C4d stain indicate complement involvement in antigen antibody reaction in the body ,it destroyed to fragment and deposited,so many immune reaction may cause positive C4d rather than AMR like:
ABO incompatible transplant
Autoimmune disease
Some infection like BK nephropathy
Wee Leng Gan
2 years ago
ABO incompatible transplant.
BKV CMV nephropathy.
Lupus nephritis, Antiphospholipid syndrome. Anca associated nephropathy.
IG A nephropathy
TMA
HUS.
Reference
1) Collins A.B., Schneeberger E.E., Pascual M.A., et al.
Complement activation in acute humoral renal allograft rejection: diagnostic significance of C4d deposits in renal transplant. J Am Soc Nephrol, 10 (1999), pp. 2208-2214
Dalia Eltahir
2 years ago
C4d deposition in peritubular capillaries is a specific marker for the presence of antidonor antibodies in renal transplant recipients and is usually associated with antibody-mediated rejection .Presence of C4D positive without AMR in :
-in ABO-incompatible renal allografts The significance of C4d staining in the absence of other histologic changes remains unclear.it seems to point at ‘graft accommodation .
-In systemic autoimmune diseases and pregnancy.In SLE patients indicate the disease activity .Viral infection especially BK virus .
Nandita Sugumar
2 years ago
POSITIVE C4D STAINING WITHOUT AMR
Graft accommodation
ABO incompatible transplants
Associated with reduced early scarring in ABO incompatible renal allografts.
Lupus nephritis
Viral infection – BKV, CMV
References :
Haas M. The significance of C4d staining with minimal histologic abnormalities. Curr Opin Organ Transplant. 2010 Feb;15(1):21-7. doi: 10.1097/MOT.0b013e3283342ebd. PMID: 19907328.
Haas M, Segev D et al. C4d deposition without rejection correlates with reduced early scarring in ABO incompatible renal allografts. JASN; 2009 : 20 (1) : 197-204. DOI: https://doi.org/10.1681/ASN.2008030279
Ahmed Fouad Omar
2 years ago
C4d is a degradation product generated from activation of the classic complement pathway. It binds covalently to the endothelial and collagen basement membranes of the graft and deposited in the PTCs serving as an immunologic footprint of complement activation and antibody-mediated injury (AMR).It can be assessed using IHC and IF(IF is more sensitive).
Other causes of C4d staining includes:
C4d positive staining with no other histological finding:
o ABO-incompatible transplantation. The presence of C4d represents graft accommodation with no active rejection, this requires follow-up with no active treatment.
o Positive C4d in pre-sensitized and positive cross matched patients should be treated as a possible AMR
C4d positive staining with no DSAs:
o C4d positive in the absence of DSAs indicates the presence of alloantibodies like anti-endothelial alloantibodies and anti-angiotensin type 1 receptor antibodies and these are not detected by standard HLA assays.
o Autoimmune diseases like Lupus nephritis (When C4d is deposited in the tubular basement membrane, it indicates disease activity while arteriolar C4d deposition signifies a poor prognosis).
o Other native renal diseases like IgA(deposition is mostly mesangial but glomerular C4d indicates disease progression and poor prognosis) MPGN(C4d along the capillary loop), membranous nephropathy(C4d along glomerular capillary wall), post infectious GN, ANCA, anti-GBM and vascular disorders like TMA(deposition in the glomerulus and arterioles)
o C4d in pregnancy: antibody-mediated pregnancy loss ( preeclampsia and anti-phospholipid syndrome
o BK nephropathy(tubular basement membrane C4d)
It is important to interpret renal biopsies with caution as C4d positivity in the absence of other histological and serological findings(DSAs) of AMR is unlikely to be significant (false positive C4d staining).
References:
1.Cohen D, Colvin RB, Daha MR, Drachenberg CB, Haas M, Nickeleit V, et al. Pros and cons for C4d as a biomarker. Kidney Int. 2012 April ; 81(7): 628–639
2. Chandra P. C4d in Native Glomerular Diseases. Am J Nephrol. 2019;49(1):81-92
3. Li P, Cheng D, Wen J, Ni X, Li X, Xie K, et al. The immunophenotyping of different stages of BK virus allograft nephropathy Renal Failure.2019;41(1): 855-861
Hamdy Hegazy
2 years ago
Under what conditions you get false positive C4d staining (positive C4d staining without AMR)?
Substantiate your answer
1- ABO incompatible transplantation: C4d reflects graft accommodation rather than AMR. Graft accommodation means C4d deposited in PTC without active rejection. More than 705 of ABO incompatible RTx showed diffuse C4d positivity in protocol biopsies. 2- Positive cross matched recipients. 2- Other conditions as autoimmune diseases like SLE, arteriolar C4d staining is a risk factor for adverse outcomes. However, tubular C4d deposition is associated with disease activity. 3- Pregnancy, especially in SLE and anti-phospholipid syndrome patients. 4- BKV nephropathy, tubular BM C4d staining indicates high viral cytopathic impact. 5- TMA, and atypical HUS. 6-Pauci-immune GN. 7-IgA Nephropathy, glomerular C4d deposition indicates disease progression and poor prognosis. 8-MPGN, MN, anti-GBM, C4 glomerulopathy, Fibrillary GN, C1q nephropathy and post infectious GN.
Akram Abdullah
2 years ago
2. Under what conditions you get false positive C4d staining (positive C4d staining without AMR)? – ABO-incompatible transplantation. 2-SLE & antiphospholipid syndrome . 3- IGA nephropathy. 4_ BK nephropathy .
Ramy Elshahat
2 years ago
C4d is an end product of c4b, which indicate classical complement pathway activation. like any other imuunodeposition in immunohistochemistry microscopy the site and the pattern of deposition differ from disease to another -in ABOi usually presented with linear depostion in the peritubular capillaries and its represent accomodation not rejection -in some glomerular disease specially 1ry membranous nephropathy it usually deposit granular and in the glomerulus -in BK infection it deposite in the tubules
refernece Danielle Cohen1, Robert B. Colvin2, Mohamed R. Daha3, Cinthia B. Drachenberg4, Mark Haas5, Volker Nickeleit6, Jane E. Salmon7, Banu Sis8, Ming-Hui Zhao9, Jan A. Bruijn1, and Ingeborg M. Bajema1. Pros and cons for C4d as a biomarker Published in final edited form as:Kidney Int. 2012 April ; 81(7): 628–639. doi:10.1038/ki.2011.497.
ahmed saleeh
2 years ago
False positive C4d staining with absent AMR :
*ABO incompatible Kidney Tx
* in presensetized patients with cross match positive
* IgA nephropathy and may be used as a marker of disease progression.
* LUPUS Nephritis associated with adverse outcomes .
* viral infections as BK nephropathy.
* Native Kidney disease like MN ,ANCA vasculature, Anti GBM , TMA ,MPGN .
Abdullah Raoof
2 years ago
Under what conditions you get false positive C4d staining (positive C4d staining without AMR)?
C4d is an end product of c4b, which indicate classical complement pathway activation.
C4d is a footprint for antibody-mediated tissue injury.
But C4d may be negative in some ABMR even when the DSA is positive .
in ABO-I transplantations C4d is present in the majority of grafts but this is ‘accommodation’ rather than AMR . therefor it is not a use full test in this situation, as it is not needed to be treated.
C4d help to detect patients at risk for the consequences of ABMR.
Therefor C4d positivity is common in ABO-I transplantation , it is not alarming and does not need treatment .
The emergence of new (though expensive ) drug that is directed toward inhibition of complement system increases the importance of C4d in early detection of a treatable related condition .
In C4d negative patient, molecular study (endothelial injury associated transcript) provide a hint to a complement-independent form of AMR or C4d-negative AMR.
C4d is scored semiquantitatively in four categories:
1- No C4d staining (0% of (peritubular) capillaries)
2- Minimal C4d staining (0–10% of (peritubular) capillaries)
3- Focal C4d staining (10–50% of (peritubular) capillaries)
4- Diffuse C4d staining (>50% of (peritubular) capillaries)
Immunofluorescence is a more sensitive method to detect C4d than immunohistochemistry, by approximately one grade of the scoring system.
– a diffuse C4d staining is defined as positive,
But the clinical significance of ‘minimal’ and ‘focal’ C4d staining remain debated.
The a focal staining pattern can be considered as a red flag, especially in
· by paraffin-embedded tissue or
· in the presence of donor-specific antibody and/or
· suspicious histopathological features.
Most laboratories consider this as ‘positive for (AMR)’.
· It is advised to treat this patient.
2- In frozen tissue combined with
· a positive test for DSA and
· histopathological features:
· The diagnosis is a ‘probable AMR’.
· Suggest to consider treatment, but further investigation is needed.
C4d positivity without detectable DSA causes :
1- It occue when Allo-antibodies are present, but they are not detected by standard anti-HLA assays (for example, anti-endothelial antibodies).
2- Allo-antibodies are absorbed by the graft, and it may reappear after graft nephrectomy.
3- Allo-antibodies are not present and C4d deposition is caused by something else than DSA (autoimmune disease, i.e., lupus nephritis or any form of lectin pathway activation). Management :
In case of diffuse C4d staining in peritubular capillaries and histological evidence for AMR: Most experts would advise to treat the patient for AMR.
In case of focal C4d staining and histological evidence for AMR: Check for other possible underlying diseases. If no other cause can be found: Treat the patient for AMR.
In case of focal or diffuse C4d staining and absence of histological changes the decision as to whether to treat for AMR is more uncertain. Treating or close follow-up are both suitable options.
C4d positivity in grafts without histological abnormalities
1- In ABO-incompatible grafts: without any other signs of ABMR (it is called graft accommodation). No treatment is needed , but close monitoring is recommended .
2- In positive cross-matched patients (pre sensitized patient), normal histology and no graft dysfunction: this is probable AMR and needs treatment.
3- Vascular disease (non-antibody complement activation )
4- Lupus nephritis due to immune complex disease(glomerular deposits, non specific )
reference’s 1-Cohen D, Colvin RB, Daha MR, Drachenberg CB, Haas M, Nickeleit V, et al. Pros and cons for C4d as a biomarker. Kidney Int. 2012 April ; 81(7): 628–639 2- peofessor Ahmed Halawa lecture .Applied transplant immunology,,2022
Balaji Kirushnan
2 years ago
It is very important to interpret C4d in a renal biopsy….C4d is a very easy staining and in expensive….It signifies complement activation…..C4d is a breakdown fragment of C4b which gets deposited in the tissues…It has strong disulphide bonds which bind to the cells and it serves as a footprint of antibody mediated rejection…. False positive C4d without any histological changes of AMR can be seen only in few conditions..
ABO incompatible kidney transplant, where it is a marker of graft accommodation.C4d has been shown to be present in the tissues without any signs of AMR or graft dysfunction…It is found in 70 to 80% of all ABOi kidney transplant recipients without signs of rejection, there is diffuse peritubular capillary deposition of C4d….
Glomerular C4d deposit indicate complement mediated diseases….In IgA nephropathy glomerular C4d deposition has been shown to be associated with worse prognosis…
In Lupus nephritis tubular C4d deposition is associated with disease activity while the arteriolar C4d deposition is associated with worse prognosis
C4d deposition is also seen in MPGN, antiphospholipid antibody syndrome.
Placental C4d was detectable in SLE and antiphospholipid syndrome cases (>60%) in diffuse staining pattern of C4d in the maternofetal interface in the placenta
BK Virus nephropathy also shows c4d positivity with viral cytopathic effects..
AMAL Anan
3 years ago
Under what conditions you get false positive C4d staining (positive C4d staining without AMR)?1- ABO-incompatible transplantation represents graft accommodation.
2- native renal diseases such ANCA associated vasculitis , anti-phospholipid ab syndrome,TMA , membranous Nephropathy MPGN , fibrillation glomerulolnepheritis , proliferating glomerulonepheritis with monoclonal IG , amyloidosis C1q nephropathy ( glomerular c4d staining) .
3- Autimmune renal diseases such as lupus nephritis( tubular c4d staining)
4-pregnancy : antibody-mediated pregnancy loss ( pre-eclamspia and anti-phospholipid antibody syndrome.
5-IgA nephropathy ( glomerular c4d staining).
6- Bk nephropathy( tubular c4d staining) viral cytopathic effect.
Reference
1-Danielle Cohen1, Robert B. Colvin2, Mohamed R. Daha3, Cinthia B. Drachenberg4, Mark Haas5, Volker Nickeleit6, Jane E. Salmon7, Banu Sis8, Ming-Hui Zhao9, Jan A. Bruijn1, and Ingeborg M. Bajema1. Pros and cons for C4d as a biomarker
Published in final edited form as:
Kidney Int. 2012 April ; 81(7): 628–639. doi:10.1038/ki.2011.497.
2- Ibrahim Batal, Hanady Zainah, Sean Stockhausen, Amit Basu, Henkie Tan, Ron Shapiro, Adriana Zeevi, Alin Girnita & Parmjeet Randhawa.
The significance of renal C4d staining in patients with BK viruria, viremia, and nephropathy
Published: 04 September 2009
Modern Pathology (2009) 22, 1468–1476
MICHAEL Farag
3 years ago
Positive C4d staining in the absence of rejection is seen in:
Native renal diseases such as ANCA associated vasculitis, antiphospholipid ab syndrome, TMA, membranous nephropathy, MPGN, fibrillary GN, proliferative GN with monoclonal Ig, amyloidosis, and C1q nephropathy. ( glomerular C4d staining).
In an autoimmune renal disease such as lupus nephritis ( tubular C4d staining).
Pregnancy: antibody-mediated pregnancy loss ( preeclampsia and APL ab syndrome).
IgA nephropathy ( glomerular C4d staining).
BK nephropathy ( tubular C4d staining) viral cytopathic effect.
References:
Cohen D, Colvin RB, Daha MR, Drachenberg CB, Haas M, Nickeleit V, et al. Pros and cons for C4d as a biomarker. Kidney Int. 2012 April ; 81(7): 628–639.
Drachenberg CB,Papadimitriou JC, Chandra P, Haririan A, Mendley S, Weir MR, et al. Epidemiology and Pathophysiology of Glomerular C4d Staining in Native Kidney Biopsies. Kidney International Reports (2019) 4, 1555–1567.
Li P, Cheng D, Wen J, Ni X, Li X, Xie K, et al. The immunophenotyping of different stages of BK virus allograft nephropathy Renal Failure.2019;41(1): 855-861.
Ahmed Omran
3 years ago
Positive C4d without AMR : ABO I graft transplantation as graft accommodation :
With diffuse C4d staining of peritubular capillaries in 70-80% of ABO I Kidney transplantation.
no histopathological findings and no graft dysfunction of Allograft
IgA nephropathy viral infection BK virus ,and atypical HUS.
Peritubular capillary deposition of C4d in lupus nephritis,
ANCA associated vasculitis In pregnancy with antibody-mediated fetal loss like SLE &APL.
Placental C4d was detectable in SLE and antiphospholipid syndrome cases (>60%) in diffuse staining pattern of C4d in the maternofetal interface in the placenta
CARLOS TADEU LEONIDIO
3 years ago
The significance of C4d staining in the absence of histologic changes to AMR remains obscure, but protocol biopsies of ABO-incompatible grafts show PTC C4d deposition that is often diffuse but only infrequently associated with histologic changes of AMR.
C4d staining without evidence of rejection was determined to be present when each of the following five criteria were met: (1) Diffuse PTC C4d staining with intensity 1; (2) PTC margination score of 0 and no evidence of TMA; (3) no concurrent ACR (Banff ’97 grade 1A or greater); (4) Banff g and cg indices of 1 and 0, respectively; and (5) presence of BGA in serum with specificity for donor blood group antigen(s).
Reference:
Mark Haas, et al. C4d Deposition without Rejection Correlates with Reduced Early Scarring in ABO-Incompatible Renal Allografts. J Am Soc Nephrol 20: 197–204, 2009. doi: 10.1681/ASN.2008030279
MOHAMED Elnafadi
3 years ago
The C4d staining as a special tissue marker for humoral immunity has served criteria of pathological diagnosis for antibody-mediated rejection (ABMR) in Banff classification since 2003,However, the sensitivity and specificity of C4d staining have been questioned, and recently, C4d-negative ABMR has been more focused in renal allograft pathology.
positive C4d staining without ABMR or rejection in ABO INCOMPATIBLITY, AUTOIMMUNE DISEASES AS SLE, POSSIBLE ORIGINAL KIDNEY DISEASE RECURRENCE.
Shereen Yousef
3 years ago
C4d staining is relatively inexpensive
C4d staining is easy to perform in basic laboratories
A diffuse staining pattern is relatively easy to interpret
C4d gives very few false positives (it is relatively specific)
C4d shows that the complement system is involved: If complement targeted therapies (eculizumab) will be part of future treatment options, a marker such as C4d will be needed to identify patients susceptible for those kind of (expensive) treatments.
But still there are some cons ;
C4d scoring is subjective and the issue of focal staining and C4d/donor-specific antibody discrepancies will not be solved
C4d is not sensitive for chronic (or chronic/active) antibody-mediated rejection
●C4d positivity in grafts without histological abnormalities
-In ABO-incompatible grafts: In case of no histopathology and no graft dysfunction: It is suggested to interpret this as ‘graft accommodation’. No treatment is necessary, but close follow-up is strongly advised, as it is unknown what happens with these grafts during long-term follow-up.
-In positive cross-matched patients (presensitized patient), this should not be seen as graft accommodation and is a rare and more worrying situation than the above: In case of normal histology and no graft dysfunction: Interpret as probable AMR and consider treating the patient. Prospective studies on the long-term follow-up of this group of patients are awaited.
-IgA nephropathy
-Viral infection BK virus
-Lupus nephritis.
-Thrombotic microangiopathy .
Alternatives for C4d are emerging (genomics, molecular diagnostics, and endothelial transcripts) that will help accurate diagnosis of AMR.
Pros and cons for C4d as a biomarker
Danielle Cohen, Robert B. Colvin, and Ingeborg M. Bajema.Kidney Int. 2012 Apr; 81(7): 628–639.
Abdul Rahim Khan
3 years ago
C4d is a degradation product in classical compliment pathway and has an important role in diagnosis of Antibody mediated rejection. In the classical pathway of compliment activation, C4 is divided into C4a and C4b which is then converted to C4d which interacts with endothelium and then initiating the immune response which leads to antibody mediated tissue injury. So C4d is a hallmark of compliment activation against donor antigens.
Flase positive C4d staing without AMR can be seen in –
· IgA Nephropathy- Glomerular C4d staining
· Immunological conditions like lupus nephritis
· BK nephropathy
· ABO incompatible transplantation- Previously referred as accommodation. It is seen in ABO incompatible Transplants in which C4d staining is seen in 80% protocol biopsies and this staining does not co relate with peritubular capilliritis. In some protocol biopsies of patients with history of positive XM C4d staining is seen without evidence of tissue injury and this group qualifies for accommodation.
· ANCA associated vasculitis
· Pregnancy with Antiphospholipid antibody syndrome,
· TG, MPGN etc
Reference :
D Cornell. Histopathologic Features of Antibody Mediated Rejection: The Banff Classification and Beyond. Front. Immunol., 27 September 2021
Esmat MD
3 years ago
In normal kidneys, C4d is detectable in the glomerular mesangium and at the vascular pole.
some biopsies, mainly from ABO-incompatible renal allografts, show C4d staining without histologic findings of AMR or cell-mediated rejection, a phenomenon known as graft accommodation.
In analogy with solid organ transplantation, C4d has recently been demonstrated in pregnancy, in particular in the setting of ‘antiphospholipid antibody-mediated fetal loss’ and preeclampsia. In autoimmune settings such as SLE, C4d might have a role in identifying patients at risk of developing thrombotic complications.
C4d is now increasingly recognized as a potential biomarker in other fields where antibodies can cause tissue damage, such as systemic autoimmune diseases and pregnancy.
Bracamonte et al and Hever et al demonstrated tubular basement membrane deposits in association with BK virus nephropathy.
In terminal complement pathway inhibition and, rarely, lupus nephritis, C4d has been described in the absence of other histopathological features of AAMR, and is considered not diagnostic of AAMR.
Drtalib Salman
3 years ago
Although peritubular capillary C4d is specific marker for Antibody mediated rejection ,its sensitivity is low and C4d negative rejection should be treated with same regimen for positive C4d.
positive C4d could occur without rejection :
-ABO incompatible blood consider part of graft accommodation .
-in case of pregnancy fetomaternal adaptation .
-Infection (viral)PK virus .
-autoimmune disease SLE .
-thrombotic microangiopathy .
but we should take our care that in patient presensitized positive C4d without histological evidence of rejection ,it very rare to consider false positive or graft adaptation but close follow up and maximize our immunosuppressive drug.
Kidney Int. 2012 April ; 81(7): 628–639. doi:10.1038/ki.2011.497.
In many patients it maybe diffuse staining while focal in others
Also can be seen in autoimmune diseases like lupus nephritis
It is good to keep in mind that C4d positivity without detectable DSA can be due to alloantibodies not detected by HLA assays (antiendothelial antibodies)
Allo-antibodies are present, but they are not detected by standard anti-HLA (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771104/)
C4d staining is usually a footprint of both acute and chronic antibody mediatd rejection (AMR). however, there are still some cases of false +ve and also false -ve of C4d staining. of these false +ve C4d staining are the following :
1- ABO incompatible allografts with stable graft function, a state of accomodation.
2- Recurrence of some glomerular disorders in allografts as MN & MPGN.
Please elaborate more as: mechanism of deposition
Diff. Patterns of distribution in relation to eitiology.
Mohamed Ghanem
3 years ago
Positive C4d without Antibody-mediated Rejection : ABO‑incompatible graft transplantation as graft accommodation :
(diffuse C4d staining of peritubular capillaries in protocol biopsies in 70-80% of ABO Incompatible Kidney transplantation. no histopathology and no graft dysfunction of Allograft IgA nephropathy Viral infection BK virus Atypical HUS without ABM rejection in Native kidney disease :
Peritubular capillary deposition of C4d in :
Lupus nephritis,
ANCA associated vasculitis
Thrombotic microangiopathy in Atypical HUS
In pregnancy with antibody-mediated fetal loss in ( SLE and antiphospholipid syndrome ) placental C4d was detectable in the majority of SLE and antiphospholipid syndrome cases (>60%) in diffuse staining pattern of C4d in the Maternofetal interface in the placenta
1. ABO incompatible as part from graft accommodation
2. Pregnancy ( Anti phospholipid fetal loss syndrome )
3. Autoimmune disease like lupus nephritis ir lectin pathway activation
4. Presensitised patients (positive cross match without AMR and histomorphological abnormalities seen in graft)
References:
Danielle Cohen et al. Pros and cons for C4d as a biomarker: Kidney Int. Author manuscript; available in PMC 2013 Sep 12.
Published in final edited form as:
Kidney Int. 2012 Apr; 81(7): 628–639.
Detection of the complement split product C4d in renal allograft biopsies is an important adjunctive tool to help understand the alloimmune response and to diagnose ABMR. C4d is a degradation product of the classic complement pathway. After an antigen-antibody complex fixes complement, a cascade of events follows, with activation of several complement proteins. The complement protein C4 is split into C4a and C4b. C4b is then converted to C4d. A unique feature of C4d is that it binds covalently to the endothelial and collagen basement membranes, thereby serving as an immunologic footprint of complement activation and antibody-mediated injury. Deposition of C4d in the PTCs has only been described in renal allografts and represents complement activity directed against donor antigen.
False positive C4d without AMR can be seen in
ABO-incompatible transplantation represents graft accommodation.
ANCA associated vasculitis, antiphospholipid antibody syndrome
TMA, membranous nephropathy, MPGN, fibrillary GN, proliferative GN with monoclonal Ig, amyloidosis, and C1q nephropathy. ( glomerular C4d staining).
In an autoimmune renal disease such as lupus nephritis it’s Maui tubular C4d staining
Pregnancy
IgA nephropathy usually leads to glomerular C4d staining
BK nephropathy shows tubular C4d staining
A false positive C4d staining in a kidney biopsy can be seen in:
– ABO incompatible renal transplant
– In native renal disease like MPGN Membranous nephropathy (along glomerular capillary wall), C4 glomerulopathy, Post-infectious GN.
– In pre-sensitized patients
– In IgA nephropathy
– Lupus nephritis
-In BK virus nephropathy
-Vasculitis
-TMA
MH, Bruijn JA, Bajema IM. Pros and cons for C4d as a biomarker. Kidney international. 2012 Apr 1;81(7):628-39. Chandra P. C4d in native glomerular diseases. American journal of nephrology. 2019;49(1):81-92.
You could have explained a little about the mechanism in each entity.
Theepa Mariamutu
3 years ago
False positive C4d staining seen in:
ABO-i transplantation -graft accommodation
Native renal diseases such as ANCA associated vasculitis, APLS, TMA, membranous nephropathy, MPGN, fibrillary GN, proliferative GN with monoclonal Ig, amyloidosis, and C1q nephropathy-glomerular C4d staining
autoimmune renal disease such as lupus nephritis-tubular C4d staining
Pregnancy: antibody-mediated pregnancy loss (preeclampsia and APLS)
IgA nephropathy-glomerular C4d staining
BK nephropathy -tubular C4d staining
References
Etta PK. C4d staining and antibody-mediated rejection in renal transplantation: Current status. Indian Journal of Transplantation. 2020 Jul 1;14(3):197.
Cohen D, Colvin RB, Daha MR, Drachenberg CB, Haas M, Nickeleit V, Salmon JE, Sis B, Zhao MH, Bruijn JA, Bajema IM. Pros and cons for C4d as a biomarker. Kidney international. 2012 Apr 1;81(7):628-39.
Well done Thepa good you are starting to join
Try to address the scenario
Heba Wagdy
3 years ago
Positive C4d staining without AMR occurs in: ABO incompatible allograft:
C4d positivity is not associated with graft dysfunction, poor outcome or histological evidence of endothelial injury, it is considered graft accommodation. Positive crossmatch in pre-sensitized patients: It should be closely monitored. Recurrence of the original disease: C4d deposition may occur in various native kidney diseases and may rarely indicate recurrence.
The intensity, distribution and staining pattern differ from AMR
IgA nephropathy: C4d deposition is mostly mesangial
Membranous nephropathy: deposition is primarily along glomerular capillary wall
Membranoproliferative GN: C4d deposited mainly along capillary loop
Lupus nephritis: deposition in glomerular capillary wall, PTC and mesangium
TMA: deposited in glomerulus and arterioles
Anti-GBM and ANCA vasculitis
Pregnancy: with antiphospholipid antibody mediated fetal loss and preeclampsia.
Etta PK. C4d staining and antibody-mediated rejection in renal transplantation: Current status. Indian Journal of Transplantation. 2020 Jul 1;14(3):197.
Cohen D, Colvin RB, Daha MR, Drachenberg CB, Haas M, Nickeleit V, Salmon JE, Sis B, Zhao MH, Bruijn JA, Bajema IM. Pros and cons for C4d as a biomarker. Kidney international. 2012 Apr 1;81(7):628-39.
Chandra P. C4d in native glomerular diseases. American journal of nephrology. 2019;49(1):81-92.
C4d is generated after activation of complement system which binds to the endothelial and collagen basement membrane. C4d is considered the footprint of complement dependant ABR. C4d deposition is usually associated with DSA in ABR, but if there is no DSA it could result from anti-endothelial alloantibodies. C4d deposition can be assessed using IHC and IF. Although it’s the mark for ABR it can occur in other settings which are:
Graft Accommodation (ABO incompatible transplant): C4d deposition in PTCs in the absence of graft rejection and regardless of DSA positivity.
Native Renal diseases such as ANCA associated vasculitis and antiphospholipid syndrome.
A positive immunohistochemical stain for C4d in peritubular capillaries is considered very specific for AbMR, although with limited sensitivity
C4d-negative AbMR was discovered following gene expression analyses of transplant biopsies, which identified a set of elevated endothelial transcripts in cases of AbMR, whether they were C4d positive or negative. Since then, a broader set of transcripts elevated in AbMR has been described, including natural killer cell transcripts.
Identification of both C4d and C1q on IF indicates activation of the CP, but the presence of C4d without C1q is more consistent with MBLP activation.
(1–3) 1- Native Proliferative GN
A- immune complex-mediated results in activation of the classical complement pathway such as MPGN, IgA nephropathy, Lupus nephritis, fibrillary GN, membranous nephropathy
B- complement-mediated such as C3 glomerulopathy (4,5) 2- ABO-incompatible graft
. C4d positivity is not associated with graft dysfunction, poor outcome, or ultrastructural evidence of endothelial injury.
While; in ABO compatible graft, occasional renal transplant biopsies show C4d +WER ( i.e. without inflammation or injury) (2)
3- Pregnancy- preeclampsia (6) 4- TMA, Anti-GBM, ANCA associated vasculitis
In anti-glomerular basement membrane (GBM) disease or ANCA-associated vasculitis. Renal biopsy was remarkable for IgA nephropathy, lesions of active thrombotic microangiopathy (TMA) and positive staining for complement factor C4d. (7) 5- BK nephropathy shows tubular basement membrane C4d staining, which correlates with marked viral cytopathic effect. (8)
References:
1. Snijders MLH, Sablik KA, van den Bosch TPP, Hesselink DA, Betjes MGH, Batal I, et al. Clinical Relevance of Arteriolar C4d Staining in Patients With Chronic-active Antibody-mediated Rejection: A Pilot Study. Transplantation [Internet]. 2020;104(5). Available from: https://journals.lww.com/transplantjournal/Fulltext/2020/05000/Clinical_Relevance_of_Arteriolar_C4d_Staining_in.31.aspx
2. Dominy KM, Willicombe M, Al Johani T, Beckwith H, Goodall D, Brookes P, et al. Molecular Assessment of C4d-Positive Renal Transplant Biopsies Without Evidence of Rejection. Kidney Int reports [Internet]. 2018 Sep 18;4(1):148–58. Available from: https://pubmed.ncbi.nlm.nih.gov/30596178
3. Drachenberg CB, Papadimitriou JC, Chandra P, Haririan A, Mendley S, Weir MR, et al. Epidemiology and Pathophysiology of Glomerular C4d Staining in Native Kidney Biopsies. Kidney Int reports [Internet]. 2019 Jul 30;4(11):1555–67. Available from: https://pubmed.ncbi.nlm.nih.gov/31890997
4. Singh G, Singh SK, Nalwa A, Singh L, Pradeep I, Barwad A, et al. Glomerular C4d Staining Does Not Exclude a C3 Glomerulopathy. Kidney Int reports. 2019 May;4(5):698–709.
5. Bashir S, Hussain M, Afzal A, Hassan U, Hameed M, Mushtaq S. C4d at Crossroads Between Post-Infectious Glomerulonephritis and C3 Glomerulopathy. Int J Nephrol Renovasc Dis [Internet]. 2021 Mar 11;14:87–95. Available from: https://pubmed.ncbi.nlm.nih.gov/33732010
6. Choi S-Y, Kim K-H, Lee M, Yeo M-K, Kim J, Suh K-S. Complement Component C4d Deposition in the Placenta of Preeclampsia Patients and Renal Glomeruli in 1 Postpartum Renal Biopsy. Appl Immunohistochem Mol Morphol AIMM. 2020 Feb;28(2):139–45.
7. Binet Q, Aydin S, Lengele J-P, Cambier J-F. Lessons for the clinical nephrologist: an uncommon cause of pulmonary-renal syndrome. J Nephrol. 2021 Jun;34(3):935–8.
8. Batal I, Zainah H, Stockhausen S, Basu A, Tan H, Shapiro R, et al. The significance of renal C4d staining in patients with BK viruria, viremia, and nephropathy. Mod Pathol an Off J United States Can Acad Pathol Inc. 2009 Nov;22(11):1468–76.
-Histological assessment of the complement split product C4 is useful for the diagnosis of acute antibody-mediated rejection. C4d is generated by C4 activation in both, the classical and the Mannose-binding lectin complement pathways. A false positive C4d staining (in absence of AMR) in a kidney biopsy can be seen in many conditions like:
1. In ABO-incompatible grafts.
2. pregnancy
3. systemic autoimmune diseases
4. Glomerular diseases ;lupus nephritis, MGN, MPGN with IC, acute postinfectious GN, fibrillary GN, and proliferative glomerulonephritis with monoclonal IgG deposits (PGMID)
5. BK nephropathy Reference :
-Danielle Cohen, Robert B. Colvin, et al.Pros and cons for C4d as a biomarker. Kidney Int. 2012 Apr; 81(7): 628–639. Cinthia B. Drachenberg
-John C. Papadimitriou ,Preeti Chandra et al Epidemiology and Pathophysiology of Glomerular C4d Staining in Native Kidney Biopsies .Clinical research . VOLUME 4, ISSUE 11, P1555-1567, NOVEMBER 01, 201
– Ibrahim Batal, Hanady Zainah et al. The significance of renal C4d staining in patients with BK viruria, viremia, and nephropathy. Modern Pathology volume 22, pages1468–1476 (2009)
C4d is generated by activating both classical and mannose-binding lectin complement pathways; it is activated by binding to the tissue component. Assessment of C4d deposition is done either by IHC or IF; the latter seems to be more sensitive.
Positive C4d staining in the absence of rejection is seen in:
Native renal diseases such as ANCA associated vasculitis, antiphospholipid ab syndrome, TMA, membranous nephropathy, MPGN, fibrillary GN, proliferative GN with monoclonal Ig, amyloidosis, and C1q nephropathy. ( glomerular C4d staining).
In an autoimmune renal disease such as lupus nephritis ( tubular C4d staining).
Pregnancy: antibody-mediated pregnancy loss ( preeclampsia and APL ab syndrome).
IgA nephropathy ( glomerular C4d staining).
BK nephropathy ( tubular C4d staining) viral cytopathic effect.
References:
Cohen D, Colvin RB, Daha MR, Drachenberg CB, Haas M, Nickeleit V, et al. Pros and cons for C4d as a biomarker. Kidney Int. 2012 April ; 81(7): 628–639.
Drachenberg CB,Papadimitriou JC, Chandra P, Haririan A, Mendley S, Weir MR, et al. Epidemiology and Pathophysiology of Glomerular C4d Staining in Native Kidney Biopsies. Kidney International Reports (2019) 4, 1555–1567.
Li P, Cheng D, Wen J, Ni X, Li X, Xie K, et al. The immunophenotyping of different stages of BK virus allograft nephropathy Renal Failure.2019;41(1): 855-861.
Low level DSA not detected by standard assays Alloantibodies may be absorbed by the graft, which are sometimes seen to reappear after graft nephrectomy. C4d may be produced due something else like autoimmune disease ABO incompatible transplants
C4d is the degradation product of classical complement pathway, which is one of the essential criteria for ABMR due to it’s long-term stability, prognostic validity and sensitivity,but it can be positive without abmr-
1.mesangium and vascular pole in normal
kidney.
2.ABOi tx (marker of accomodation)
3.Lupus Nephritis(c4d on tbm is disease activity
and arteriolar c4d is poor prognosis)
4.IgA nephropathy, MPGN like autoimmune
disorder.(marker of complement activation)
5.BK virus nephropathy on tbm(viral cytopathic
effect)
6.pregnancy (in eclampsia and apla)
7.TMA (vascular involvement by complement)
A false positive C4d staining (in absence of AMR) in a kidney biopsy can be seen in many conditions like: 1) ABO incompatible kidney transplant, where it is a marker of graft accommodation. (1,2,3,4) 2) In positive cross-matched/ pre-sensitized patients. (4) 3) In autoimmune diseases, like Lupus nephritis. Tubular basement membrane C4d deposition in lupus nephritis is associated with disease activity while arteriolar C4d deposition is associated with adverse outcomes. (4, 5) 4) In IgA nephropathy, glomerular C4d deposition can be seen, is a marker of disease progression, and is associated with adverse prognosis. (6) 5) In BK virus nephropathy, tubular basement membrane C4d staining correlates with marked viral cytopathic effect. (7) 6) In other native renal disease like MPGN (along capillary loop), Membranous nephropathy (along glomerular capillary wall), ANCA vasculitis, Anti-GBM disease, C4 glomerulopathy, Post infectious glomerulonephritis, and TMA. (8)
So it is very important to interpret a C4d deposition in kidney biopsy cautiously. References: 1) Haas M, Sis B, Racusen LC, Solez K, Glotz D, Colvin RB, Castro MC, David DS, David-Neto E, Bagnasco SM, Cendales LC, Cornell LD, Demetris AJ, Drachenberg CB, Farver CF, Farris AB 3rd, Gibson IW, Kraus E, Liapis H, Loupy A, Nickeleit V, Randhawa P, Rodriguez ER, Rush D, Smith RN, Tan CD, Wallace WD, Mengel M; Banff meeting report writing committee. Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions. Am J Transplant. 2014 Feb;14(2):272-83. doi: 10.1111/ajt.12590. Erratum in: Am J Transplant. 2015 Oct;15(10):2784. Rangel, Erika [corrected to Rangel, Erika B]. PMID: 24472190. 2) Haas M, Rahman MH, Racusen LC, Kraus ES, Bagnasco SM, Segev DL, Simpkins CE, Warren DS, King KE, Zachary AA, Montgomery RA. C4d and C3d staining in biopsies of ABO- and HLA-incompatible renal allografts: correlation with histologic findings. Am J Transplant. 2006 Aug;6(8):1829-40. doi: 10.1111/j.1600-6143.2006.01356.x. PMID: 16889542. 3) Setoguchi K, Ishida H, Shimmura H, Shimizu T, Shirakawa H, Omoto K, Toki D, Iida S, Setoguchi S, Tokumoto T, Horita S, Nakayama H, Yamaguchi Y, Tanabe K. Analysis of renal transplant protocol biopsies in ABO-incompatible kidney transplantation. Am J Transplant. 2008 Jan;8(1):86-94. doi: 10.1111/j.1600-6143.2007.02036.x. Epub 2007 Nov 12. PMID: 18021283. 4) Cohen D, Colvin RB, Daha MR, Drachenberg CB, Haas M, Nickeleit V, Salmon JE, Sis B, Zhao MH, Bruijn JA, Bajema IM. Pros and cons for C4d as a biomarker. Kidney Int. 2012 Apr;81(7):628-39. doi: 10.1038/ki.2011.497. Epub 2012 Feb 1. PMID: 22297669; PMCID: PMC3771104. 5) Ding Y, Yu X, Wu L, Tan Y, Qu Z, Yu F. The Spectrum of C4d Deposition in Renal Biopsies of Lupus Nephritis Patients. Front Immunol. 2021 Jul 1;12:654652. doi: 10.3389/fimmu.2021.654652. PMID: 34276649; PMCID: PMC8281350. 6) Jiang Y, Zan J, Shi S, Hou W, Zhao W, Zhong X, Zhou X, Lv J, Zhang H. Glomerular C4d Deposition and Kidney Disease Progression in IgA Nephropathy: A Systematic Review and Meta-analysis. Kidney Med. 2021 Aug 6;3(6):1014-1021. doi: 10.1016/j.xkme.2021.06.009. PMID: 34939010; PMCID: PMC8664744. 7) Batal I, Zainah H, Stockhausen S, Basu A, Tan H, Shapiro R, Zeevi A, Girnita A, Randhawa P. The significance of renal C4d staining in patients with BK viruria, viremia, and nephropathy. Mod Pathol. 2009 Nov;22(11):1468-76. doi: 10.1038/modpathol.2009.118. Epub 2009 Sep 4. PMID: 19734851. 8) Chandra P. C4d in Native Glomerular Diseases. Am J Nephrol. 2019;49(1):81-92. doi: 10.1159/000496059. Epub 2019 Jan 4. PMID: 30612132.
Systemic autoimmune diseases ( activation of classical pathway of complement had an important role in lupus nephritis. Presence of C4d deposition in TBm associated with disease activity while arteriolar C4d deposition had prognostic value for renal outcome).
Pregnancy.
TMA
Glomerulonephritis
Acute TCMR
References:
Cohen D., Colven R., Daha M., Drachenberg C., Haas M., et al. Pros and cons for C4d as a biomarker. kidney Int.2012, 81(7):628-639.
Reuter S., Kentrup D., Grabner A., Kohler G., Buscher K. and Edmir B. C4d Deposition after Allogenic Renal Transplantation in Rats Is Involved in Initial Apoptotic Cell Clearance. Cell, 2021;10:3499.
Ding Y., Yu X., Wu L., Tan YQu Z. and Yu F. The Spectrum of C4d Deposition in Renal Biopsies of Lupus Nephritis Patients. Frontiers in immunology. 2021;12.
C4d staining in the absence of concomitant histologic evidence of rejection in renal allografts from patients with ABO incompatibility may serve as a signal for stable graft accommodation.
Autoimmune disorders such as lupus nephritis, IgA nephropathy, or any sort of lectin pathway activation can also result in C4d accumulation.
C4d staining of the tubular basement membrane can also be seen in BK nephropathy.
C4d deposition within peritubular capillaries (PTCs) in renal allograft biopsies can be used to diagnose (AMR) in patients.
Cohen D, Colvin RC, Daha M, et al. Pros and cons for C4d as a biomarker. Kidney Int.
-In ABO-incompatible grafts with no histopathology nor graft dysfunction considred as ‘graft accommodation’. No treatment is necessary, but close follow-up is needed.
-In positive cross-matched patients (presensitized patient), it is a rare but more seious condition. In case of normal histology without graft dysfunction ,it is considered as probable AMR and consider treating the patient.
-In native kidney disease, peritubular capillary C4d staining was investigated in many forms of glomerulonephritis. The only exception was lupus nephritis, in which granular peritubular capillary staining has been rarely described, therefore the diagnosis of AMR in a transplanted systemic lupus erythematosus (SLE) patient is considered or the recurrence of the original disease should then be ruled out.
-C4d is detected in pregnancy, in particular in the setting of ‘antiphospholipid antibody-mediated fetal loss’ and preeclampsia. In autoimmune settings C4d might have a role in identifying patients at risk of developing thrombotic complications.
diffuse C4d staining of peritubular capillaries in these biopsies was commonly found, even in protocol biopsies. However, the fact that more than 70–80% of ABO-incompatible grafts showed diffuse C4d positivity
2-C4d IN NATIVE RENAL DISEASE
In lupus nephritis, glomerular C4d deposition can be detected in the majority of cases with a full-house immuno-fluorescence pattern, as a result of immune complex deposition
detected glomerular C4d only in a small subgroup of patients with anti-neutrophil autoanti-body-negative pauci-immune glomerulonephritis, whereas in the anti-neutrophil autoantibody-positive patients, it was absent.
3-C4d IN PREGNANCY: ANTIBODY-MEDIATED PREGNANCY LOSS
placental C4d was detectable in the majority of SLE and antiphospholipid syndrome cases (>60%) in a diffuse staining pattern at the fetal-maternal interface ,whereas in normal pregnancies C4d was always negative. Excessive placental C4d was related to impaired fetal outcome due to fetal loss or due to prematurity in the setting of preeclampsia.
4-BK nephropathy
A subset of biopsies with BK nephropathy shows tubular basement membrane C4d staining, which correlates with marked viral cytopathic effect.
Reference
1-Danielle Cohen1, Robert B. Colvin2, Mohamed R. Daha3, Cinthia B. Drachenberg4, Mark Haas5, Volker Nickeleit6, Jane E. Salmon7, Banu Sis8, Ming-Hui Zhao9, Jan A. Bruijn1, and Ingeborg M. Bajema1. Pros and cons for C4d as a biomarker
Published in final edited form as:
Kidney Int. 2012 April ; 81(7): 628–639. doi:10.1038/ki.2011.497.
2- Ibrahim Batal, Hanady Zainah, Sean Stockhausen, Amit Basu, Henkie Tan, Ron Shapiro, Adriana Zeevi, Alin Girnita & Parmjeet Randhawa.
The significance of renal C4d staining in patients with BK viruria, viremia, and nephropathy
Published: 04 September 2009
Modern Pathology (2009) 22, 1468–1476
ABMR occurs due to the binding of circulating antibodies to donor alloantigens located on graft endothelium leading to complement activation ( classical complement pathway ) with the final production of c5b, c3b, c3a, c5a leading to inflammation, cell damage, and graft dysfunction.
1.ABO-incompatible renal allografts, show C4d staining without histologic findings of AMR or cell-mediated rejection.
2.ln positive cross-match and conventional renal allografts such C4d deposition is uncommon, and may indicate potentially reversible graft injury.
3.C4d is now increasingly recognized as a potential biomarker in other fields where antibodies can cause tissue damage, such as systemic autoimmune diseases and pregnancy. In all these fields, C4d holds promise to detect patients at risk for the consequences of antibody-mediated disease.
Ref:
1.lecture professor Tareg Albaz
2.Danielle Cohen, et al” Pros and cons for C4d as a biomarker”
3.Review Pros and cons for C4d as a biomarker
Author links open overlay panelDanielleCohen1Ingeborg M.Bajema1
Dear Dr Manal C4d positive in the absence of AMR. Please review your answer
Manal Malik
3 years ago
follow
Diffuse PTC C4d staining can occur in the absence of other histologic features of injury in recipients of ABO incompatible kideny transplant,a phenomoenon konwn as graft accommodation
Yes, this what we want to see, well done, but expand more
Manal Malik
3 years ago
Graft dysfunction due to ABMR, as defined by DSA or C4d positivity,can be present despite the absence of histomorphologic features of rejection.
C4d is degradation product of classic complement pathway, that bind s covalenty to the endothelial and collagen basement membranes
It is serving as an immunologic foot footprint of complement activation and antibody- mediated injury.
C4d is detecable in the glomerular mesangium and vascular pole in normal kideny, but deposition in PTCs has only been in renal allografts.
C4d is reported as diffusely postive when invoving >50% ofv PTCs.
C4d staining postive still has limitations in diagnosis of ABMR .by the following observations:
Diffuse PTC C4d staining can occur in the absence of other histologic features of injury in recipients,a phenomenon konwn as graft accommodation .
REFERENCES
1.Rush DN,Henrt sf,jeffery jr,et al, Histological finings in early routine biopsies of stable allograft recipients,Transplantation 1994,57:208.
2-Kee.TY.Chapman jR Oconnell pj,et al,Treatment of subclinical rejection diagnosed by protocol biopsy of kideny transplant,Transplantation2006,82:36.
-The accommodation is defined as C4d deposition in PTCs in the absence of active rejection with or without DSA positivity, mostly seen in ABO‐incompatible graft transplantation.
-BK nephropathy.
-Autoimmune disease
-presence of Alloantibodies.
– TMA
Under what conditions you get false positive C4d staining (positive C4d staining without AMR)? C4d positivity without detectable DSA
Allontibodies are present, but they are not detected by standard anti HLA assays (for example, anti endothelial antibodies).
Alloantibodies are absorbed by the graft, as is sometimes shown by reappearance of alloantibodies in the blood after graft nephrectomy.
Alloantibodies are not present and C4d deposition is caused by something else than DSA (for instance autoimmune disease, i.e., lupus nephritis or any form of lectin pathway activation)
BKV nephropathy
C4d positivity in grafts without histological abnormalities
ABO incompatible grafts.
In positive cross matched patients (presensitized patient), this should not be seen as graft accommodation and is a rare and more worrying situation In case of normal histology and no graft dysfunction: Interpret as probable AMR and consider treating the patient.
o in fact, c4d represents activation of classic complement pathway.
o It remains bound to endothelium at site of injury by covalent bonds, so remain detectable for longer period even after disappearance of antibodies.
o it can present in case of ABO incompatible transplantation with accomodation to their presence without immune mediated damage of the graft.
in addition, presence of them in any immune mediated kidney disease either in recurrence of original kidney disease or originally in the donor and was not identified such as ;lupus nephritis (deposits mainly glomerular and mesangial..
however, peculiar deposition in ptc may be specific for AMR.
( C4d depotion without assoaciated histological evidence of acute or chronic graft damage)
– ABO incompitable transplantation where C4d reflects graft accommodation rather than AMR
– C4d may occur with other conditions as autoimmune diseases and pregnancy Cohen D, Colvin RB, Daha MR, et al. Pros and cons for C4d as a biomarker. Kidney Int. 2012;81(7):628-639. doi:10.1038/ki.2011.497
Tahani Ashmaig
3 years ago
Positive C4d staining without AMR:
__________________________________
▪︎C4d deposition within peritubular capillaries (PTCs) in renal allograft biopsies is a useful tool for diagnosis of AMR.
▪︎C4d staining without associated histologic findings of rejection may represent a marker for stable graft accommodation in ABO-incompatible renal allografts[1]
▪︎A state of C4d staining without associated graft injury may be inducible in positive cross-match grafts by complement inhibition.
▪︎C4d deposition can also be caused by autoimmune diseases, i.e., lupus nephritis, IgA nephropathy or any form of lectin pathway activation[2].
▪︎BK nephropathy also can show tubular basement membrane C4d staining [3]
__________________
Ref:
[1] Mark Hass. “The significance of C4d staining with minimal histologic abnormalities” Curr Opin Organ Transplant. 2010 Feb.
[2] Danielle Cohen, et al” Pros and cons for C4d as a biomarker”
[3] E Honsová et al. ” BK-virus nephropathy and simultaneous C4d positive staining in renal allografts”. Cesk Patol. 2005 Oct.
Under what conditions you get false positive C4d staining (positive C4d staining without AMR)?
# C4d positivity without detectable DSA
Possible explanations:
* Allo antibodies are present, but they are not detected by standard anti HLA assays (for example, anti endothelial antibodies).
* Allo antibodies are absorbed by the graft, as is sometimes shown by reappearance of allo antibodies in the blood after graft nephrectomy.
* Allo antibodies are not present and C4d deposition is caused by something else than DSA (for instance autoimmune disease, i.e., lupus nephritis or any form of lectin pathway activation)
# C4d positivity in grafts without histological abnormalities
*In ABO incompatible grafts:
In case of no histopathology and no graft dysfunction: It is suggested to interpret this as ‘graft accommodation’. No treatment is necessary, but close follow-up is strongly advised, as it is unknown what happens with these grafts during long-term followup.
* In positive cross matched patients (presensitized patient), this should not be seen as graft accommodation and is a rare and more worrying situation than the above: In case of normal histology and no graft dysfunction: Interpret as probable AMR and consider treating the patient.
References
1. Nickeleit V, Mihatsch MJ. Kidney transplants, antibodies and rejection: is C4d a magic marker? Nephrol Dial Transplant. 2003;18:2232–2239. [PubMed] [Google Scholar]
2. Sarma JV, Ward PA. The complement system. Cell Tissue Res. 2011;343:227–235. [PMC free article] [PubMed] [Google Scholar]
3. Sis B, Halloran PF. Endothelial transcripts uncover a previously unknown phenotype: C4d-negative antibody-mediated rejection. Curr Opin Organ Transplant. 2010;15:42–48. [PubMed] [Google Scholar]
4. Regele H, Bohmig GA, Habicht A, et al. Capillary deposition of complement split product C4d in renal allografts is associated with basement membrane injury in peritubular and glomerular capillaries: a contribution of humoral immunity to chronic allograft rejection. J Am Soc Nephrol. 2002;13:2371–2380. [PubMed] [Google Scholar]
5. Berger SP, Roos A, Daha MR. Complement and the kidney: what the nephrologist needs to know in 2006? Nephrol Dial Transplant. 2005;20:2613–2619. [PubMed] [Google Scholar] et.al
2. Under what conditions you get false positive C4d staining (positive C4d staining without AMR)?
Substantiate your answer
Causes of C4d positivity without detectable DSA:
1. Presence of alloantibodies(e.g. anti-endothelial antibodies)that are not detected by the standard anti-HLA assays. 2. Alloantibodies are absorbed by the graft. These antibodies sometimes reappear in the blood post graft nephrectomy. 3. Autoimmune diseases such as lupus nephritis. Here alloantibodies not present & C4d deposition is not caused by DSA. 4. BKV nephropathy
Causes of C4d positivity in graft without histological abnormalities: 1. ABOi grafts: if no graft dysfunction as well, this is considered graft accommodation. No need for treatment but only close follow up. It shouldn’t be seen as graft accommodation if this happened in presensitized, positive cross matched patients. It should be treated as probable AMR. Reference ros and cons for C4d as a biomarker Danielle Cohen, Robert B. Colvin,Mohamed R. Daha et al Pros and cons for C4d as a biomarker Kidney International Volume 81,Issue 7 April 2012
C4d stain indicate complement involvement in antigen antibody reaction in the body ,it destroyed to fragment and deposited,so many immune reaction may cause positive C4d rather than AMR like:
ABO incompatible transplant
Autoimmune disease
Some infection like BK nephropathy
ABO incompatible transplant.
BKV CMV nephropathy.
Lupus nephritis, Antiphospholipid syndrome. Anca associated nephropathy.
IG A nephropathy
TMA
HUS.
Reference
1) Collins A.B., Schneeberger E.E., Pascual M.A., et al.
Complement activation in acute humoral renal allograft rejection: diagnostic significance of C4d deposits in renal transplant. J Am Soc Nephrol, 10 (1999), pp. 2208-2214
C4d deposition in peritubular capillaries is a specific marker for the presence of antidonor antibodies in renal transplant recipients and is usually associated with antibody-mediated rejection .Presence of C4D positive without AMR in :
-in ABO-incompatible renal allografts The significance of C4d staining in the absence of other histologic changes remains unclear.it seems to point at ‘graft accommodation .
-In systemic autoimmune diseases and pregnancy.In SLE patients indicate the disease activity .Viral infection especially BK virus .
POSITIVE C4D STAINING WITHOUT AMR
References :
C4d is a degradation product generated from activation of the classic complement pathway. It binds covalently to the endothelial and collagen basement membranes of the graft and deposited in the PTCs serving as an immunologic footprint of complement activation and antibody-mediated injury (AMR).It can be assessed using IHC and IF(IF is more sensitive).
Other causes of C4d staining includes:
C4d positive staining with no other histological finding:
o ABO-incompatible transplantation. The presence of C4d represents graft accommodation with no active rejection, this requires follow-up with no active treatment.
o Positive C4d in pre-sensitized and positive cross matched patients should be treated as a possible AMR
C4d positive staining with no DSAs:
o C4d positive in the absence of DSAs indicates the presence of alloantibodies like anti-endothelial alloantibodies and anti-angiotensin type 1 receptor antibodies and these are not detected by standard HLA assays.
o Autoimmune diseases like Lupus nephritis (When C4d is deposited in the tubular basement membrane, it indicates disease activity while arteriolar C4d deposition signifies a poor prognosis).
o Other native renal diseases like IgA(deposition is mostly mesangial but glomerular C4d indicates disease progression and poor prognosis) MPGN(C4d along the capillary loop), membranous nephropathy(C4d along glomerular capillary wall), post infectious GN, ANCA, anti-GBM and vascular disorders like TMA(deposition in the glomerulus and arterioles)
o C4d in pregnancy: antibody-mediated pregnancy loss ( preeclampsia and anti-phospholipid syndrome
o BK nephropathy(tubular basement membrane C4d)
It is important to interpret renal biopsies with caution as C4d positivity in the absence of other histological and serological findings(DSAs) of AMR is unlikely to be significant (false positive C4d staining).
References:
1.Cohen D, Colvin RB, Daha MR, Drachenberg CB, Haas M, Nickeleit V, et al. Pros and cons for C4d as a biomarker. Kidney Int. 2012 April ; 81(7): 628–639
2. Chandra P. C4d in Native Glomerular Diseases. Am J Nephrol. 2019;49(1):81-92
3. Li P, Cheng D, Wen J, Ni X, Li X, Xie K, et al. The immunophenotyping of different stages of BK virus allograft nephropathy Renal Failure.2019;41(1): 855-861
Under what conditions you get false positive C4d staining (positive C4d staining without AMR)?
1- ABO incompatible transplantation: C4d reflects graft accommodation rather than AMR. Graft accommodation means C4d deposited in PTC without active rejection. More than 705 of ABO incompatible RTx showed diffuse C4d positivity in protocol biopsies.
2- Positive cross matched recipients.
2- Other conditions as autoimmune diseases like SLE, arteriolar C4d staining is a risk factor for adverse outcomes. However, tubular C4d deposition is associated with disease activity.
3- Pregnancy, especially in SLE and anti-phospholipid syndrome patients.
4- BKV nephropathy, tubular BM C4d staining indicates high viral cytopathic impact.
5- TMA, and atypical HUS.
6-Pauci-immune GN.
7-IgA Nephropathy, glomerular C4d deposition indicates disease progression and poor prognosis.
8-MPGN, MN, anti-GBM, C4 glomerulopathy, Fibrillary GN, C1q nephropathy and post infectious GN.
2. Under what conditions you get false positive C4d staining (positive C4d staining without AMR)?
– ABO-incompatible transplantation.
2-SLE & antiphospholipid syndrome .
3- IGA nephropathy.
4_ BK nephropathy .
C4d is an end product of c4b, which indicate classical complement pathway activation.
like any other imuunodeposition in immunohistochemistry microscopy the site and the pattern of deposition differ from disease to another
-in ABOi usually presented with linear depostion in the peritubular capillaries and its represent accomodation not rejection
-in some glomerular disease specially 1ry membranous nephropathy it usually deposit granular and in the glomerulus
-in BK infection it deposite in the tubules
refernece
Danielle Cohen1, Robert B. Colvin2, Mohamed R. Daha3, Cinthia B. Drachenberg4, Mark Haas5, Volker Nickeleit6, Jane E. Salmon7, Banu Sis8, Ming-Hui Zhao9, Jan A. Bruijn1, and Ingeborg M. Bajema1. Pros and cons for C4d as a biomarker Published in final edited form as:Kidney Int. 2012 April ; 81(7): 628–639. doi:10.1038/ki.2011.497.
False positive C4d staining with absent AMR :
*ABO incompatible Kidney Tx
* in presensetized patients with cross match positive
* IgA nephropathy and may be used as a marker of disease progression.
* LUPUS Nephritis associated with adverse outcomes .
* viral infections as BK nephropathy.
* Native Kidney disease like MN ,ANCA vasculature, Anti GBM , TMA ,MPGN .
Under what conditions you get false positive C4d staining (positive C4d staining without AMR)?
C4d is an end product of c4b, which indicate classical complement pathway activation.
C4d is a footprint for antibody-mediated tissue injury.
But C4d may be negative in some ABMR even when the DSA is positive .
in ABO-I transplantations C4d is present in the majority of grafts but this is ‘accommodation’ rather than AMR . therefor it is not a use full test in this situation, as it is not needed to be treated.
C4d help to detect patients at risk for the consequences of ABMR.
Therefor C4d positivity is common in ABO-I transplantation , it is not alarming and does not need treatment .
The emergence of new (though expensive ) drug that is directed toward inhibition of complement system increases the importance of C4d in early detection of a treatable related condition .
In C4d negative patient, molecular study (endothelial injury associated transcript) provide a hint to a complement-independent form of AMR or C4d-negative AMR.
C4d is scored semiquantitatively in four categories:
1- No C4d staining (0% of (peritubular) capillaries)
2- Minimal C4d staining (0–10% of (peritubular) capillaries)
3- Focal C4d staining (10–50% of (peritubular) capillaries)
4- Diffuse C4d staining (>50% of (peritubular) capillaries)
Immunofluorescence is a more sensitive method to detect C4d than immunohistochemistry, by approximately one grade of the scoring system.
– a diffuse C4d staining is defined as positive,
But the clinical significance of ‘minimal’ and ‘focal’ C4d staining remain debated.
The a focal staining pattern can be considered as a red flag, especially in
· by paraffin-embedded tissue or
· in the presence of donor-specific antibody and/or
· suspicious histopathological features.
Most laboratories consider this as ‘positive for (AMR)’.
· It is advised to treat this patient.
2- In frozen tissue combined with
· a positive test for DSA and
· histopathological features:
· The diagnosis is a ‘probable AMR’.
· Suggest to consider treatment, but further investigation is needed.
C4d positivity without detectable DSA causes :
1- It occue when Allo-antibodies are present, but they are not detected by standard anti-HLA assays (for example, anti-endothelial antibodies).
2- Allo-antibodies are absorbed by the graft, and it may reappear after graft nephrectomy.
3- Allo-antibodies are not present and C4d deposition is caused by something else than DSA (autoimmune disease, i.e., lupus nephritis or any form of lectin pathway activation).
Management :
In case of diffuse C4d staining in peritubular capillaries and histological evidence for AMR: Most experts would advise to treat the patient for AMR.
In case of focal C4d staining and histological evidence for AMR: Check for other possible underlying diseases. If no other cause can be found: Treat the patient for AMR.
In case of focal or diffuse C4d staining and absence of histological changes the decision as to whether to treat for AMR is more uncertain. Treating or close follow-up are both suitable options.
C4d positivity in grafts without histological abnormalities
1- In ABO-incompatible grafts: without any other signs of ABMR (it is called graft accommodation). No treatment is needed , but close monitoring is recommended .
2- In positive cross-matched patients (pre sensitized patient), normal histology and no graft dysfunction: this is probable AMR and needs treatment.
3- Vascular disease (non-antibody complement activation )
4- Lupus nephritis due to immune complex disease(glomerular deposits, non specific )
reference’s
1-Cohen D, Colvin RB, Daha MR, Drachenberg CB, Haas M, Nickeleit V, et al. Pros and cons for C4d as a biomarker. Kidney Int. 2012 April ; 81(7): 628–639
2- peofessor Ahmed Halawa lecture .Applied transplant immunology,,2022
It is very important to interpret C4d in a renal biopsy….C4d is a very easy staining and in expensive….It signifies complement activation…..C4d is a breakdown fragment of C4b which gets deposited in the tissues…It has strong disulphide bonds which bind to the cells and it serves as a footprint of antibody mediated rejection…. False positive C4d without any histological changes of AMR can be seen only in few conditions..
ABO incompatible kidney transplant, where it is a marker of graft accommodation.C4d has been shown to be present in the tissues without any signs of AMR or graft dysfunction…It is found in 70 to 80% of all ABOi kidney transplant recipients without signs of rejection, there is diffuse peritubular capillary deposition of C4d….
Glomerular C4d deposit indicate complement mediated diseases….In IgA nephropathy glomerular C4d deposition has been shown to be associated with worse prognosis…
In Lupus nephritis tubular C4d deposition is associated with disease activity while the arteriolar C4d deposition is associated with worse prognosis
C4d deposition is also seen in MPGN, antiphospholipid antibody syndrome.
Placental C4d was detectable in SLE and antiphospholipid syndrome cases (>60%) in diffuse staining pattern of C4d in the maternofetal interface in the placenta
BK Virus nephropathy also shows c4d positivity with viral cytopathic effects..
Under what conditions you get false positive C4d staining (positive C4d staining without AMR)?1- ABO-incompatible transplantation represents graft accommodation.
2- native renal diseases such ANCA associated vasculitis , anti-phospholipid ab syndrome,TMA , membranous Nephropathy MPGN , fibrillation glomerulolnepheritis , proliferating glomerulonepheritis with monoclonal IG , amyloidosis C1q nephropathy ( glomerular c4d staining) .
3- Autimmune renal diseases such as lupus nephritis( tubular c4d staining)
4-pregnancy : antibody-mediated pregnancy loss ( pre-eclamspia and anti-phospholipid antibody syndrome.
5-IgA nephropathy ( glomerular c4d staining).
6- Bk nephropathy( tubular c4d staining) viral cytopathic effect.
Reference
1-Danielle Cohen1, Robert B. Colvin2, Mohamed R. Daha3, Cinthia B. Drachenberg4, Mark Haas5, Volker Nickeleit6, Jane E. Salmon7, Banu Sis8, Ming-Hui Zhao9, Jan A. Bruijn1, and Ingeborg M. Bajema1. Pros and cons for C4d as a biomarker
Published in final edited form as:
Kidney Int. 2012 April ; 81(7): 628–639. doi:10.1038/ki.2011.497.
2- Ibrahim Batal, Hanady Zainah, Sean Stockhausen, Amit Basu, Henkie Tan, Ron Shapiro, Adriana Zeevi, Alin Girnita & Parmjeet Randhawa.
The significance of renal C4d staining in patients with BK viruria, viremia, and nephropathy
Published: 04 September 2009
Modern Pathology (2009) 22, 1468–1476
Positive C4d staining in the absence of rejection is seen in:
References:
Positive C4d without AMR :
ABO I graft transplantation as graft accommodation :
With diffuse C4d staining of peritubular capillaries in 70-80% of ABO I Kidney transplantation.
no histopathological findings and no graft dysfunction of Allograft
IgA nephropathy viral infection BK virus ,and atypical HUS.
Peritubular capillary deposition of C4d in lupus nephritis,
ANCA associated vasculitis
In pregnancy with antibody-mediated fetal loss like SLE &APL.
Placental C4d was detectable in SLE and antiphospholipid syndrome cases (>60%) in diffuse staining pattern of C4d in the maternofetal interface in the placenta
The significance of C4d staining in the absence of histologic changes to AMR remains obscure, but protocol biopsies of ABO-incompatible grafts show PTC C4d deposition that is often diffuse but only infrequently associated with histologic changes of AMR.
C4d staining without evidence of rejection was determined to be present when each of the following five criteria were met: (1) Diffuse PTC C4d staining with intensity 1; (2) PTC margination score of 0 and no evidence of TMA; (3) no concurrent ACR (Banff ’97 grade 1A or greater); (4) Banff g and cg indices of 1 and 0, respectively; and (5) presence of BGA in serum with specificity for donor blood group antigen(s).
Reference:
Mark Haas, et al. C4d Deposition without Rejection Correlates with Reduced Early Scarring in ABO-Incompatible Renal Allografts. J Am Soc Nephrol 20: 197–204, 2009. doi: 10.1681/ASN.2008030279
The C4d staining as a special tissue marker for humoral immunity has served criteria of pathological diagnosis for antibody-mediated rejection (ABMR) in Banff classification since 2003,However, the sensitivity and specificity of C4d staining have been questioned, and recently, C4d-negative ABMR has been more focused in renal allograft pathology.
positive C4d staining without ABMR or rejection in ABO INCOMPATIBLITY, AUTOIMMUNE DISEASES AS SLE, POSSIBLE ORIGINAL KIDNEY DISEASE RECURRENCE.
C4d staining is relatively inexpensive
C4d staining is easy to perform in basic laboratories
A diffuse staining pattern is relatively easy to interpret
C4d gives very few false positives (it is relatively specific)
C4d shows that the complement system is involved: If complement targeted therapies (eculizumab) will be part of future treatment options, a marker such as C4d will be needed to identify patients susceptible for those kind of (expensive) treatments.
But still there are some cons ;
C4d scoring is subjective and the issue of focal staining and C4d/donor-specific antibody discrepancies will not be solved
C4d is not sensitive for chronic (or chronic/active) antibody-mediated rejection
●C4d positivity in grafts without histological abnormalities
-In ABO-incompatible grafts: In case of no histopathology and no graft dysfunction: It is suggested to interpret this as ‘graft accommodation’. No treatment is necessary, but close follow-up is strongly advised, as it is unknown what happens with these grafts during long-term follow-up.
-In positive cross-matched patients (presensitized patient), this should not be seen as graft accommodation and is a rare and more worrying situation than the above: In case of normal histology and no graft dysfunction: Interpret as probable AMR and consider treating the patient. Prospective studies on the long-term follow-up of this group of patients are awaited.
-IgA nephropathy
-Viral infection BK virus
-Lupus nephritis.
-Thrombotic microangiopathy .
Alternatives for C4d are emerging (genomics, molecular diagnostics, and endothelial transcripts) that will help accurate diagnosis of AMR.
Pros and cons for C4d as a biomarker
Danielle Cohen, Robert B. Colvin, and Ingeborg M. Bajema.Kidney Int. 2012 Apr; 81(7): 628–639.
C4d is a degradation product in classical compliment pathway and has an important role in diagnosis of Antibody mediated rejection. In the classical pathway of compliment activation, C4 is divided into C4a and C4b which is then converted to C4d which interacts with endothelium and then initiating the immune response which leads to antibody mediated tissue injury. So C4d is a hallmark of compliment activation against donor antigens.
Flase positive C4d staing without AMR can be seen in –
· IgA Nephropathy- Glomerular C4d staining
· Immunological conditions like lupus nephritis
· BK nephropathy
· ABO incompatible transplantation- Previously referred as accommodation. It is seen in ABO incompatible Transplants in which C4d staining is seen in 80% protocol biopsies and this staining does not co relate with peritubular capilliritis. In some protocol biopsies of patients with history of positive XM C4d staining is seen without evidence of tissue injury and this group qualifies for accommodation.
· ANCA associated vasculitis
· Pregnancy with Antiphospholipid antibody syndrome,
· TG, MPGN etc
Reference :
D Cornell. Histopathologic Features of Antibody Mediated Rejection: The Banff Classification and Beyond. Front. Immunol., 27 September 2021
In normal kidneys, C4d is detectable in the glomerular mesangium and at the vascular pole.
some biopsies, mainly from ABO-incompatible renal allografts, show C4d staining without histologic findings of AMR or cell-mediated rejection, a phenomenon known as graft accommodation.
In analogy with solid organ transplantation, C4d has recently been demonstrated in pregnancy, in particular in the setting of ‘antiphospholipid antibody-mediated fetal loss’ and preeclampsia. In autoimmune settings such as SLE, C4d might have a role in identifying patients at risk of developing thrombotic complications.
C4d is now increasingly recognized as a potential biomarker in other fields where antibodies can cause tissue damage, such as systemic autoimmune diseases and pregnancy.
Bracamonte et al and Hever et al demonstrated tubular basement membrane deposits in association with BK virus nephropathy.
In terminal complement pathway inhibition and, rarely, lupus nephritis, C4d has been described in the absence of other histopathological features of AAMR, and is considered not diagnostic of AAMR.
Although peritubular capillary C4d is specific marker for Antibody mediated rejection ,its sensitivity is low and C4d negative rejection should be treated with same regimen for positive C4d.
positive C4d could occur without rejection :
-ABO incompatible blood consider part of graft accommodation .
-in case of pregnancy fetomaternal adaptation .
-Infection (viral)PK virus .
-autoimmune disease SLE .
-thrombotic microangiopathy .
but we should take our care that in patient presensitized positive C4d without histological evidence of rejection ,it very rare to consider false positive or graft adaptation but close follow up and maximize our immunosuppressive drug.
Kidney Int. 2012 April ; 81(7): 628–639. doi:10.1038/ki.2011.497.
although c4d staining in the peritubular capillaries is very suggestive of AMR, in some situations we may have cd4 staining without evidence of rejection. ABO incompatibility s one of these conditions as shown in protocol biopsies ( C4d Deposition without Rejection Correlates with Reduced Early Scarring in ABO-Incompatible Renal Allografts
Mark Haas, Dorry L. Segev, Lorraine C. Racusen, Serena M. Bagnasco, Jayme E. Locke, Daniel S. Warren, Christopher E. Simpkins, Diane Lepley, Karen E. King, Edward S. Kraus, Robert A. Montgomery
JASN Jan 2009, 20 (1) 197-204; DOI: 10.1681/ASN.2008030279)
In many patients it maybe diffuse staining while focal in others
Also can be seen in autoimmune diseases like lupus nephritis
It is good to keep in mind that C4d positivity without detectable DSA can be due to
alloantibodies not detected by HLA assays (antiendothelial antibodies)
Allo-antibodies are present, but they are not detected by standard anti-HLA (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771104/)
Thank You
*in ABO incompitability
*if C4d deposition not in peri tubular capillary (may be in basement membrane (membranous))
Thank You
Any other conditions?
1- ABO incompatible allografts with stable graft function, a state of accomodation.
2- Recurrence of some glomerular disorders in allografts as MN & MPGN.
Please elaborate more as: mechanism of deposition
Diff. Patterns of distribution in relation to eitiology.
Positive C4d without Antibody-mediated Rejection :
ABO‑incompatible graft transplantation as graft accommodation :
(diffuse C4d staining of peritubular capillaries in protocol biopsies in 70-80% of ABO Incompatible Kidney transplantation.
no histopathology and no graft dysfunction of Allograft
IgA nephropathy
Viral infection BK virus
Atypical HUS without ABM rejection
in Native kidney disease :
Peritubular capillary deposition of C4d in :
Lupus nephritis,
ANCA associated vasculitis
Thrombotic microangiopathy in Atypical HUS
In pregnancy with antibody-mediated fetal loss in ( SLE and antiphospholipid syndrome )
placental C4d was detectable in the majority of SLE and antiphospholipid syndrome cases (>60%) in diffuse staining pattern of C4d in the Maternofetal interface in the placenta
Pros and cons for C4d as a biomarkerDanielle Cohen,1 Robert B. Colvin,2 Mohamed R. Daha,3 Cinthia B. Drachenberg,4 Mark Haas,5 Volker Nickeleit,6 Jane E. Salmon,7 Banu Sis,8 Ming-Hui Zhao,9 Jan A. Bruijn,1 and Ingeborg M. Bajema1
Excellent
1. ABO incompatible as part from graft accommodation
2. Pregnancy ( Anti phospholipid fetal loss syndrome )
3. Autoimmune disease like lupus nephritis ir lectin pathway activation
4. Presensitised patients (positive cross match without AMR and histomorphological abnormalities seen in graft)
References:
Danielle Cohen et al. Pros and cons for C4d as a biomarker: Kidney Int. Author manuscript; available in PMC 2013 Sep 12.
Published in final edited form as:
Kidney Int. 2012 Apr; 81(7): 628–639.
Can you explain what you mean in (4)!
Detection of the complement split product C4d in renal allograft biopsies is an important adjunctive tool to help understand the alloimmune response and to diagnose ABMR. C4d is a degradation product of the classic complement pathway. After an antigen-antibody complex fixes complement, a cascade of events follows, with activation of several complement proteins. The complement protein C4 is split into C4a and C4b. C4b is then converted to C4d. A unique feature of C4d is that it binds covalently to the endothelial and collagen basement membranes, thereby serving as an immunologic footprint of complement activation and antibody-mediated injury. Deposition of C4d in the PTCs has only been described in renal allografts and represents complement activity directed against donor antigen.
False positive C4d without AMR can be seen in
ABO-incompatible transplantation represents graft accommodation.
ANCA associated vasculitis, antiphospholipid antibody syndrome
TMA, membranous nephropathy, MPGN, fibrillary GN, proliferative GN with monoclonal Ig, amyloidosis, and C1q nephropathy. ( glomerular C4d staining).
In an autoimmune renal disease such as lupus nephritis it’s Maui tubular C4d staining
Pregnancy
IgA nephropathy usually leads to glomerular C4d staining
BK nephropathy shows tubular C4d staining
V.good
A false positive C4d staining in a kidney biopsy can be seen in:
– ABO incompatible renal transplant
– In native renal disease like MPGN Membranous nephropathy (along glomerular capillary wall), C4 glomerulopathy, Post-infectious GN.
– In pre-sensitized patients
– In IgA nephropathy
– Lupus nephritis
-In BK virus nephropathy
-Vasculitis
-TMA
MH, Bruijn JA, Bajema IM. Pros and cons for C4d as a biomarker. Kidney international. 2012 Apr 1;81(7):628-39.
Chandra P. C4d in native glomerular diseases. American journal of nephrology. 2019;49(1):81-92.
You could have explained a little about the mechanism in each entity.
False positive C4d staining seen in:
References
Well done Thepa good you are starting to join
Try to address the scenario
Positive C4d staining without AMR occurs in:
ABO incompatible allograft:
C4d positivity is not associated with graft dysfunction, poor outcome or histological evidence of endothelial injury, it is considered graft accommodation.
Positive crossmatch in pre-sensitized patients: It should be closely monitored.
Recurrence of the original disease:
C4d deposition may occur in various native kidney diseases and may rarely indicate recurrence.
The intensity, distribution and staining pattern differ from AMR
Pregnancy: with antiphospholipid antibody mediated fetal loss and preeclampsia.
Etta PK. C4d staining and antibody-mediated rejection in renal transplantation: Current status. Indian Journal of Transplantation. 2020 Jul 1;14(3):197.
Cohen D, Colvin RB, Daha MR, Drachenberg CB, Haas M, Nickeleit V, Salmon JE, Sis B, Zhao MH, Bruijn JA, Bajema IM. Pros and cons for C4d as a biomarker. Kidney international. 2012 Apr 1;81(7):628-39.
Chandra P. C4d in native glomerular diseases. American journal of nephrology. 2019;49(1):81-92.
Well done
C4d is generated after activation of complement system which binds to the endothelial and collagen basement membrane. C4d is considered the footprint of complement dependant ABR. C4d deposition is usually associated with DSA in ABR, but if there is no DSA it could result from anti-endothelial alloantibodies. C4d deposition can be assessed using IHC and IF. Although it’s the mark for ABR it can occur in other settings which are:
V. Good
C4d staining:
(1–3)
1- Native Proliferative GN
A- immune complex-mediated results in activation of the classical complement pathway such as MPGN, IgA nephropathy, Lupus nephritis, fibrillary GN, membranous nephropathy
B- complement-mediated such as C3 glomerulopathy (4,5)
2- ABO-incompatible graft
. C4d positivity is not associated with graft dysfunction, poor outcome, or ultrastructural evidence of endothelial injury.
While; in ABO compatible graft, occasional renal transplant biopsies show C4d +WER ( i.e. without inflammation or injury) (2)
3- Pregnancy- preeclampsia (6)
4- TMA, Anti-GBM, ANCA associated vasculitis
In anti-glomerular basement membrane (GBM) disease or ANCA-associated vasculitis. Renal biopsy was remarkable for IgA nephropathy, lesions of active thrombotic microangiopathy (TMA) and positive staining for complement factor C4d. (7)
5- BK nephropathy shows tubular basement membrane C4d staining, which correlates with marked viral cytopathic effect. (8)
References:
1. Snijders MLH, Sablik KA, van den Bosch TPP, Hesselink DA, Betjes MGH, Batal I, et al. Clinical Relevance of Arteriolar C4d Staining in Patients With Chronic-active Antibody-mediated Rejection: A Pilot Study. Transplantation [Internet]. 2020;104(5). Available from: https://journals.lww.com/transplantjournal/Fulltext/2020/05000/Clinical_Relevance_of_Arteriolar_C4d_Staining_in.31.aspx
2. Dominy KM, Willicombe M, Al Johani T, Beckwith H, Goodall D, Brookes P, et al. Molecular Assessment of C4d-Positive Renal Transplant Biopsies Without Evidence of Rejection. Kidney Int reports [Internet]. 2018 Sep 18;4(1):148–58. Available from: https://pubmed.ncbi.nlm.nih.gov/30596178
3. Drachenberg CB, Papadimitriou JC, Chandra P, Haririan A, Mendley S, Weir MR, et al. Epidemiology and Pathophysiology of Glomerular C4d Staining in Native Kidney Biopsies. Kidney Int reports [Internet]. 2019 Jul 30;4(11):1555–67. Available from: https://pubmed.ncbi.nlm.nih.gov/31890997
4. Singh G, Singh SK, Nalwa A, Singh L, Pradeep I, Barwad A, et al. Glomerular C4d Staining Does Not Exclude a C3 Glomerulopathy. Kidney Int reports. 2019 May;4(5):698–709.
5. Bashir S, Hussain M, Afzal A, Hassan U, Hameed M, Mushtaq S. C4d at Crossroads Between Post-Infectious Glomerulonephritis and C3 Glomerulopathy. Int J Nephrol Renovasc Dis [Internet]. 2021 Mar 11;14:87–95. Available from: https://pubmed.ncbi.nlm.nih.gov/33732010
6. Choi S-Y, Kim K-H, Lee M, Yeo M-K, Kim J, Suh K-S. Complement Component C4d Deposition in the Placenta of Preeclampsia Patients and Renal Glomeruli in 1 Postpartum Renal Biopsy. Appl Immunohistochem Mol Morphol AIMM. 2020 Feb;28(2):139–45.
7. Binet Q, Aydin S, Lengele J-P, Cambier J-F. Lessons for the clinical nephrologist: an uncommon cause of pulmonary-renal syndrome. J Nephrol. 2021 Jun;34(3):935–8.
8. Batal I, Zainah H, Stockhausen S, Basu A, Tan H, Shapiro R, et al. The significance of renal C4d staining in patients with BK viruria, viremia, and nephropathy. Mod Pathol an Off J United States Can Acad Pathol Inc. 2009 Nov;22(11):1468–76.
Thanks Jamila
-Histological assessment of the complement split product C4 is useful for the diagnosis of acute antibody-mediated rejection. C4d is generated by C4 activation in both, the classical and the Mannose-binding lectin complement pathways. A false positive C4d staining (in absence of AMR) in a kidney biopsy can be seen in many conditions like:
1. In ABO-incompatible grafts.
2. pregnancy
3. systemic autoimmune diseases
4. Glomerular diseases ;lupus nephritis, MGN, MPGN with IC, acute postinfectious GN, fibrillary GN, and proliferative glomerulonephritis with monoclonal IgG deposits (PGMID)
5. BK nephropathy
Reference :
-Danielle Cohen, Robert B. Colvin, et al.Pros and cons for C4d as a biomarker. Kidney Int. 2012 Apr; 81(7): 628–639. Cinthia B. Drachenberg
-John C. Papadimitriou ,Preeti Chandra et al Epidemiology and Pathophysiology of Glomerular C4d Staining in Native Kidney Biopsies .Clinical research . VOLUME 4, ISSUE 11, P1555-1567, NOVEMBER 01, 201
– Ibrahim Batal, Hanady Zainah et al. The significance of renal C4d staining in patients with BK viruria, viremia, and nephropathy. Modern Pathology volume 22, pages1468–1476 (2009)
Thanks Reem
C4d is generated by activating both classical and mannose-binding lectin complement pathways; it is activated by binding to the tissue component. Assessment of C4d deposition is done either by IHC or IF; the latter seems to be more sensitive.
Positive C4d staining in the absence of rejection is seen in:
References:
Thanks Huda
Low level DSA not detected by standard assays
Alloantibodies may be absorbed by the graft, which are sometimes seen to reappear after graft nephrectomy.
C4d may be produced due something else like autoimmune disease
ABO incompatible transplants
This is very short answer Innocent
C4d is the degradation product of classical complement pathway, which is one of the essential criteria for ABMR due to it’s long-term stability, prognostic validity and sensitivity,but it can be positive without abmr-
1.mesangium and vascular pole in normal
kidney.
2.ABOi tx (marker of accomodation)
3.Lupus Nephritis(c4d on tbm is disease activity
and arteriolar c4d is poor prognosis)
4.IgA nephropathy, MPGN like autoimmune
disorder.(marker of complement activation)
5.BK virus nephropathy on tbm(viral cytopathic
effect)
6.pregnancy (in eclampsia and apla)
7.TMA (vascular involvement by complement)
Thanks Avijeet
A false positive C4d staining (in absence of AMR) in a kidney biopsy can be seen in many conditions like:
1) ABO incompatible kidney transplant, where it is a marker of graft accommodation. (1,2,3,4)
2) In positive cross-matched/ pre-sensitized patients. (4)
3) In autoimmune diseases, like Lupus nephritis. Tubular basement membrane C4d deposition in lupus nephritis is associated with disease activity while arteriolar C4d deposition is associated with adverse outcomes. (4, 5)
4) In IgA nephropathy, glomerular C4d deposition can be seen, is a marker of disease progression, and is associated with adverse prognosis. (6)
5) In BK virus nephropathy, tubular basement membrane C4d staining correlates with marked viral cytopathic effect. (7)
6) In other native renal disease like MPGN (along capillary loop), Membranous nephropathy (along glomerular capillary wall), ANCA vasculitis, Anti-GBM disease, C4 glomerulopathy, Post infectious glomerulonephritis, and TMA. (8)
So it is very important to interpret a C4d deposition in kidney biopsy cautiously.
References:
1) Haas M, Sis B, Racusen LC, Solez K, Glotz D, Colvin RB, Castro MC, David DS, David-Neto E, Bagnasco SM, Cendales LC, Cornell LD, Demetris AJ, Drachenberg CB, Farver CF, Farris AB 3rd, Gibson IW, Kraus E, Liapis H, Loupy A, Nickeleit V, Randhawa P, Rodriguez ER, Rush D, Smith RN, Tan CD, Wallace WD, Mengel M; Banff meeting report writing committee. Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions. Am J Transplant. 2014 Feb;14(2):272-83. doi: 10.1111/ajt.12590. Erratum in: Am J Transplant. 2015 Oct;15(10):2784. Rangel, Erika [corrected to Rangel, Erika B]. PMID: 24472190.
2) Haas M, Rahman MH, Racusen LC, Kraus ES, Bagnasco SM, Segev DL, Simpkins CE, Warren DS, King KE, Zachary AA, Montgomery RA. C4d and C3d staining in biopsies of ABO- and HLA-incompatible renal allografts: correlation with histologic findings. Am J Transplant. 2006 Aug;6(8):1829-40. doi: 10.1111/j.1600-6143.2006.01356.x. PMID: 16889542.
3) Setoguchi K, Ishida H, Shimmura H, Shimizu T, Shirakawa H, Omoto K, Toki D, Iida S, Setoguchi S, Tokumoto T, Horita S, Nakayama H, Yamaguchi Y, Tanabe K. Analysis of renal transplant protocol biopsies in ABO-incompatible kidney transplantation. Am J Transplant. 2008 Jan;8(1):86-94. doi: 10.1111/j.1600-6143.2007.02036.x. Epub 2007 Nov 12. PMID: 18021283.
4) Cohen D, Colvin RB, Daha MR, Drachenberg CB, Haas M, Nickeleit V, Salmon JE, Sis B, Zhao MH, Bruijn JA, Bajema IM. Pros and cons for C4d as a biomarker. Kidney Int. 2012 Apr;81(7):628-39. doi: 10.1038/ki.2011.497. Epub 2012 Feb 1. PMID: 22297669; PMCID: PMC3771104.
5) Ding Y, Yu X, Wu L, Tan Y, Qu Z, Yu F. The Spectrum of C4d Deposition in Renal Biopsies of Lupus Nephritis Patients. Front Immunol. 2021 Jul 1;12:654652. doi: 10.3389/fimmu.2021.654652. PMID: 34276649; PMCID: PMC8281350.
6) Jiang Y, Zan J, Shi S, Hou W, Zhao W, Zhong X, Zhou X, Lv J, Zhang H. Glomerular C4d Deposition and Kidney Disease Progression in IgA Nephropathy: A Systematic Review and Meta-analysis. Kidney Med. 2021 Aug 6;3(6):1014-1021. doi: 10.1016/j.xkme.2021.06.009. PMID: 34939010; PMCID: PMC8664744.
7) Batal I, Zainah H, Stockhausen S, Basu A, Tan H, Shapiro R, Zeevi A, Girnita A, Randhawa P. The significance of renal C4d staining in patients with BK viruria, viremia, and nephropathy. Mod Pathol. 2009 Nov;22(11):1468-76. doi: 10.1038/modpathol.2009.118. Epub 2009 Sep 4. PMID: 19734851.
8) Chandra P. C4d in Native Glomerular Diseases. Am J Nephrol. 2019;49(1):81-92. doi: 10.1159/000496059. Epub 2019 Jan 4. PMID: 30612132.
Excellent
Thanks, Amit
One or two references are enough
Very right Amit, in short, you could say that c4d staining in absence of any histologic signs is unlikely to be significant
C4d is a less sensitive marker of ABMR than initially thought. It can appear in many conditions with out evidence of AMR as:
References:
good but elaborate on the answer, please.
C4d staining in the absence of concomitant histologic evidence of rejection in renal allografts from patients with ABO incompatibility may serve as a signal for stable graft accommodation.
Autoimmune disorders such as lupus nephritis, IgA nephropathy, or any sort of lectin pathway activation can also result in C4d accumulation.
C4d staining of the tubular basement membrane can also be seen in BK nephropathy.
C4d deposition within peritubular capillaries (PTCs) in renal allograft biopsies can be used to diagnose (AMR) in patients.
Cohen D, Colvin RC, Daha M, et al. Pros and cons for C4d as a biomarker. Kidney Int.
Thanks
-In ABO-incompatible grafts with no histopathology nor graft dysfunction considred as ‘graft accommodation’. No treatment is necessary, but close follow-up is needed.
-In positive cross-matched patients (presensitized patient), it is a rare but more seious condition. In case of normal histology without graft dysfunction ,it is considered as probable AMR and consider treating the patient.
-In native kidney disease, peritubular capillary C4d staining was investigated in many forms of glomerulonephritis. The only exception was lupus nephritis, in which granular peritubular capillary staining has been rarely described, therefore the diagnosis of AMR in a transplanted systemic lupus erythematosus (SLE) patient is considered or the recurrence of the original disease should then be ruled out.
-C4d is detected in pregnancy, in particular in the setting of ‘antiphospholipid antibody-mediated fetal loss’ and preeclampsia. In autoimmune settings C4d might have a role in identifying patients at risk of developing thrombotic complications.
Reference
Cohen D .et al. Pros and cons for C4d as a biomarker. Kidney Int. 2012 Apr; 81(7): 628–639.
Thanks
1- ABO-incompatiblility renal transplantation
diffuse C4d staining of peritubular capillaries in these biopsies was commonly found, even in protocol biopsies. However, the fact that more than 70–80% of ABO-incompatible grafts showed diffuse C4d positivity
2-C4d IN NATIVE RENAL DISEASE
In lupus nephritis, glomerular C4d deposition can be detected in the majority of cases with a full-house immuno-fluorescence pattern, as a result of immune complex deposition
detected glomerular C4d only in a small subgroup of patients with anti-neutrophil autoanti-body-negative pauci-immune glomerulonephritis, whereas in the anti-neutrophil autoantibody-positive patients, it was absent.
3-C4d IN PREGNANCY: ANTIBODY-MEDIATED PREGNANCY LOSS
placental C4d was detectable in the majority of SLE and antiphospholipid syndrome cases (>60%) in a diffuse staining pattern at the fetal-maternal interface ,whereas in normal pregnancies C4d was always negative. Excessive placental C4d was related to impaired fetal outcome due to fetal loss or due to prematurity in the setting of preeclampsia.
4-BK nephropathy
A subset of biopsies with BK nephropathy shows tubular basement membrane C4d staining, which correlates with marked viral cytopathic effect.
Reference
1-Danielle Cohen1, Robert B. Colvin2, Mohamed R. Daha3, Cinthia B. Drachenberg4, Mark Haas5, Volker Nickeleit6, Jane E. Salmon7, Banu Sis8, Ming-Hui Zhao9, Jan A. Bruijn1, and Ingeborg M. Bajema1. Pros and cons for C4d as a biomarker
Published in final edited form as:
Kidney Int. 2012 April ; 81(7): 628–639. doi:10.1038/ki.2011.497.
2- Ibrahim Batal, Hanady Zainah, Sean Stockhausen, Amit Basu, Henkie Tan, Ron Shapiro, Adriana Zeevi, Alin Girnita & Parmjeet Randhawa.
The significance of renal C4d staining in patients with BK viruria, viremia, and nephropathy
Published: 04 September 2009
Modern Pathology (2009) 22, 1468–1476
Thanks
ABMR occurs due to the binding of circulating antibodies to donor alloantigens located on graft endothelium leading to complement activation ( classical complement pathway ) with the final production of c5b, c3b, c3a, c5a leading to inflammation, cell damage, and graft dysfunction.
1.ABO-incompatible renal allografts, show C4d staining without histologic findings of AMR or cell-mediated rejection.
2.ln positive cross-match and conventional renal allografts such C4d deposition is uncommon, and may indicate potentially reversible graft injury.
3.C4d is now increasingly recognized as a potential biomarker in other fields where antibodies can cause tissue damage, such as systemic autoimmune diseases and pregnancy. In all these fields, C4d holds promise to detect patients at risk for the consequences of antibody-mediated disease.
Ref:
1.lecture professor Tareg Albaz
2.Danielle Cohen, et al” Pros and cons for C4d as a biomarker”
3.Review Pros and cons for C4d as a biomarker
Author links open overlay panelDanielleCohen1Ingeborg M.Bajema1
Dear Dr Manal
C4d positive in the absence of AMR. Please review your answer
follow
Diffuse PTC C4d staining can occur in the absence of other histologic features of injury in recipients of ABO incompatible kideny transplant,a phenomoenon konwn as graft accommodation
Yes, this what we want to see, well done, but expand more
Graft dysfunction due to ABMR, as defined by DSA or C4d positivity,can be present despite the absence of histomorphologic features of rejection.
C4d is degradation product of classic complement pathway, that bind s covalenty to the endothelial and collagen basement membranes
It is serving as an immunologic foot footprint of complement activation and antibody- mediated injury.
C4d is detecable in the glomerular mesangium and vascular pole in normal kideny, but deposition in PTCs has only been in renal allografts.
C4d is reported as diffusely postive when invoving >50% ofv PTCs.
C4d staining postive still has limitations in diagnosis of ABMR .by the following observations:
Diffuse PTC C4d staining can occur in the absence of other histologic features of injury in recipients,a phenomenon konwn as graft accommodation .
REFERENCES
1.Rush DN,Henrt sf,jeffery jr,et al, Histological finings in early routine biopsies of stable allograft recipients,Transplantation 1994,57:208.
2-Kee.TY.Chapman jR Oconnell pj,et al,Treatment of subclinical rejection diagnosed by protocol biopsy of kideny transplant,Transplantation2006,82:36.
Thanks
-The accommodation is defined as C4d deposition in PTCs in the absence of active rejection with or without DSA positivity, mostly seen in ABO‐incompatible graft transplantation.
-BK nephropathy.
-Autoimmune disease
-presence of Alloantibodies.
– TMA
Simple and informative
Under what conditions you get false positive C4d staining (positive C4d staining without AMR)?
C4d positivity without detectable DSA
C4d positivity in grafts without histological abnormalities
Excellent
o in fact, c4d represents activation of classic complement pathway.
o It remains bound to endothelium at site of injury by covalent bonds, so remain detectable for longer period even after disappearance of antibodies.
o it can present in case of ABO incompatible transplantation with accomodation to their presence without immune mediated damage of the graft.
in addition, presence of them in any immune mediated kidney disease either in recurrence of original kidney disease or originally in the donor and was not identified such as ;lupus nephritis (deposits mainly glomerular and mesangial..
however, peculiar deposition in ptc may be specific for AMR.
·
Thanks Mai
false positive C4d staining
( C4d depotion without assoaciated histological evidence of acute or chronic graft damage)
– ABO incompitable transplantation where C4d reflects graft accommodation rather than AMR
– C4d may occur with other conditions as autoimmune diseases and pregnancy
Cohen D, Colvin RB, Daha MR, et al. Pros and cons for C4d as a biomarker. Kidney Int. 2012;81(7):628-639. doi:10.1038/ki.2011.497
Positive C4d staining without AMR:
__________________________________
▪︎C4d deposition within peritubular capillaries (PTCs) in renal allograft biopsies is a useful tool for diagnosis of AMR.
▪︎C4d staining without associated histologic findings of rejection may represent a marker for stable graft accommodation in ABO-incompatible renal allografts[1]
▪︎A state of C4d staining without associated graft injury may be inducible in positive cross-match grafts by complement inhibition.
▪︎C4d deposition can also be caused by autoimmune diseases, i.e., lupus nephritis, IgA nephropathy or any form of lectin pathway activation[2].
▪︎BK nephropathy also can show tubular basement membrane C4d staining [3]
__________________
Ref:
[1] Mark Hass. “The significance of C4d staining with minimal histologic abnormalities” Curr Opin Organ Transplant. 2010 Feb.
[2] Danielle Cohen, et al” Pros and cons for C4d as a biomarker”
[3] E Honsová et al. ” BK-virus nephropathy and simultaneous C4d positive staining in renal allografts”. Cesk Patol. 2005 Oct.
Thanks Tahani
Under what conditions you get false positive C4d staining (positive C4d staining without AMR)?
# C4d positivity without detectable DSA
Possible explanations:
* Allo antibodies are present, but they are not detected by standard anti HLA assays (for example, anti endothelial antibodies).
* Allo antibodies are absorbed by the graft, as is sometimes shown by reappearance of allo antibodies in the blood after graft nephrectomy.
* Allo antibodies are not present and C4d deposition is caused by something else than DSA (for instance autoimmune disease, i.e., lupus nephritis or any form of lectin pathway activation)
# C4d positivity in grafts without histological abnormalities
*In ABO incompatible grafts:
In case of no histopathology and no graft dysfunction: It is suggested to interpret this as ‘graft accommodation’. No treatment is necessary, but close follow-up is strongly advised, as it is unknown what happens with these grafts during long-term followup.
* In positive cross matched patients (presensitized patient), this should not be seen as graft accommodation and is a rare and more worrying situation than the above: In case of normal histology and no graft dysfunction: Interpret as probable AMR and consider treating the patient.
References
1. Nickeleit V, Mihatsch MJ. Kidney transplants, antibodies and rejection: is C4d a magic marker? Nephrol Dial Transplant. 2003;18:2232–2239. [PubMed] [Google Scholar]
2. Sarma JV, Ward PA. The complement system. Cell Tissue Res. 2011;343:227–235. [PMC free article] [PubMed] [Google Scholar]
3. Sis B, Halloran PF. Endothelial transcripts uncover a previously unknown phenotype: C4d-negative antibody-mediated rejection. Curr Opin Organ Transplant. 2010;15:42–48. [PubMed] [Google Scholar]
4. Regele H, Bohmig GA, Habicht A, et al. Capillary deposition of complement split product C4d in renal allografts is associated with basement membrane injury in peritubular and glomerular capillaries: a contribution of humoral immunity to chronic allograft rejection. J Am Soc Nephrol. 2002;13:2371–2380. [PubMed] [Google Scholar]
5. Berger SP, Roos A, Daha MR. Complement and the kidney: what the nephrologist needs to know in 2006? Nephrol Dial Transplant. 2005;20:2613–2619. [PubMed] [Google Scholar] et.al
Thanks
2. Under what conditions you get false positive C4d staining (positive C4d staining without AMR)?
Substantiate your answer
Causes of C4d positivity without detectable DSA:
1. Presence of alloantibodies(e.g. anti-endothelial antibodies)that are not detected by the standard anti-HLA assays.
2. Alloantibodies are absorbed by the graft. These antibodies sometimes reappear in the blood post graft nephrectomy.
3. Autoimmune diseases such as lupus nephritis. Here alloantibodies not present & C4d deposition is not caused by DSA.
4. BKV nephropathy
Causes of C4d positivity in graft without histological abnormalities:
1. ABOi grafts: if no graft dysfunction as well, this is considered graft accommodation. No need for treatment but only close follow up.
It shouldn’t be seen as graft accommodation if this happened in presensitized, positive cross matched patients. It should be treated as probable AMR.
Reference ros and cons for C4d as a biomarker
Danielle Cohen, Robert B. Colvin, Mohamed R. Daha et al Pros and cons for C4d as a biomarker Kidney International Volume 81,Issue 7 April 2012
Thanks