(ii) MVI or
(iii) Positivity for C4d. &
(iv) Serologic evidence DSA
The aim of this study was to know whether cases suspicious for c-aABMR (DSA-ve, n = 24) differ from cases of c-aABMR (DSA+ve, n = 17) regarding:
– renal histology
– allograft function
– long-term graft survival
A total of 41 patients, who fulfilled the histological criteria on biopsy done following progressive graft dysfunction, were divided into 2 groups according to the presence or absence of DSA at the time of biopsy.
All patients, regardless of DSA status, were given same treatment: 3 doses of 1 g MP/day for 3 days plus 1 dose of IVIG (1 g/kg bw) on the 2nd day of treatment. PP was not used.
Renal biopsies were re-evaluated & the lesions were scored according to the Banff ’15 by 2 independent pathologists.
Alternative diagnoses for the biopsy changes compatible
with c-aABMR such as HCV infection, MPGN or chronic TMA were excluded, by IF & clinical analysis.
C4d was evaluated using IHC. IF staining done with anti-bodies against IgG, IgM, IgA, C3c, C1q, kappa & lambda
MVI score was calculated by combining glomerulitis & peritubular capillaritis score. MVI score ≥2 considered moderate to severe & diagnostic for c-aABMR.
Chronic inflammation score was calculated as (interstitial fibrosis (ci) + tubular atrophy (ct) + total inflammation (ti) (Patri et al.).
Change in allograft function was evaluated by including all eGFR (MDRD) measurements 1 year prior & after diagnosis.
Return to dialysis or re-transplantation was considered allograft failure.
Characterization of anti-HLA antibodies
CDC-XM was negative in all patients at time of transplantation.
DSA was retested at the time of biopsy patients.
If DSA were present, it was determined whether this is de novo DSA. If DSA was negative, serum samples for DSA in the 2 years prior to diagnosis were analysed.
Samples that were considered positive for either HLA class I or II antibodies were further analyzed with
a Luminex.
Results
24 patients were diagnosed as suspicious for c-aABMR (DSA-ve) & 17 with c-aABMR (DSA+ve).
No significant differences in baseline characteristics between the 2 groups. No difference in the average time of diagnosis after transplantation.
There was, a difference of almost 1 g/l more proteinuria
in the DSA+ve patients (statistically insignificant, 0.15).
No significant between DSA-ve C4d+ & DSA-ve C4d-patients.
Anti-HLA antibodies:
17 of the 41 patients were +ve for DSA at time of biopsy, these cases are included in the c-aABMR (DSA+ve) group.
DSA detected were were mainly against HLA-DQ (78%)
One patient had both HLA-DQ & HLA-A antibodies.
All others only had 1 specificity of circulating DSA.
All DSA were found to be de novo DSA.
MFI was between 2336 & 25 588; an average of 13 477.
Histopathological comparison of DSA+ve & DSA-ve
Cases:
Total number of glomeruli available/biopsy was significantly different between DSA+ve (median of 21 glomeruli) & DSA-ve group of (13 glomeruli).
However no significant difference in the % of global glomerulosclerosis.
GBM double contours were present in all patients.
Majority of patients in both groups had severe (cg3) capillary loop involvement.
All biopsies had a MVI score of > 2.
Both groups showed vast glomerulitis (g3) together with moderate to severe PTCs (ptc2-3).
8 patients were positive for C4d staining in the DSA+ve group (unknown n = 1)
Only 9 of 24 DSA-ve patients were positive for C4d staining.
4 patients (1 DSA+ve; 3 DSA-ve) had a form of tubulitis (t ≥ 1) + arteritis.
7 patients presented with isolated v-lesions
(4 DSA+ve; 3 DSA-ve).
No significant differences in the individual Banff lesions
between DSA+ve & DSA-ve cases.
No histomorphological difference between DSA-ve C4d+ & DSA-ve C4d-patients.
Both the DSA+ve & DSA-ve cases showed a substantial
‘chronic inflammation score’ of 5 & 6, respectively.
No significant differences in the ‘chronic inflammation score’ or MVI between the 2 groups.
Renal allograft function
Average eGFR at baseline(approx. 31 ml/min/1.732), was similar in both patient groups.
DSA-ve cases had a slightly greater reduction in allograft
function.
Loss of graft function was more attenuated following treatment in both groups.
Response to treatment was similar irrespective to DSA or C4d status.
No significant difference in overall graft survival between DSA+ve & DSA-ve cases.
No significant difference in survival after diagnosis (4.6 years in DSA+ve vs. 3.7 years in DSA-ve).
A decrease in graft survival was seen in all cases with
high IFTA & total inflammation.
The presence or absence of C4d was not associated with
a difference in graft survival.
Conclusions
There was no histological or clinical differences between cases with c-a ABMR & cases suspicious for c-aABMR.
This study reported 17 cases of c-aABMR & 24 cases suspicious for c-aABMR.
In the c-aABMR group, all DSA were de novo & mainly directed against HLA-DQ.
DSA was not associated with a difference in response to treatment or graft survival.
Similar clinical & histological findings were seen between DSA+ve & DSA-ve cases.
Irrespective to DSA status, cases with moderate to severe IFTA showed significantly worse allograft survival.
Absence of detectable DSA doesn’t mean absence of an antibody-mediated process.
Only one case was DSA-ve at time of biopsy but
DSA+ve 1 & 2 years prior to biopsy.
Similar fluctuating nature of C4d-positive staining has led
to the development of the C4d-ve category of ABMR.
In addition to C4d+ve staining, a MVI score ≥2 indicates current or recent antibody interaction with the vascular endothelium.
The progression to graft failure was independent of DSA status.
Although the study gave detailed information about the presence of DSA at time of biopsy, however its sample is relatively small.
Data on non-HLA antibodies were not included.
Standardized treatment regimen used in all regardless of DSA. This permits accurate comparison of both clinical & histological data.
For the current study, we have chosen to use the previous
The study suggests that patients with a biopsy classified as ‘suspicious’ for c-aABMR according to the Banff 2015 classification also represent c-aABMR.
Renal histology & clinical outcome of patients with c-aABMR do not significantly differ from those suspicious for c-aABMR.
The presence of DSA doesn’t seem essential to establish diagnosis of c-aABMR when other criteria indicative of chronic tissue injury & current/recent antibody interaction with vascular endothelium are present.
What is the kind of this study?
Retrospective cohort study
What is the level of evidence?
Level III
Thanks
Chronic-active antibody-mediated rejection with or without donor-specific antibodies has similar histomorphology and clinical outcome – a retrospective study
Introdution
Chronic-active antibody-mediated rejection (c-aABMR) is currently defined by the Banff classification by (i) histologic evidence of chronic tissue injury, (ii) evidence of current or recent antibody interaction with vascular endothelium and (iii) serologic evidence of donor-specific antibodies (DSA). In the clinical setting, however, it is not uncommon for these diagnostic criteria to appear as an incomplete combination. This is largely due to the requirement of DSA positivity as DSA cannot be detected in a substantial number of patient. Cases in which renal histology show chronic endothelial activation as evidenced by glomerular basement membrane duplication, known as transplant glomerulopathy (TG), and C4d-positive staining and/or significant microvascular inflammation (MVI) with no detectable DSA are considered suspicious for c-aABMR.
Patients and methods
We retrospectively included all patients with the histomorphological diagnosis of chronic-active antibody-mediated rejection upon for cause biopsy which was performed after a progressive decline in renal allograft function. Patients were excluded if the biopsy was within the first-year post-transplantation (inaccurate information about renal allograft function) or the requirement of a minimum of 5 eGFR measurements per year was not met. Patients were divided into two groups based on the presence of detectable DSA in their serum at time of biopsy ( DSAneg X DSApos ) . Renal biopsies were re-evaluated and the individual lesions were scored according to the Banff ’15 classification by two independent pathologists. Alternative diagnoses for the histomorphological changes compatible with c-aABMR such as hepatitis C virus infection, membranoproliferative glomerulonephritis (MPGN) or (chronic) thrombotic microangiopathy (cTMA) were excluded, by immunofluorescence and clinical analysis.
Change in renal allograft function in time was evaluated by including all estimated glomerular filtration rate (eGFR, MDRD) measurements 1 year prior to diagnosis and 1 year after diagnosis for both patient groups. All patients were transplanted with a CDC-negative cross-match. To determine the definite diagnosis of each patient, serum samples at the time of biopsy were reevaluated and tested for the presence of donor-specific antibodies against HLA (DSA). If DSA were found to be present, it was determined whether this concerned de novo DSA. If samples were found to be negative.
The characteristics between the DSApos and DSAneg groups were compared using unpaired t test for continuous variables, Mann–Whitney U test for ordinal variables and chi-square or Fisher exact test for categorical variables. Similarly, a subgroup analysis between DSAneg C4d+ and DSAneg C4d patients was performed. All statistical analysis was performed using the R statistical programming environment and SPSS software version 21. A P-value of less than 0.05 was considered to represent a statistically significant difference.
Results
Identified 24 patients with the diagnosis of suspicious for c-aABMR (DSAneg) and 17 with c-aABMR (DSApos). Baseline characteristics did not differ significantly between the two groups. The diagnosis was made on average 77 months after transplantation (80 months DSApos vs. 75 months DSAneg, P = 0.76). There was, a noteworthy difference of almost 1 g/l more proteinuria in the DSApos patients, although this was not statistically significant (P = 0.15). Of interest, no significant differences were found between DSAneg C4d+ and DSAneg C4d patients (data not shown).
Seventeen of the 41 patients were tested positive for circulating DSA at time of biopsy, these cases are included in the c-aABMR (DSApos) group. The vast majority of the circulating DSA detected were directed against HLA-DQ (78%). All circulating DSA were found to be de novo DAS and the mean fluorescent intensity (MFI) ranged between 2336 and 25 588 with an average MFI of 13 477.
All renal biopsies were re-evaluated and the individual lesions were scored according to the Banff 2015 classification. A comparison between the histomorphological characteristics of the DSApos and DSAneg cases showed no significant differences in the individual Banff lesions score. Neither was there a difference in histomorphology between DSAneg C4d+ and DSAneg C4d patients. Both the DSApos and DSAneg cases showed a substantial ‘chronic inflammation score’ of 5 and 6, respectively. Furthermore, there was considerable presence of MVI. The groups showed no significant differences in the ‘chronic inflammation score’ or MVI.
All patients had a progressive decline in renal allograft function at the time of renal biopsy, the average eGFR at baseline, was similar in both patient groups (P = 0.44). After diagnosis and treatment with IVIG/MP both groups showed a more mitigated loss of allograft function than before diagnosis (P < 0.001). The response to treatment was similar regardless of DSA status (P = 0.93). Similarly, there was no significant difference in response to therapy upon comparison of DSAneg C4d+ and DSAneg C4d patients. There was no significant difference (log rank; P = 0.93) in overall graft survival between DSApos and DSAneg cases (12.2 vs. 13 years, respectively). In addition, there was no significant difference in survival after diagnosis with an average survival of 4.6 years in the DSApos cases vs. 3.7 years in the DSAneg cases (log rank; P = 0.58).
Discussion
The contribution of donor-specific antibodies to the diagnosis of c-aABMR has become an important topic of discussion. The Banff ’15 criteria do not allow for the classifying diagnosis of c-aABMR if there are no DSA present. Instead, these cases are diagnosed as suspicious for c-aABMR. Therefore, the significance of DSA and their contribution to the loss of allograft function and relation to renal histomorphology have not yet been fully explored. We found that there are no histological or clinical differences between cases with caABMR and cases suspicious for c-aABMR.
This article is a primary study , in retrospective cohort.
Evidence 03.
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Chronic-active antibody-mediated rejection with or without donor-specific antibodies has similar histomorphology and clinical outcome – a retrospective study
Chronic-active antibody mediated rejection (c-aABMR) is diagnosed on the basis of histological evidence of chronic tissue injury, current or recent interaction of antibody with vascular endothelium and presence of donor specific antibody (DSA) as per Banff classification. DSA is not detected in many patients, thereby labelling such patients suspicious of c-aABMR.
This retrospective study was conducted from January 2007 to November 2014 and included all patients with histological diagnosis of c-aABMR except patients in first year post-transplant and patients with poor follow-up (less than 5 eGFR measurements per year). Kidney biopsy and DSA levels were evaluated.
Patients were divided in 2 groups on the basis of presence or absence of DSA {c-aABMR (DSApos) and c-aABMR (DSAneg)}. Microvascular inflammation (MVI), calculated by adding glomerulitis and peritubular capillaritis score, ≥2 was a diagnostic criterion for c-aABMR. Chronic inflammation score was calculated by adding interstitial fibrosis, tubular atrophy and total inflammation score.
All the patients were treated with IVIG and injection methylprednisolone. Patients were followed up for minimum 1 year or till graft failure (return to dialysis or re-transplant).
A total of 41 {24 c-aABMR (DSAneg) and 17 c-aABMR (DSApos)} patients were included in the study. The diagnosis was made approximately six and a half years post-transplant.
The level of proteinuria was higher in DSA positive group. All the DSA were de novo, with mean MFI of 13477 and majority were anti HLA-DQ antibodies. One patient had historical DSA while at the time of biopsy DSA were not present.
The histomorphological characteristics were similar in the 2 groups. Both the groups showed progressive decrease in graft function with the DSAneg group having a larger annual fall in eGFR and similar response to therapy. The graft survival was similar in the 2 groups.
There was no clinical and histological difference between c-aABMR (DSApos) and suspicious c-aABMR (DSAneg) patients. As per Banff classification, presence of DSA is an essential criterion to diagnose c-aABMR but in this study, it had no effect on the graft biopsy characteristics, response to therapy as well as graft survival.
Patients with moderate to severe chronic inflammation score (interstitial fibrosis, tubular atrophy and total inflammation) had worse graft prognosis. Due to a false negative DSA because of possible transient nature of detectable DSA, a patient will not be diagnosed and treated as c-aABMR leading to worse outcomes. Similarly, patients with a negative C4d stain (due to fluctuating nature of C4d positivity) have also been shown to have AMR.
Strictly applying the Banff criteria for c-aABMR would have led to exclusion of a large number of these patients from the diagnosis.
Despite limitations like a retrospective study, biopsies indicated for cause (rather protocol biopsies), a small sample size and non-analysis of non-HLA antibodies, the study has shown that DSA presence has no bearing on the graft if transplant glomerulopathy and microvascular inflammation is present.
Retrospective cohort study
Level of evidence is level 3
Thank You
Chronic-active antibody-mediated rejection (c-aABMR) is currently defined by the Banff classification by (i) histologic evidence of chronic tissue injury, (ii) evidence of current or recent antibody interaction with vascular endothelium and (iii) serologic evidence of donor-specific antibodies (DSA).
the presence of donor-specific antibodies (DSA) is currently still mandatory for the diagnosis of c-aABMR.
Cases in which renal histology show chronic endothelial activation as evidenced by glomerular basement membrane duplication, known as transplant glomerulopathy (TG), and C4d-positive staining and/or significant microvascular inflammation (MVI) with no detectable DSA are considered suspicious for c-aABMR .
In this retrospective study, they investigated whether allograft outcome and renal histomorphology differed between cases suspicious for c-aABMR (DSAneg) and cases with c-a-ABMR (DSApos).
Study population:
Patients were identified from the pathology database between January 2007 and November 2014.
C4d was evaluated using immunohistochemical staining.
Renal allograft function:
Change in renal allograft function in time was evaluated by including all estimated glomerular filtration rate (eGFR, MDRD) measurements 1 year prior to diagnosis and 1 year after diagnosis for both patient groups
Characterization of anti-HLA antibodies:
To determine the definite diagnosis of each patient, serum samples at the time of biopsy were re- evaluated and tested for the presence of donor-specific antibodies against HLA (DSA). If DSA were found to be present, it was determined whether this concerned de novo DSA. If samples were found to be negative, addi- tional screening was performed by analyzing serum samples for DSA in the 2 years prior to diagnosis.
Results:
Patient characteristics:
Baseline characteristics did not differ significantly between the two groups.
no significant differences were found between DSAneg C4d+ and DSAneg C4d patients (data not shown).
Anti-HLA antibodies:
All circulating DSA were found to be de novo DSA
The vast majority of the circulating DSA detected were directed against HLA-DQ
Histopathological comparison of DSApos and DSAneg cases:
A comparison between the histomorphological char- acteristics of the DSApos and DSAneg cases showed no significant differences in the individual Banff lesions score (Table 3). Neither was there a difference in histo- morphology between DSAneg C4d+ and DSAneg C4d patients.
Renal allograft function:
All patients had a progressive decline in renal allograft function at the time of renal biopsy.
The response to treatment was similar regardless of DSA status.
there was no significant difference in response to ther- apy upon comparison of DSAneg C4d+ and DSAneg C4d patients.
The presence of DSA was not associated with a dif- ference in response to therapy or graft survival.
In conclusion, they show that renal histology and clinical outcome of patients with c-aABMR do not significantly differ from patients suspicious for c-aABMR.
They believe that the data they presented adds to the growing body of evidence that the presence of DSA is not a con- ditio sine qua non to establish the diagnosis of c-aABMR when other criteria indicative of chronic tissue injury and current/recent antibody interaction with vascular endothelium are met.
This is a retrospective study
Level of evidence 3
Thanks Asmaa
Chronic active AMR with or without DSA has similar clinical & histomorphological outcome.
Chronic active AMR is chronic endothelial injury called transplant glomerulopathy manifested by micro vascular inflammation and positive C4d staining
chronic active ABMR according to banff classification:
1. it’s histologic evidence of chronic tissue injury
2. evidence of current or recent antibody interaction with vascular endothelium
3. serological evidence of DSA
Method & Material:
it’s retrospective study done in pathological department between January 2007 to November 2014.
it’s investigate risk factors and allograft outcome between CaABMR DSA positive and CaABMR DSA negative in all biopsies done after one year post transplant.
All biopsies done within one year are excluded from study; Also alternative diagnosis of histomorphological changes with CaABMR like HCV membrane glomerulopathy and TMA are excluded and all eGFR influenced by antibiotics and IVF are excluded.
Character anti HLA antibodies:
All patients transplanted are CDC negative cross match and serum DSA level was taken at time of biopsy.
If DSA positive is considered de novo DSA
If DSA negative rescreening DSA in 2 year prior to diagnosis.
Screening for presence of HLA AB done by using luminex platform/ life codes life sceen deluxe kit.
Samples were considered positive for HLA class I ( HLA A HLA B HLA C )or HLA class II DQ; DR antibody are screening by luminex single antigen assay.
Results:
Majority of cases DSA directed against HLA DQ and HLA A antibody
All circulating DSA were found to be de novo DSA
Histomorphological evidence:
All biopsies are scored according to banff classification 2015
All patients had glomerular basement membrane double contour
All patients in both groups had severe capillary loop involvement.
From all 41 patients only 3 patients diagnosis as C1q based on electron microscopy.
All patients with DSA negative or positive shows glomerulitis and moderate to severe peritubular capillarities.
comparison histomorphological of DSA positive and DSA negative shows no significant difference in presence of chronic inflammation.
Clinically all patients had progressive decline in renal allograft at time of biopsy in average eGFR 31 ml/min for negative DSA and eGFR 8 ml/min or less in patients with DSA positive.
After treatment with intravenous immunoglobulin and pulse therapy of steroid; all patients shows response to treatment and no difference in graft survival in both groups.
Average graft survival rate 4.6 year in all groups.
Decrease in graft survival was seen in all cases with high tubular atrophy and interstitial fibrosis and total inflammation.
Limitations of this study are small size groups and it’s retrospective study.
it’s retrospective study
Evidence 3
Thanks
Chronic-active antibody-mediated rejection with or without donor-specific antibodies has similar histomorphology and clinical outcome – a retrospective study
Chronic active AMR defined as;
Histological evidence of chronic tissue injury i.e. Transplant glomerulopathy
C4d positivity / microvascular inflammation
Donor-specific antibodies (DSA)
Objective(s)
Investigates differences in allograft outcomes and histological features between patients with c-aABMR (DSAneg) and cases with c-a-ABMR (DSApos).
Methods
Retrospective study of patients with histological features of chronic-active antibody-mediated rejection upon for cause biopsy
All patients received similar anti-rejection treatment
None received plasmapheresis
C4d tested with immunohistochemistry
Immunofluorescence done for antibodies against IgG, IgM, IgA, C3c, C1q, kappa and lambda on snap frozen material
Serum samples at the time of biopsy were tested for the presence DSA
Results
24 patients had c-aABMR (DSAneg)
17 had c-aABMR (DSApos)
DSA pos patients had more proteinuria by 1 g/dl
Most DSA detected were directed against HLA-DQ (78%). All de novo DSA
Histological comparison
6 patients had few sclerosed glomeruli to qualify for Banff scoring
DSA pos had a median of 13% sclerosed glomeruli vs 8 %for DSA neg
All renal transplant biopsies (n = 41) had GBM double contours
Both DSA pos and DSA neg had severe capillary loop involvement, vast glomerulitis and microvascular scores of > 2.
1 DSA pos had no C4d staining available
8/16 DSA pos were C4d positive vs 9/24 DSA neg were C4d positive
No significant differences in Banff scores between the two groups
Renal allograft function
All patients had a progressive decline in renal function at the time of biopsy.
Average eGFR 31ml/min
DSA neg had more decline in renal function at time of biopsy
Both groups showed a slower decline in renal function after anti-rejection treatment with IVIG/MP
Similar response to treatment and graft survival in both groups
Tubular atrophy, interstitial fibrosis and total inflammation was associated with decreased graft survival
C4d status was not associated with a difference in graft survival.
Conclusion
There was no difference in renal histology and clinical outcomes in patients with c-aABMR whether DSA positive or negative.
retrospective cohort study
level 3
Thanks
Introduction ;
Patients & Methods ;
Renal allograft function
Characterization of anti-HLA antibodies
Statistical analysis ;
Anti-HLA antibodies ;
Histologic comparison of DSA+ve & DSA -ve cases ;
Renal allograft function ;
Long-term survival ;
Discussion ;
Limitation of this study ;
Conclusion ;
Thanks Ben
Most welcom prof
Chronic-active antibody-mediated rejection with or without donor-specific antibodies has similar histomorphology and clinical outcome – a retrospective study.
A retrospective study on 41 patients to assess clinical outcome and renal histomorphology between DSA positive(n=17) and DSA negative(n=24) chronic -active ABMR, by Renal biopsies and kidney function assessment by (eGFR, MDRD) measurements 1 year prior to diagnosis and 1 year after diagnosis for both patient groups
Definition of (c-aABMR) based on BANFF 15 classification which depends on fulfil of histological chronic tissue injury changes , evidence of current or recent antibody interaction with vascular endothelium and serologic evidence of donor-specific antibodies (DSA).
Patient with chronic histological changes e.g. TG and C4d-positive staining and/or significant microvascular inflammation (MVI) with no detectable DSA are considered suspicious for c-aABMR
Two group received similar treatment with three doses of 1 g intravenous methylprednisolone (MP) over a 3-day period combined with a single dose of intravenous immunoglobulins (IVIG) (1 g/kg body weight) on the second day of treatment. None of the patients had plasmapheresis.
Results:
-The majority of the circulating DSA detected were directed against HLA-DQ (78%).
-All circulating DSA were found to be de novo DSA with (MFI) ranged between 2336 and 25 588 with an average MFI of 13 477.
-A comparison between the histomorphological characteristics of the DSA positive and DSA negative cases showed no significant differences in the individual Banff lesions score.
-The response to treatment was similar regardless of DSA status.
-The presence or absence of C4d did not associate with a difference in graft survival.
Conclusion:
There are no histological or clinical differences between cases with caABMR and cases suspicious for c-aABMR.
The presence of DSA was not associated with a difference in response to therapy or graft survival.
A retrospective study.
Level evidence III.
The provided article is a retrospective study with level if vidence 3,that investigated 41 patients with c-aABMR, subdivided into DSA negative, n = 24 and DSA positive, n = 17. The aim of the study is to evaluate the difference in terms of renal histology, allograft function and long-term graft survival. This study also focus on the ongoing debate whether DSAs are needed or not for the diagnosis of c-aABMR.
Kidney biopsies were assessed according to the Banff 15 criteria.
c-aABMR is defined based on the presence of:
1- histological evidence of chronic endothelial injury (cg), also known as transplant glomerulopathy, and either microvascular inflammation (MVI
2- Positivity for C4d
3- Presence of donor-specific antibodies
Patients were excluded if the biopsy was within the first-year post-transplantation.
All patients received similar treatment with three doses of 1 g intravenous methylprednisolone over a 3-day period combined with a single dose of intravenous immunoglobulins (IVIG) (1 g/kg body weight) on the second day of treatment. None of the patients had plasmapheresis.
Results
• 17 out of the 41 patients were DSA+ at time of biopsy. The majority of the circulating DSA detected were directed against HLA class II in particular HLA-DQ (78%).
• In DSA + GROUP,all circulating DSA were found to be de novo DSA
• MFI was in a wide range 2500 to25000
• All renal transplant biopsies irrespective of DSA stutus, had glomerular basement membrane double contours. The majority of patients in both DSApos and DSAneg cases had severe (cg3) capillary loop involvement.
• A comparison between the histomorphological characteristics of the DSApos and DSAneg cases showed no significant differences in the individual Banff lesions score.
• The groups showed no significant differences in the ‘chronic inflammation score’ or MVI.
• All patients had a progressive decline in renal allograft function at the time of renal biopsy with similar average eGFR at baseline.
• The response to treatment of ca ABMR was similar regardless of DSA status.
Conclusion
The presence of DSA was not associated with a difference in response to therapy or graft survival. The results of this study did not show a significant impact of DSA on renal allograft survival in transplant patients with evidence for antibody-mediated rejection either acute or chronic
Thanks
Chronic active AMR (c-aAMR) diagnosis continues to be associated with negative long term prognosis of renal allograft . Characteristically, on histopathological level,(C-aAMR) entails evidence of chronic endothelial injury a phenotyp of transplant glomerulopathy (tg), microvascular inflammation (mvi) or the presence of C4d. The criteria for diagnising (c-aAMR) set by Banff classification includes
1)Histology evidence of chronic tissue injury.
2)evidence of current or recent antibody interaction with vascular endothelial C4d
3)serologic evidence of DSAs.
However, DSAs can’t be detected in a substantial number of patients.
DSAs negative c-aAMR;
By definition, chronic endothelial activation evidenced by glomerular basement membrane duplication (TG),C4d positive staining ,and significant micrivascular inflammation,with no.detectable DSAs.
This study investigated whether allograft outcome and renal histomorphology differed between c-aAMR (DSA pos.),and c-aAMR (DSAs negative.)
It’s a retrospective study ,involved all patients with histomorphological diagnos8s of c_aAMR.
Clinically , all patients presented with progressive decline in allograft function. Presented after the first year post transplantation. Each had at least 5 eGFR measurment per year
Patients cohort identified between 2007 and 2014.
The patients were divided into 2 groups depending on the presence of detectable DSAs in their serum at time of biopsy.
Both groups received similar therapeutic protocol with 3 doses of methylprednisolon over 3 days,combined with single dose IVIG. No PE was done.
DSAs in c-aAM R(DSAs pos) characteristics:
1-the majority of DSAs are against Class II
2- directed against HLA DQ
3-all are de novo DSAs.
4-MFI RANGED BETWEEN 2336 and 25588.
Renal transplant biopsy:
Cg3 , MVI 2, g3, ptc2-3
Conclusio :
Both the DSApos and DSAneg cases showed no significant difference in clinical presentation,histopathol9gic pattern and respons to therapy.
The study is retrospective single center study.
Level of evidence is 3
Thanks