Banff classification allowed the diagnosis of Antibody-mediated rejection without peritubular staining for c4d with the term (C4d negative ABMR).
Wee Leng Gan
2 years ago
C4d Positive AMR
DSA profile
DSA Present
Immunopathologic :
IF:Diffuse positive C4d at PTC
IHC: Diffuse or focal positive c4d at PTC.
Onset
Early. More responsive to treatment.
Prognosis : Poor allograft survival.
C4d Negative AMR
DSA Present
Immunopathologic : Negative C4d stain
Onset : Late . Less responsive to treatment.
Prognosis : Better allograft survival.
dina omar
2 years ago
DSA profiles : C4d +ve AMR : Complement fixing antibodies IgG class 1 and 3 ,early onset and usually results from preformed antibodies. It results in more aggressive AMR but ; responds better d to treatment. C4d -ve AMR : Complement non- fixing antibodies IgG class 2 and 4, later onset and caused by De Novo Antibodies. It results in more chronic subclinical course and less response to treatment.
Ahmed Fouad Omar
2 years ago
What is the difference between C4d negative and C4d positive AMR addressing the following points?
The DSA profiles
The onset
The prognosis
· Regarding DSA profiles :
C4d positive AMR results from Complement fixing antibodies IgG class 1 and 3
C4d Negative AMR results from Complement non fixing antibodies IgG class 2 and 4
· Regarding onset :
C4d positive AMR is characterized by early onset and usually results from preformed ABS
C4d Negative AMR is characterized by a later onset and is usually caused by De Novo Antibodies
· Regarding prognosis :
C4d positive results in more aggressive AMR but responds better d to treatment.
· C4d Negative has a more chronic subclinical course but shows less response to treatment
References:
1. Rubin Zhang et al. Donor-Specific Antibodies in Kidney Transplant Recipients.
CJASN January 2018, 13 (1)
2. Lecture of prof Ahmed Halawa
Prognosis Less odds for graft survival Better odds for graft surviva
Last edited 2 years ago by Mahmoud Hamada
Hamdy Hegazy
2 years ago
What is the difference between C4d negative and C4d positive AMR addressing the following points?
C4d positive ABMR: DSA profiles: Complement fixing DSAs such as IgG 1,3. High titer of DSA. DSAs are anti HLA especially class I. DSAs are usually preformed The onset: Early post RTx due to preformed DSAs.Acute and aggressive The prognosis: Lower graft function and survival.Early graft loss. More response to treatment. C4d negative ABMR DSA profiles: Non-complement fixing DSAs such as IgG 2,4. Low titer DSAs DSAs are usually non-HLA or class II HLA. DSAs are usually denovo The onset: Late (after first 12 months) post RTx due to low titer or denovo DSAs.Chronic and subclinical The prognosis: Better graft function and survival. Presents with late graft failure. Less response to treatment
ahmed saleeh
2 years ago
C4d positive and C4d Negative
Regarding DSA profiles :
C4d positive : Complement fixing antibodies IgG 1 and 3
C4d Negative: Complement non fixing antibodies igG 2 and 4
Regarding onset :
C4d positive : early onset , preformed ABS
C4d Negative: late onset , DeNovo Abs , more than 1 year
Regarding prognosis :
C4d positive: may better respond to treatment, but has a more aggressive course
C4d Negative: may carry a subclinical chronic course , less progressive than C4d positive but less responsive to treatment
MICHAEL Farag
3 years ago
The DSA profiles :
DSA is of complement-fixing type in C4d +ve AMR but in C4d-ve AMR, it is usually of non-complement fixing type.
DSA is usually of high titre in C4d +ve AMR, but in C4d -ve AMR, it is usually of high titre.
DSA is usually of anti-HLA type in C4d +ve AMR, but in C4d -ve AMR, it is often of Non-HLA type.
DSA is usually pre-formed in C4d+ve AMR, but in C4d -ve AMR, it is usually de novo
The onset :
C4d +ve AMR usually occurs early in post-transplantation due to high titre of pre-formed DSA.
C4d -ve AMR usually occurs late in post-transplantation due to low titre and de novo DSA.
C4d -ve AMR can appear in earlier lesions of AMR before becoming C4d +ve AMR.
The prognosis :
the prognosis of C4d -ve AMR is generally better than C4d +ve AMR regarding graft function and survival
Shereen Yousef
3 years ago
What is the difference between C4d negative and C4d positive AMR addressing the following points?
Recently published molecular, clinicopathologic, and ultrastructural studies provide strong evidence that microvascular injury in the presence of donor-specific alloantibodies (DSA) has the potential to cause interstitial fibrosis/tubular atrophy, transplant glomerulopathy, and graft loss, whether or not peritubular capillary (PTC) C4d is present
C4d-positive AMR may represent a more severe form of AMR
C4d-negative AMR in renal allografts, characterized by microvascular injury in the presence of DSA but without PTC C4d staining
●The onset
C4d positive AMR usually occurs early post-transplant.
C4d-negative AMR may occur early or late posttransplantation but usually late .
●The DSA profiles
C4d-positive AMR is more often seen in patients with DSA against HLA class I, and in those with DSA against both class I and class II.
While C4d-negative AMR occurs with with non complement fixing de novo antibodies .
●The prognosis
Although C4d-negative AMR may not be as severe as C4d-positive AMR with regard to potential for causing transplant glomerulopathy, interstitial fibrosis/tubular
atrophy, and graft loss, if not treated C4d-negative AMR can definitely result in all of these.
Mark Haas.Pathology of C4d-negative antibody-mediatedrejection in renal allograft. 2012Current Opinion in Organ Transplantation 18(3)
Ahmed Omran
3 years ago
DSA profiles
C4d is a marker of complement fixing circulating ABs
DSAs with poor complement fixation, complement independent pathway and auto antibodies to angiotensin II type 1 receptor can causes C4d negative AMR
C4d positive AMR is accompanied by HLA antibodies against class I and/or II Onset
C4d -ve AMR is more likely to develop later post transplant while C4d +ve AMR tends to occur early in pre sensitized patients Prognosis
Better Graft outcome is found in patient with C4d negative AMR..
Sapir-Pichhadze R, Curran SP, John R, Tricco AC, Uleryk E, Laupacis A, Tinckam K, Sis B, Beyene J, Logan AG, Kim SJ. A systematic review of the role of C4d in the diagnosis of acute antibody-mediated rejection. Kidney International. 2015 Jan 1;87(1):182-94.
Nigam LK, Vanikar AV, Kanodia KV, Patel RD, Suthar KS, Patel HV. C4d-negative antibody-mediated rejection: A pathologist’s perspective and clinical outcome. Saudi Journal of Kidney Diseases and Transplantation. 2018 Jan 1;29(1):39.
Tahani Ashmaig
3 years ago
☆The difference between C4d negative and C4d positive AMR:
¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤
☆The DSA profiles:
_____________________
C4d positive:
▪︎Usually of high titre anti- HLA antibodies ▪︎ Fix the complement.
▪︎Preformed DSA
C4d negative:
▪︎Usually of low titre non HLA antibodies ▪︎Don’t fix the complement.
▪︎De novo DSA
☆The onset:
______________
▪︎Both may occur early or late post-transplantation [1].
▪︎C4d -ve AMR can appear in earlier lesions of AMR before becoming C4d +ve AMR.
☆The prognosis:
__________________
C4d-positive and C4d-negative AMR show similar degrees of glomerulitis and peritubular capillaritis, similar frequencies of concurrent cell-mediated rejection [1]
______________________
Ref:
[1] Mark Hass. “Pathology of C4d-negative antibody-mediated rejection in renal allografts”.
Curr Opin Organ Transplant. 2013 Jun.
Mohammed Sobair
3 years ago
The DSA profiles
C4dnegative is due to de novo DSA development class 11
C4d positive. due to preformed DSA, class 1.
The onset:
C4d positive. type appears early in the posttransplant period .
C4dnegative develops late posttransplant .
The prognosis
C4dnegative subclinical presentation with better graft outcome than C4d POSTIVE and
late graft loss.
References:
Rubin Zhang et al.Donor-Specific Antibodies in Kidney Transplant Recipients.
CJASN January 2018, 13 (1)
CARLOS TADEU LEONIDIO
3 years ago
The DSA profiles
Studies reported the risk for allograft failure as a function of C4d and DSA. Worthington et al. found that the proportion of allografts failing within 15 years of follow-up in patients with acute allograft dysfunction was highest among patients with both DSA and C4d (75%), compared with patients with C4d alone (23%), DSA alone (0%), or neither of the two (9%). So, the presence of C4d positive is essential for dysfunction associated with DSA.
The onset
C4d‑negative AMR morphologically have higher intrarenal endothelial gene expression, alloantibodies expression
The prognosis
While microcirculatory inflamation appeared to be the most important determinant of allograft outcomes, in most instances the presence of C4d increased the risk for allograft loss beyond that observed as a function of DSA or MI alone. So, C4d positive has a worse prognosis in AMR.
REFERENCE:
– A systematic review of the role of C4d in the diagnosis of acute antibody-mediated rejection. Kidney International (2015) 87, 182–194; doi:10.1038/ki.2014.166;
amiri elaf
3 years ago
*** The DSA profiles
DSA in the C4d positive ABMR is pre formed antibodies against HLA Class I and itis a complement fixing antibodies IgG1 and IgG3
C4d negative ABMR usually de novo antibodies due to non complement fixing antibodies IgG2 and IgG4 against HLA class1I
*** The onset
C4d positive ABMR Usually occur early posttransplatatio with acute presentation and more aggressive.
C4d negative ABMR Usually occur late may be chronic or subclinical presentation. C4d negative AMR, in association with TCR, can present earlier than C4d positive ABMR.
*** The prognosis
C4d positive ABMR
More responsive to treatment, but with early graft loss.
C4d negative ABMR
Less responsive to treatment but with better prognosis than C4d positive ABMR with late graft loss.
Although C4d negative AMR may not be as severe as C4d positive AMR with regard to potential for causing transplant glomerulopathy, interstitial fibrosis/tubular
atrophy, and graft loss, if not treated C4d negative AMR can definitely result in all of these.
References:
1) Nigam LK, Vanikar AV, Kanodia KV, Patel RD, Suthar KS, Patel HV. C4d-negative antibody-mediated rejection: A pathologist’s perspective and clinical outcome. Saudi J Kidney Dis Transpl. 2018 Jan-Feb;29(1):39-49. doi: 10.4103/1319-2442.225206. PMID: 29456206.
Nasrin Esfandiar
3 years ago
C4d positive ABMR is associated with DSA against class Ⅰ or both class Ⅰ and class Ⅱ. C4d positive ABMRs are usually presented as early acute ABMR within the first month post-TX and are associated with preexisting DSA with worse prognosis. While C4d negative ABMR is associated with class Ⅱ DSA and has late (more than 30 days) presentation. Both of them if untreated, could lead to graft loss. But C4d+ ABMR, especially if is associated with other morphological aspects such as TMA, has worse prognosis even with treatment.
Jamila Elamouri
3 years ago
C4d positive AMR
1- Associated with complement-fixing DSA against Class I, preformed.
2- Early-onset AMR, and graft loss
3- Respond to treatment better than C4d negative one
C4d negative AMR
1- Associated with non-complement fixing, de novo, class II, or non- HLA, DSA
2- Late-onset
3- Poor response to treatment
4- Chronic graft loss
manal jamid
3 years ago
In renal allografts, microvascular injury in the presence of DSA but with negative C4d staining in PTC nonetheless is indicative of humorally mediated graft injury that has the potential to cause tubular atrophy/interstitial fibrosis, transplant glomerulopathy, and graft loss. C4d positive AMR: Due to complement fixing antibodies ( IgG1 and IgG3), usually pre-formed antibodies. Class I DSA C4d negative AMR: Due to non-complement fixing antibodies (IgG2 and IgG4), usually de-novo antibodies against Class II DSA(DQ)
The onset
C4d positive AMR: Usually occur early, acute presentation, more aggressive. C4d negative AMR: Usually occur late (>1-year post transplant), chronic or subclinical presentation. C4d negative AMR, in association with TCR, can present earlier than C4d positive AMR. -Out comes C4d positive AMR: More responsive to treatment, but has early graft loss. C4d negative AMR: Less responsive to treatment, but has better prognosis than C4d positive AMR, with late graft loss.
REF 1) Zhang R. Donor-Specific Antibodies in Kidney Transplant Recipients. Clin J Am Soc Nephrol. 2018 Jan 6;13(1):182-192. doi: 10.2215/CJN.00700117. Epub 2017 Apr 26. PMID: 28446536; PMCID: PMC5753302.
nawaf yehia
3 years ago
DSA profiles
C4d + AMR is associated with preformed DSA of class I , II
C4d – AMR is associated with DeNovo DSA class II
Onset
C4d + AMR present early post Tx
C4d – AMR present late post Tx ( may be subclinical and Dx on a protocol Bx )
Prognosis
Both associated with poor graft outcomes ( graft dysfuntion& graft loss ) , although C4d – may have more chronic tissue damage at time of Dx & is less responsive to Rx .
Manal Malik
3 years ago
difference between C4d negative and C4d positive AMR
The DSA profiles
C4d positive ABMR associated with class11 and 1 preformed DSA and c4d negative ABMR associated with class11(de novo) post renal transplant DSA such as endothelial associated transcripts. the onset
c4d postiveABMR occure early postrenal transplantaion when c4d negative occure late and subclincal
the prognosis
Both c4d positive and c4d negative ABMR are associated with increased graft loss and more information needs to be gathered about the efficacy of intervention in preventing TG and improving graft survival. References: 1. Hayde N, Bao Y, Pullman J, Ye B, Calder RB, Chung M, Schwartz D, Lubetzky M, Ajaimy M, de Boccardo G, Akalin E. The clinical and genomic significance of donor-specific antibody-positive/C4d-negative and donor-specific antibody-negative/C4d-negative transplant glomerulopathy. Clin J Am Soc Nephrol. 2013 Dec;8(12):2141-8. doi: 10.2215/CJN.04240413. Epub 2013 Sep 12. PMID: 24030736; PMCID: PMC3848403. 2. Haas M. Pathology of C4d-negative antibody-mediated rejection in renal allografts. Current opinion in organ transplantation. 2013 Jun 1;18(3):319-26.
dalia
3 years ago
C4d +ve AMR associated with class II and I performed DSA which occur early post transplant while C4d -ve AMR associated with class II and occur late post transplant . Both phenotypes are associated with increased graft loss and thus warrant consideration for intervention .
Mohamed Ghanem
3 years ago
The DSA profile and onset :
C4d positive usually early in Acute ABM rejection due to the presence of Antibodies in pre-sensitized patient usually
C4d negative usually present late due to De novo DSA mostly against HLA class II
Many studies showed that C4d negative tend to occur later post-transplant with subclinical presentation
and usually due to the non-complement dependent pathway of ABMR
However C4d negative may occur due to :
Technical issues related to the type of fixative used
different methods of C4d detection
poor complement fixation by some DSAs
Prognosis
incidence of C4d negative ABM rejection was 18.2% with less than C4d positive ABMR (72.3%)
with better graft outcome in C4d negative ABMR than C4d- positive ABMR.
The overall graft survival of patients with C4d-negative ABMR was 97.5% as against C4d-positive ABMR which was 95.5%
Although associated with better graft survival, the C4d-negative ABMR does have a poorer graft function as reflected by the higher serum creatinine levels. This proves that although negative for C4d, this immune injury is responsible for graft attrition over time and needs aggressive treatment like ABMR with C4d positive.
C4d-Negative Antibody-Mediated Rejection: A Pathologist’s Perspective and Clinical Outcome Lovelesh Kumar Nigam1 , Aruna V. Vanikar1 , Kamal V. Kanodia1 , Rashmi D. Patel1 , Kamlesh S. Suthar1 , Himanshu V. Patel2
fakhriya Alalawi
3 years ago
DSA profile: in C4d + AMR the DSA is usually against Class 1 anti HLA and preformed DSA while in C4d –ve mainly against Non-HLA antibodies and de novo DSA.
Several studies have shown several endothelial-associated transcripts in kidney transplants, expression related to the processes of endothelial cell activation, repair, and angiogenesis in cases with chronic AMR. The majority of these cases with chronic AMR features had no C4d staining.
Onset: both may occur early or late post-transplantation.
Prognosis:
Although C4d-positive AMR may represent a more severe form of AMR, Haas M. et al in their data suggest that C4d-positive and C4d-negative AMR show similar degrees of glomerulitis and peritubular capillaritis, similar frequencies of concurrent cell-mediated rejection.
Botermans JM et al found no difference in the occurrence of steroid resistance or graft survival for patients who in retrospect showed a C4d+ or a C4d− graft rejections and he concluded that the C4d staining pattern during an early graft rejections does not predict renal allograft function or survival over time. On the other hand, Batal I et al, found that diffuse C4d was associated with inferior outcomes even in the absence of demonstrable donor-specific antibodies.
Recent studies have found that in patients with DSA, microvascular injury (glomerulitis, peritubular capillaritis) is more strongly associated with graft loss than C4d deposition. A recent study on renal biopsies with AMR has shown that the combination of early C4d positivity and thrombotic microangiopathy confers a significant risk of graft loss when compared to the patients with C4d positivity without thrombotic microangiopathy. These data demonstrate that the association of C4d staining with other morphological aspects has a more prognostic value.
References:
1. Hayde N, Bao Y, Pullman J, Ye B, Calder RB, Chung M, Schwartz D, Lubetzky M, Ajaimy M, de Boccardo G, Akalin E. The clinical and genomic significance of donor-specific antibody-positive/C4d-negative and donor-specific antibody-negative/C4d-negative transplant glomerulopathy. Clin J Am Soc Nephrol. 2013 Dec;8(12):2141-8. doi: 10.2215/CJN.04240413. Epub 2013 Sep 12. PMID: 24030736; PMCID: PMC3848403.
2. Haas M. Pathology of C4d-negative antibody-mediated rejection in renal allografts. Current opinion in organ transplantation. 2013 Jun 1;18(3):319-26.
3. Botermans JM, de Kort H, Eikmans M, Koop K, Baelde HJ, Mallat MJ, Zuidwijk K, van Kooten C, de Heer E, Goemaere NN, Claas FH. C4d staining in renal allograft biopsies with early acute rejection and subsequent clinical outcome. Clinical Journal of the American Society of Nephrology. 2011 May 1;6(5):1207-13.
4. Corrêa RR, Machado JR, da Silva MV, Helmo FR, Guimarães CS, Rocha LP, Faleiros AC, dos Reis MA. The importance of C4d in biopsies of kidney transplant recipients. Clinical and Developmental Immunology. 2013 Jul 9;2013.
Dalia Ali
3 years ago
DSA PROFILE
*C4d positive AMR is associated with DSA class I, II (preformed DSA)
*C4d negative AMR is associated with class II DSA.( De novo)
ONSET
C4d positive AMR occur mainly in early post transplant period
(acute AMR)
C4d negative AMR occurs in late post transplant time
(Chronic AMR)
PROGNOSIS
Graft outcomes overall were better for the C4d-negative AMR, but this did not reach statistical significance, although both groups were associated with significantly worse graft survival compared with AMR-free patients.
Reference
B. J. Orandi, N. Alachkar, E. S. Kraus, F. Naqvi, B. E. Lonze, L. Lees, K. J. Van Arendonk, C. Wickliffe, S. M. Bagnasco, A. A. Zachary, D. L. Segev, R. A. Montgomery. Presentation and Outcomes of C4d-Negative Antibody-Mediated Rejection After Kidney Transplantation. American Journal of TransplantationVolume 16, Issue 1 p. 213-220
Ahmed Abd El Razek
3 years ago
In terms of extent of staining, with IF, Banff Lesion Score C4d ≥ 2 is considered positive and a criterion for antibody interaction with tissue and as equivalent to DSA.
(1) Linear or finely granular peritubular capillary staining was classified as diffuse when it was seen in more than 50% of microscopic fields available for evaluation. It was referred to as focal when present in 10–50% of biopsied tissue, and negative if the staining did not even reach that threshold.
(2) Glomerular basement membrane staining was evaluated according to the most intensely stained glomerulus. It was further classified as global, segmental and minimal when more than 50, 10–50 or less than 10% of glomerular capillaries were stained, respectively. It was considered negative when no glomerular basement membrane staining was observed.
(3) Tubular basement membrane staining was evaluated only within the cortex, as medullary tubules can be difficult to distinguish from the vasa recta by routine light microscopy. In individual tubules, staining was considered to be present if more than half of the tubular basement membrane circumference was stained. Staining was further characterized as diffuse, focal and negative when 450, 10–50 and less
than 10% of the tubules showed C4d deposits, respectively.
(4) Arteriolar staining was classified as diffuse, focal or negative, when 450, 10–50 or o10% of arterioles showed C4d deposits, respectively. Similar criteria were used for arterial staining evaluation. However, when only one artery was available for evaluation, the designations diffuse and focal reflected the percent of circumferential area of that vessel showing C4d deposits.
Circulating Donor-Specific Antibodies:
Donor-specific antibodies were defined as antibodies directed against one or more donor HLA type. diffuse C4d peritubular capillary staining was associated more often with the presence of circulating donor-specific antibodies compared to focally and negatively stained
With regard to the association between C4d staining and detection of donor-specific antibodies, Nadasdy et al found that 9/14 (64%) of diffuse and1/2 (50%) of focal staining in frozen biopsies were associated with donor-specific antibodies, whereas in paraffin-embedded biopsies, 7/10 (70%) diffuse and 2/5 (40%) focal staining reactions were associated with these antibodies.
The absence of detectable circulating donor-specific antibodies in some patients with C4d-positive biopsies has been noted; explanations include technical issues, different
approaches for peritubular capillary C4d staining evaluation and scoring, complete absorbance of high affinity antibodies by allograft tissue and non-HLA antibodies, which would not be detected during routine testing of donor-specific antibody.
Onset:
DSA could be pre-existing(in highly sensitized recipients ), or Denovo (more realated to patients’ nonadherence)
C4D usually late(6 months post tx)
prognosis:
combined both C4D and DSA are of worse diagnosis and least graft survival with less response to treatment.
biopsies
Last edited 3 years ago by Ahmed Abd El Razek
Zahid Nabi
3 years ago
DSA profiles
C4d + AMR is usually due to complement fixing DSA whereas C4d – AMR is due to non complement fixing DSA
DSA is usually against Class 1 , a higher titer and usually anti HLA in case of C4d + AMR however in C4d – it is of lower titer can be against Non HLA antibodies and mostly against class 2 like DQ Ab
As C4d + AMR mostly occurs early so DSA is usually preformed where as in C4d- it is de novo.
The onset :
C4d +ve AMR usually occurs early in post-transplantation more severe in clinical presentation.
C4d -ve AMR usually occurs late in post-transplantation usually 1 year post transplant
The prognosis :
the prognosis of C4d -ve AMR is generally better than C4d +ve AMR regarding graft function and survival
mai shawky
3 years ago
as regard DSA profile
C4d -ve usually associated with anti HLA Class II DSA, mainly formed de novo after transplantation. It cause graft injury by lectin pathway of complement or by Antibody mediated cellular cytotoxicity, hence classical complement pathway (C4d) activation is not seen
C4d +ve are usually positive to anti HLA Class I DSA in significant MFI. They cause complement activation through classical pathway activation and C4d deposition which is seen as the foot print of AMR Onset:
C4d negative AMR has late onset of presentation after transplant and has low titres of DSA predominantly class II which are formed de novo
C4d positive AMR is associated with pre existing DSA and has an early onset of AMR after transplant Prognosis:
C4d positive AMR is associated with worse prognosis and is severe. C4d negative AMR is less severe in nature. however, C4d -ve is less responsive to treatment.
Theepa Mariamutu
3 years ago
What is the difference between C4d negative and C4d positive AMR addressing the following points?
The DSA profiles
The onset
The prognosis
C4d is a classical pathway complement degradation product.
C4d positive AMR
Biopsy evidence of deposition of C4d in the peritubular capillaries, morphological evidence of AMR, such as renal injury, allograft dysfunction, & the presence of DSA in plasma.
PTC C4d positivity seen in about 20-50% of indicated transplant biopsies and 2% of protocol biopsies.
starts with the formation of DSA
DSA may or may not lead to active AMR
Not all active AMR will progress to chronic active AMR
Over time, chronic histological features such as TG occur, & the patient develops allograft dysfunction, proteinuria, & poaaibly allograft loss.
Therefore, finding an active vs chronic a-cAMR on the biopsy may be more reflective of the timing of the biopsy rather than the underlying pathological process itself.
Clinical phenotypes of AMR:
Early Posttransplant (<30 Days) Active AMR: Preformed DSA at the time of kidney transplant or H/O sensitizing event. The risk of early AMR increases with growing DSA strength or breadth at the time of transplant as determined by:
– DSA MFI
– Degree of FCM-XM positivity
– The number or breadth of cross-reactive DSA specificities.
Early AMR is generally uncommon, as it is common practice to avoid transplanting patients with known preformed DSA
Early AMR occurs in up to 40% of patients with preformed DSA & a positive FCM-XM
Early AMR is aggressive & presents with an abrupt increase in DSA & allograft dysfunction. C4d is usually positive.
If not recognized & promptly treated, it can lead to cortical necrosis & allograft loss within days.
Histological features of active AMR frequently resolve completely if treated early. Otherwise it can persist & progress to chronic AMR.
Late (>30 Days) posttransplant AMR with pre-existing DSA
An indolent and progressive form of AMR
Usually detected on a protocol biopsy (stable function) or on a for-cause biopsy for mild allograft dysfunction.
Late (>30 Days) AMR Associated With dnDSA
The most common form of AMR is associated with dnDSA.
dnDSA is a new DSA detected after >3 months posttransplant
Occurs in context of inadequate IS due to nonadherence, physician directed, or genetical variability in metabolism of IS drugs.
This form of AMR often presents with allograft dysfunction and concomitant or pre-existing TCMR.
AMR with dnDSA is associated with inferior graft survival compared with AMR from pre-existing DSA.
In renal allografts, MVI in the presence of DSA but with negative C4d staining in PTC is indicative of humorally mediated graft injury that has the potential to cause IF/TA, & graft loss.
So,
The DSA profiles
C4d positive AMR: Due to complement fixing antibodies (IgG1 and IgG3), usually Class I DSA, usually pre-formed antibodies.
C4d negative AMR: Due to non-complement fixing antibodies (IgG2 and IgG4), usually Class II DSA, usually de-novo antibodies.
The onset
C4d positive AMR: Usually occur early, acute presentation, more aggressive.
C4d negative AMR: Usually occur late (>1 year post transplant), chronic or subclinical presentation. C4d negative AMR, in association with TCR, can present earlier than C4d positive AMR.
The prognosis
C4d positive AMR: More responsive to treatment but has early graft loss.
C4d negative AMR: Less responsive to treatment, but has better prognosis than C4d positive AMR, with late graft loss.
Reference
Schinstock, Carrie A. ; Mannon, Roslyn B. ; Budde, Klemens et al Transplantation: May 2020 – Volume 104 – Issue 5 – p 911-922 doi: 10.1097/TP.0000000000003095
Balaji Kirushnan
3 years ago
DSA profiles:
C4d negative AMR are usually associated with DSA Class II which are formed de novo after years of renal transplantation. These de novo DSA Class II antibodies cause graft injury by lectin pathway of complement or by Antibody mediated cellular cytotoxicity, hence classical complement pathway and C4d activation is not seen
C4d Positive AMR are usually DSA positive to Class I and II in significant MFI. They cause complement classical pathway activation and C4d deposition which is seen as the foot print of AMR
Onset:
C4d negative AMR has late onset of presentation after transplant and has low titres of DSA predominantly class II which are formed de novo
C4d positive AMR is associated with pre existing DSA and has an early onset of AMR after transplant
Prognosis:
C4d positive AMR is associated with worse prognosis and is severe. C4d negative AMR is less severe in nature
Sahar elkharraz
3 years ago
C4d positive is a marker of AMR occur due to activation of classical pathway against HLA type class I associated with high titre of DSA level.
C4d is a morphological evidence by presence of C4d staining in peritubular capillarities along basement membrane.
C4d negative is due non HLA antibodies (de novo DSA).
it’s microvascular injury in absence of c4d staining
it’s due to presence of alloantibodies like natural killer cell.
Incidence of c4d positive rejection more than negative c4d
Patient’s with c4d positive have higher serum creatinine levels than those negative c4d.
Onset:
c4d positive is early in coarse (Acute),and aggressive but treatable.
c4d negative is late in coarse after one year of transplant associated with chronic transplant glomerulopathy and loss of graft.
Prognosis:
c4d negative is poor prognosis in term of graft survival rather than C4d positive.
References:
Rosana Rosa et al; The Importance of C4d in biopsies of kidney transplant recipient: Journal of immunology researchers, Volume 2013.
Heba Wagdy
3 years ago
The DSA profiles
C4d is a marker of complement fixing circulating antibodies.
DSAs with poor complement fixation, complement independent pathway and auto antibodies to angiotensin II type 1 receptor are causes of C4d negative AMR
C4d positive AMR is associated with HLA antibodies against class I and/or II
The onset
C4d negative AMR is more likely to develop later post transplant while C4d positive AMR tends to occur early in presensitized patients
The prognosis
Graft outcome is better in patient with C4d negative antibody mediated rejection.
Sapir-Pichhadze R, Curran SP, John R, Tricco AC, Uleryk E, Laupacis A, Tinckam K, Sis B, Beyene J, Logan AG, Kim SJ. A systematic review of the role of C4d in the diagnosis of acute antibody-mediated rejection. Kidney International. 2015 Jan 1;87(1):182-94.
Nigam LK, Vanikar AV, Kanodia KV, Patel RD, Suthar KS, Patel HV. C4d-negative antibody-mediated rejection: A pathologist’s perspective and clinical outcome. Saudi Journal of Kidney Diseases and Transplantation. 2018 Jan 1;29(1):39.
Mahmud Islam
3 years ago
C4d positive AMR is usually due to class I antibodies, usually with complement fixingIgG1 and IgG3 subtype. mostly due to preformed DSAs. the onset is early and more aggressive. response to treatment is better, may lead to graft failure early. On the other hand, C4d negative AMR is mostly due to class and due to de novo DSAs. the onset is late so maybe missed subclinical and less responsive to treatmentDSA class I
In sum: DSA class I/onset acute/prognosis better in C4D positive AMR DSA class II/onset late/ worse prognosis. in c4d negative AMR
Mohamed Mohamed
3 years ago
5. What is the difference between C4d negative and C4d positive AMR addressing the following points?
The DSA profiles
The onset
The prognosis
C4d is a classical pathway complement degradation product.
C4d positive AMR
Diagnosis by: – Biopsy evidence of deposition of C4d in the peritubular capillaries, morphological evidence of AMR, such as renal injury, allograft dysfunction, & the presence of DSA in plasma.
PTC C4d positivity, a marker for AMR, is seen in about 20-50% of indicated transplant biopsies & in just 2% of protocol biopsies.
The Banff classification has 3 AMR diagnostic categories (including chronic AMR with TG & current or prior DSA but no MVI or C4d).
AMR is frequently a chronic progressive disease process.
This chronic disease process starts with the formation of DSA.
DSA may or may not lead to active AMR.
Not all active AMR will progress to chronic active AMR.
Over time, chronic histological features such as TG occur, & the patient develops allograft dysfunction, proteinuria, & poaaibly allograft loss. Therefore, finding an active vs chronic a-cAMR on the biopsy may be more reflective of the timing of the biopsy rather than the underlying pathological process itself. =================================================================
Clinical phenotypes of AMR: 1.Early Posttransplant (<30 Days) Active AMR:Preformed DSA at the time of kidney transplant or H/O sensitizing event.The risk of early AMR increases with growing DSA strength or breadth at the time of transplant as determined by: – DSA MFI – Degree of FCM-XM positivity – The number or breadth of cross-reactive DSA specificities. Early AMR is generally uncommon, as it is common practice to avoid transplanting patients with known preformed DSA Early AMR occurs in up to 40% of patients with preformed DSA & a positive FCM-XM Early AMR is aggressive & presents with an abrupt increase in DSA & allograft dysfunction. C4d is usually positive. If not recognized & promptly treated, it can lead to cortical necrosis & allograft loss within days. Histological features of active AMR frequently resolve completely if treated early. Otherwise it can persist & progress to chronic AMR. 2. Late (>30 Days) posttransplant AMR with preexisting DSA An indolent and progressive form of AMR Usually detected on a protocol biopsy (stable function) or on a for-cause biopsy for mild allograft dysfunction. 3.Late (>30 Days) AMR Associated With dnDSA The most common form of AMR is associated with dnDSA. dnDSA is a new DSA detected after >3 months posttransplant Occurs in context of inadequate IS due to nonadherence, physician directed, or genetical variability in metabolism of IS drugs. This form of AMR often presents with allograft dysfunction and concomitant or preexisting TCMR. AMR with dnDSA is associated with inferior graft survival compared with AMR from preexisting DSA. ============================================================= In renal allografts, MVI in the presence of DSA but with negative C4d staining in PTC is indicative of humorally mediated graft injury that has the potential to cause IF/TA, & graft loss. Reference Schinstock, Carrie A. ; Mannon, Roslyn B. ; Budde, Klemenset alTransplantation: May 2020 – Volume 104 – Issue 5 – p 911-922 doi: 10.1097/TP.0000000000003095
Doaa Elwasly
3 years ago
C4d positive AMR
-DSA profile: class 1 DSA is detected with complement fixing IgG subclass 1, 3,
-Onset: it presents early with rapid deterioration of graft function
-Prognosis :early graft loss occurs meanwhile it is more responsive to treatment (1)
C4 d negative AMR
-DSA profile: Class 2 DSA is detected with non complement fixing IgG subclass 2, 4
-Onset: It presents later subclinicaly with slower deterioration of graft function
-Prognosis: late graft loss occurs meanwhile it is less responsive to treatment (1)
C4d-negative ABMR usually occurs >12 months after transplantation but can occur acutely in highly sensitized patients with persistent DSAs (even after desensitization).
C4 d negative AMR could be due to denovo DSA and autoantibodies to the angiotensin II type 1 receptor Fc receptors on NK cells (FcRIIA) can be involved too.
Some studies demonstrated that C4 negative AMR had better graft survival but worse graft function in comparison to C4 d positive AMR.
Loupy et al reported that some patients with ABMR transit between negative C4d staining and positive C4d deposition in the peritubular capillaries
Other studies concluded that C4d-positive and C4d-negative ABMR show similar frequencies of concurrent cell-mediated rejection and both can occur early or late posttransplant. (2)
Non-HLA antibodiesanti-endothelial cell antibodies (AECA) has arisen due to reports of antibody-mediated rejection or C4d deposition in the absence of circulating donor specific HLA antibodies.(3)
Difference between C4d negative and C4d positive AMR
Antibody mediated rejection is important cause of allograft dysfunction. The acute antibody mediated rejection is characterised by evidence of circulating DSA and histologically it shows peritubular capillaritis , cell necrosis , thrombotic microangiopathy and glomerulitis. while in Chronic ABMR we can see transplant glomerulopathy which results from inflammatory and thrombotic events leading endothelial injury and graft loss. C4d staining is an important hallmark of ABMR but has low sensitivity.
C4d is an activation product of classical compliment pathway and contains an occult sulfhydral group which forms covalent thioester bond with proteins on activation by C1. C4b and C4d remain in tissues for several days after IG have been released . Follwoing activation the thioester groups are exposed allowing binding of C4d with endothelial cells and matrix components of vascular basement membrane near the C4 activation site. C4d is found in intracytoplasmic vacuoles of endothelial cells. Because of covalent binding it becomes stable molecules and is easily detected by immunohistochemistry thus making it a footprint of antibody response
C4d Positive ABMR
It is usually due to DSA against class 1 HLA antigens. These are compliment fixing DSA usually IgG 1&3. It usually presents s early within 6 months and because of C4d positivity can be detected early and will usually respond well to treatment with better outcome as compared to C4d negative ABMR.
C4d negative ABMR
It usually presents within 6-12 months and is less severe in intensity as compared to C4d Positive ABMR and leads to chronic graft dysfunction i.e. transplant glomerulopathy. TG responds poorly to treatment. The mechanism can be direct endothelial cell injury or Antibody mediated cell cytotoxicity. It is usually due to DSA against class 2 HLA antigens and are non compliment fixing- usually IgG 2&4. These are usually against HLA DQ and can be denovo due to poor compliance , inadequate HLA match or poor drug levels.
Lovelish Kumar Negam. et al. C4d-negative antibody-mediated rejection: A pathologist’s perspective and clinical outcome. saudi Journal of transplantation and kidney diseases. 2018 Vol29:39-49.
Murad Hemadneh
3 years ago
I summarized the differences in a table and attached it to this comment as a picture.
Amit Sharma
3 years ago
The difference between C4d negative and C4d positive AMR as per:
The DSA profiles
C4d positive AMR: Due to complement fixing antibodies (IgG1 and IgG3), usually Class I DSA, usually pre-formed antibodies.
C4d negative AMR: Due to non-complement fixing antibodies (IgG2 and IgG4), usually Class II DSA, usually de-novo antibodies.
The onset
C4d positive AMR: Usually occur early, acute presentation, more aggressive.
C4d negative AMR: Usually occur late (>1 year post transplant), chronic or subclinical presentation. C4d negative AMR, in association with TCR, can present earlier than C4d positive AMR.
The prognosis
C4d positive AMR: More responsive to treatment, but has early graft loss.
C4d negative AMR: Less responsive to treatment, but has better prognosis than C4d positive AMR, with late graft loss.
References:
1) Nigam LK, Vanikar AV, Kanodia KV, Patel RD, Suthar KS, Patel HV. C4d-negative antibody-mediated rejection: A pathologist’s perspective and clinical outcome. Saudi J Kidney Dis Transpl. 2018 Jan-Feb;29(1):39-49. doi: 10.4103/1319-2442.225206. PMID: 29456206. 2) Zhang R. Donor-Specific Antibodies in Kidney Transplant Recipients. Clin J Am Soc Nephrol. 2018 Jan 6;13(1):182-192. doi: 10.2215/CJN.00700117. Epub 2017 Apr 26. PMID: 28446536; PMCID: PMC5753302.
kumar avijeet
3 years ago
C4d positivity means the rejection is complement mediated,which tells many things about the rejection process .
1.C4d positive ABMR-
.Basically by DSA to class 1HLA,and some times
both class 1 and 2 HLA(presensitized patient)
.Normally IgG1 and 3 ab(complement binding)
.Early to appear first 6mnts(as presensitised)
.Very severe form with graft dysfunction
.Response to tpe and ivig is good
.As detected early due to graft dysfunction, so
amenable to treatment without being
undetected like c4d neg abmr.
2.C4d negative ABMR-
.Basically by DSA to class 2 HLA (DQ,DR) due to
formation of denovo Ab (due to incompliant to
immunosuppressive meds,hla mismatch,low
level immunosuppression)
.Normally IgG 2 and 4 ab(noncomplement bind)
.Late to appear mainly after 6-12mnth.
.though less severe than c4d positive but leads
to formation of transplant
glomerulopathy,leading to chronic graft dysfunction.
.response to therapy is very poor.
.Mainly damage by direct endothelial toxicity
Or ab dependant cell cytotoxicity by NK cell.
.As very subtle in action, not detected and licks
out the graft without being unnoticed,so more
dangerous than c4d positive ABMR.
.Without treatment both c4d positive and negative abmr have worse prognosis but even with treatment c4d negative not behave well, though very rare in occurrence.
Ala Ali
Admin
3 years ago
Acute and chronic definitions of ABMR based on C4d positivity.
As shown in the diagram in the attachment C4d negative AMR is explained by multiple causes one of them is the type of Noncomplement fixing DSA which is mostly of IgG 2,4 type. it usually develops late after 1st 6m-1 y after kidney transplantation and usually against class II DQ and it usually presents with late graft failure and not respond to treatment
C4d positive AMR is caused by complement-fixing antibodies mostly of IgG 1,3 which usually occurs early post-transplant and leads to rapid deterioration of graft function and usually against class I HLA It shows more response to treatment and early graft loss
EXCELLENT Ramy
But remember there are many exceptions.
Weam Elnazer
3 years ago
The most recent Banff meeting update high- lights two major phenotypes of ABMR. The first type appears early in the posttransplant period in a pre-sensitized patient and is more likely to be C4d positive.
type develops late post-transplant and is due to de novo DSA development and is likely to be C4d negative. The second phenotype is an important factor in late graft loss. C4d-negative ABMR usually occurs >12 months after transplantation but can occur
acutely in highly sensitized patients with persistent DSAs (even after desensitization).
– DSAs related to C4d negative AMR:
Antigen against the HLA class II antigen., Frequently used against the DR-Q HLA antigen, The majority of DSAs are de novo., IgG DSAs are classified into two classes: class II and class IV., There is no complement-fixing., Associated with an asymptomatic and mild decrease of Allograft function and proteinuria over a long period of time, The symptoms generally appear 6 months after the transplantation.
– AMR is histologically related to both chronic active and chronic inactive disease states. Chronic AMR is represented by Transplant Glomerulopathy (TG) and Chronic Peritubular Capillaritis (PTC) is represented by PTC multilayering in the classic form.
HLA incompatibility, particularly for class II antigen, and non-adherence to anti-rejection drugs are two of the most significant risks.
-It is known that DSAs against HLA antigens of Class I are related to C4d positive AMR;
Antibody-mediated rejection (ABMR), also termed humoral rejection, is one of the most important causes of allograft dysfunction and loss accounting for up to 76% of death-censored graft failures beyond the first year of transplantation .
Active (acute) ABMR is characterized by serological evidence of DSA, peritubular capillaritis, glomerulitis, cellular necrosis, thrombotic microangiopathy.
Chronic ABMR, on the other hand, is characterized by transplant glomerulopathy, a distinct pathophysiological process resulting from a repetitive pattern of thrombotic events and inflammatory changes that lead to endothelial cell injury and allograft matrix remodeling,which is non reversible by any means of treatment.
C4d staining has been shown to have significant limitations for diagnosis of ABMR due to low sensitivity, with negative results in up to 50% of patients with antibody-mediated rejection .
1-C4D POSITIVE ABMR
usualy presented due to class 1 or 2 HLA antibiodies performed befor transplantion.
usually occurs in first period after kidney transplantion first 6 month
reversivle by aggrisive treatment mesures like plex with iv igg and rituximmab.
risk of early grfat loss.
2-C4D NEGATIVE ABMR
occurs late in post transplant period >12 months, but can occur earlier in sensitized patients with persistent DSA even after desensitization.
Usually associated with de novo DSA.
mostly occurs with Anti HLA class II antigen(Commonly against DR-Q HLA antigen)
more risky for late graft loss.
Fatima AlTaher
3 years ago
C4d -ve ABMR was defined by Banff 13 guidelines as
Presence of microvascular injury as glomeruli this , peritubular capilaritis or TMA associated with DSA and no C4d deposition
Causes
Non complement fixing Ab
Alloantibodies against FC receptors on NK cells
Type of associated DSA : Commonly class II , non complement fixing Ab , de no vo DSA
Clinical presentation: chronic ABMR , less common acute ABMR
Poor graft outcome
C4d + ve ABMR
DSA: Class I, complement fixing , preformed DSA
Clinical presentation: acute ABMR ,shortly after transplantion
Poor graft outcome
Reem Younis
3 years ago
The Banff classifies ABMR into :
1. The first type appears early in the posttransplant period in a presensitized patient and is more likely to be C4d positive ABMR.DSA against HLA class I or both class I and II. It is more severe than C4d negative.
2. The second type develops late post-transplant (>12 months after transplantation ) or early,and is due to de novo DSA development and is likely to be C4d negative ABMR. DSA to Class II HLA antigens.
– The endothelial damage in C4d negative ABMR is mediated by NK cells and, to a lesser extent, monocytes and neutrophils; antibody-dependent cell-mediated cytotoxicity.
– C4d ABMR has a subclinical presentation with better graft outcome than C4dpositive. Reference :
-Lovelesh Kumar Nigam1 etal .Suthar1, Himanshu V. Patel2C4d-Negative Antibody-Mediated Rejection: A Pathologist’s Perspective and Clinical Outcome. Saudi J Kidney Dis Transpl 2018;29(1):39-49.
Complement Fixing vs Non-Complement Fixing DSA:
Both C4d positive and C4d negative AMR are associated with worse prognosis compared to no AMR.
Complement binding DSAs target class 1 HLA on endothelial cells, activate the classic complement cascade, and deliver complement-dependent cytotoxicity in AMR which occurred early and mainly associated with C4d positive ABMR which ccc by (early onset ,acute, rapid and responsive to treatment).
Complement nonbinding DSAs target the class 2 HLA on endothelial cells and recruit innate immune cells through Fc receptors and lead to antibody-dependent cellular toxicity or direct stimulation effects that cause tissue injury, cellular recruitment, and endothelial proliferation which mainly associated with C4d negative ABMR which ccc by(late onset, chronic or sub-clinical presentation and resistant to treatment)(1).
C4D negative is less common than C4D + cases ,C4D positive ABMR occurs earlier and more severe than C4D -ve.(2).
Graft outcomes: better in c4d –ve and Both C4D +&- require intervention(3).
References:
1-Applied Transplant Immunology; Case-based Discussion (Part 2),lecture of professor: A. Halwa ,(ASNRT).
2-Renal Allograft Rejection (Part 3) lecture By Professor Tarek Abbas(ASNRT).
3-Nigam L., Vanikar A., Kanodia K., Patel R., Suthar K. and et al. C4d-Negative Antibody -Mediated Rejection: A Pathologist Perspective and Clinical Outcome. Saudi J Kidney Dis Transplant, 2018;29(1):39-49.
Mohamed Fouad
3 years ago
The link between peri tubular C4d deposition and graft survival was first reported in 1993. It was demonstrated that patients have suspected ABMR and positive C4d staining is associated with impaired graft function.
In 2003, C4d staining was included in the Banff classification for diagnosing ABMR. Some chronic ABMR rejection related to C4d staining and some are not, which suggests that C4d is specific but not sensitive.
In patients with circulating DSA, deteriorating graft function and long term graft survival have been observed in biopsies with C4d positive versus negative C4d staining, suggesting that C4d is a marker of more significant humoral injury
C4d negative antibody-mediated rejection: The updated Banff Classification included the diagnosis of antibody mediated rejection in the absence of peritubular capillary C4d staining. Some patients have histopathologic evidence of ABMR with microvascular inflammation and circulating DSA but have no C4d staining in the PTCs.
In C4d negative ABMR, DSA binding to endothelial cells may cause injury through non complement dependent mechanisms like direct endothelial injury. Patients with C4d negative ABMR who were not treated for ABMR had a higher rate of progression to transplant glomerulopathy.
C4d-negative AMR less common in comparison to C4d-positive AMR most likely develop in late post-transplant period and less likely to have a clinical presentation (usually sub clinical course). The risk of graft loss for C4d negative AMR patients is low in comparison with C4d positive AMR patients. There is no difference in DSA class I vs. class II in terms of the C4d phenotype either C4d positive or negative.
References Sis B, Jhangri GS, Bunnag S, Allanach K, Kaplan B, Halloran PF. Endothelial gene expression in kidney transplants with alloantibody indicates antibody-mediated damage despite lack of C4d staining. Am J Transplant. 2009;9(10):2312–2323.
Batool Butt
3 years ago
C4d positive AMR is more common and DSA is detected early post-transplant and are preformed ,patients usually symptomatic and in acute severe form, and usually class I ,complement fixing DSA.Histologically, microvascular inflammation ( MVI) , glomerulitis and capillaritis ,and or variable degree of arteritis .C4d positive AMR had a higher risk for graft loss and had better response to treatment
C4d negative AMR DSA tends to be subclinical or chronic and occurs late post transplant and are usually denovo but it is non complement fixing and usually class II, it is less severe, less symptomatic , and responsible for late graft dysfunction and loss, no c4d deposition. Histologically associated with Chronic active and chronic inactive AMR. C4d negative AMR less aggressive but poor responsive to the treatment and associated with poor outcome
REFERENCE:
1- Orandi BJ, Alachkar N, Kraus ES, Naqvi F, Lonze BE, Lees L, et al. Presentation and Outcomes of C4d-Negative Antibody-Mediated Rejection After Kidney Transplantation. American Journal of Transplantation 2016; 16: 213–220.
2- Montgomery RA, Loupy A, Segev DL. Antibody-mediated rejection: New approaches in prevention and management. Am J Transplant. 2018 Jan;18 Suppl 3:3-17.
Ban Mezher
3 years ago
Recent Banff classification update show 2 subtypes of ABMR:
C4d negative AMR: appear late in post transplant period (>12 months, subclinical) but can occur earlier in sensitized patients with persistent DSA even after desensitization. Usually associated with de novo DSA. Injury mediated by NK cells, monocytes, & neutrophils ( antibody-dependent cell mediated cytotoxicity through HLA classII ). It had better graft outcome than C4d positive AMR. Less common than C4d +AMR
C4d positive AMR: It occur in early post transplant period ( acutely), commonly in presensitized patients ( preformed DSA), associated strongly with DSA class I/II Ag. More common subtypes & associated with worse graft outcome.
References:
Orandi B., Alachkar N., Kraus E., Naqvi F., Lonze B. and et al. Presentation and Outcome of C4d-Negative Antibody-Mediated Rejection After Kidney Transplantation. Am J Transplant. 2016;16(1)213-220.
Nigam L., Vanikar A., Kanodia K., Patel R., Suthar K. and et al. C4d-Negative Antibody -Mediated Rejection: A Pathologist Perspective and Clinical Outcome. Saudi J Kidney Dis Transplant, 2018;29(1):39-49.
Riham Marzouk
3 years ago
C4d is a degradation of complement cascade which binds covalently with endothelium and the deposits detected by IF or IHC in the peritubular capillary.
Acute or chronic AMR can be c4d negative or positive
C4d positive AMR, DSA is detected and usually class I, it is complement fixing DSA, happens early post transplant , it is more common, acute severe form , and more symptomatic than c4d negative , with c4d deposition peritubular capillary.
C4d negative AMR, DSA is detected but it is non complement fixing and usually class II, it is less severe, less symptomatic , tends to be subclinical or chronic and occurs late post transplant and responsible for late graft dysfunction and loss, no c4d deposition.
Both c4d positive and negative AMR have worse prognosis in comparison to no AMR
references:
lecture of Dr Ahmed Halawa
lecture of Dr Tarek Abass
Wael Jebur
3 years ago
The DSAs associated with C4d positive AMR are:
1) DSAs against Class I HLA antigen (HLA A,B).
2) usually pre existing DSAs. With positive flow cytometric cross -match and variable FMI.
3) Complement fixing
4) Cause Acute severe clinical AMR.
5) They are usually class I and Class III IgG Antibody type.
6) Can happened any time post transplantation, usually inthe first 6 months.
7) Histologically , presented with Microvascular inflammation ( MVI) glomerulitis and per tubular capillaritis g+ptc >2 according to Banff classification ,and or variable degree of arteritis (intimal to trans-mural ,and fibrinoid necrosis)
Onset:
Early onset ,symptomatic,with Acute AMR and rapid rise of creatinine.
Prognosis:
Is relatively better as it’s
1) reversible with plasma exchange to remove the preformed DSAs,IVIG,and Rituximab to delete B lymphocytes clone that is interacting with the mismatched HLA antigens..Furthermore Bortizomib might have a role in depleting the plasma cells producing DSAs.
2) Frequent follow up of DSAs MFI with flow cytometric assessment and Luminex assay.
3)low threshold for allograft biopsy when clinically indicated or DSAs titer is significantly increasing.
C4d Negative AMR:
DSAs associated with C4d negative AMR:
1) Anti HLA class II antigen.
2) Commonly against DR-Q HLA antigen
3) Mostly De novo DSAs
4) DSAs are class II and class IV IgG DSAs.
5) Non complement fixing .
6) associated with subtle and chronic asymptomatic deterioration of Allograft function and proteinuria
7) usually presented after 6 months post transplantation.
8) Histologically associated with Chronic active and chronic inactive AMR. Classically Chronic AMR represented by Transplant Glomerulopathy TG, and Chronic peritubular capillaritis reflected by PTC multilayring
9) Mechanism of endothelial damage is Antibody dependent Cytotoxicity by Natural killer Cells.
10) Risk factors : HLA incompatibility especially for class II antigen, and non adherence to anti rejection medications.
Onset :
of C4d negative AMR is late with chronic subtle deterioration of allograft function and proteinuria . usually after 6 months to years post transplantation.
Prognosis:
Is poor.
As chronic AMR (TG and PTCML) is the harbinger for chronic Allograft failure.
Banff classification allowed the diagnosis of Antibody-mediated rejection without peritubular staining for c4d with the term (C4d negative ABMR).
C4d Positive AMR
DSA profile
DSA Present
Immunopathologic :
IF:Diffuse positive C4d at PTC
IHC: Diffuse or focal positive c4d at PTC.
Onset
Early. More responsive to treatment.
Prognosis : Poor allograft survival.
C4d Negative AMR
DSA Present
Immunopathologic : Negative C4d stain
Onset : Late . Less responsive to treatment.
Prognosis : Better allograft survival.
DSA profiles :
C4d +ve AMR : Complement fixing antibodies IgG class 1 and 3 ,early onset and usually results from preformed antibodies. It results in more aggressive AMR but ; responds better d to treatment.
C4d -ve AMR : Complement non- fixing antibodies IgG class 2 and 4, later onset and caused by De Novo Antibodies. It results in more chronic subclinical course and less response to treatment.
What is the difference between C4d negative and C4d positive AMR addressing the following points?
· Regarding DSA profiles :
C4d positive AMR results from Complement fixing antibodies IgG class 1 and 3
C4d Negative AMR results from Complement non fixing antibodies IgG class 2 and 4
· Regarding onset :
C4d positive AMR is characterized by early onset and usually results from preformed ABS
C4d Negative AMR is characterized by a later onset and is usually caused by De Novo Antibodies
· Regarding prognosis :
C4d positive results in more aggressive AMR but responds better d to treatment.
· C4d Negative has a more chronic subclinical course but shows less response to treatment
References:
1. Rubin Zhang et al. Donor-Specific Antibodies in Kidney Transplant Recipients.
CJASN January 2018, 13 (1)
2. Lecture of prof Ahmed Halawa
C4d PSOTIVE C4d negative
DSA : Complement fixing Abs IgG 1 & 3 Non-complement fixing DSAs e.g. IgG 2&4
Onset timing Early Late
Prognosis Less odds for graft survival Better odds for graft surviva
What is the difference between C4d negative and C4d positive AMR addressing the following points?
C4d positive ABMR:
DSA profiles: Complement fixing DSAs such as IgG 1,3. High titer of DSA. DSAs are anti HLA especially class I. DSAs are usually preformed
The onset: Early post RTx due to preformed DSAs. Acute and aggressive
The prognosis: Lower graft function and survival. Early graft loss. More response to treatment.
C4d negative ABMR
DSA profiles: Non-complement fixing DSAs such as IgG 2,4. Low titer DSAs
DSAs are usually non-HLA or class II HLA. DSAs are usually denovo
The onset: Late (after first 12 months) post RTx due to low titer or denovo DSAs. Chronic and subclinical
The prognosis: Better graft function and survival. Presents with late graft failure.
Less response to treatment
C4d positive and C4d Negative
Regarding DSA profiles :
C4d positive : Complement fixing antibodies IgG 1 and 3
C4d Negative: Complement non fixing antibodies igG 2 and 4
Regarding onset :
C4d positive : early onset , preformed ABS
C4d Negative: late onset , DeNovo Abs , more than 1 year
Regarding prognosis :
C4d positive: may better respond to treatment, but has a more aggressive course
C4d Negative: may carry a subclinical chronic course , less progressive than C4d positive but less responsive to treatment
The DSA profiles :
The onset :
The prognosis :
What is the difference between C4d negative and C4d positive AMR addressing the following points?
Recently published molecular, clinicopathologic, and ultrastructural studies provide strong evidence that microvascular injury in the presence of donor-specific alloantibodies (DSA) has the potential to cause interstitial fibrosis/tubular atrophy, transplant glomerulopathy, and graft loss, whether or not peritubular capillary (PTC) C4d is present
C4d-positive AMR may represent a more severe form of AMR
C4d-negative AMR in renal allografts, characterized by microvascular injury in the presence of DSA but without PTC C4d staining
●The onset
C4d positive AMR usually occurs early post-transplant.
C4d-negative AMR may occur early or late posttransplantation but usually late .
●The DSA profiles
C4d-positive AMR is more often seen in patients with DSA against HLA class I, and in those with DSA against both class I and class II.
While C4d-negative AMR occurs with with non complement fixing de novo antibodies .
●The prognosis
Although C4d-negative AMR may not be as severe as C4d-positive AMR with regard to potential for causing transplant glomerulopathy, interstitial fibrosis/tubular
atrophy, and graft loss, if not treated C4d-negative AMR can definitely result in all of these.
Mark Haas.Pathology of C4d-negative antibody-mediatedrejection in renal allograft. 2012Current Opinion in Organ Transplantation 18(3)
DSA profiles
C4d is a marker of complement fixing circulating ABs
DSAs with poor complement fixation, complement independent pathway and auto antibodies to angiotensin II type 1 receptor can causes C4d negative AMR
C4d positive AMR is accompanied by HLA antibodies against class I and/or II
Onset
C4d -ve AMR is more likely to develop later post transplant while C4d +ve AMR tends to occur early in pre sensitized patients
Prognosis
Better Graft outcome is found in patient with C4d negative AMR..
Sapir-Pichhadze R, Curran SP, John R, Tricco AC, Uleryk E, Laupacis A, Tinckam K, Sis B, Beyene J, Logan AG, Kim SJ. A systematic review of the role of C4d in the diagnosis of acute antibody-mediated rejection. Kidney International. 2015 Jan 1;87(1):182-94.
Nigam LK, Vanikar AV, Kanodia KV, Patel RD, Suthar KS, Patel HV. C4d-negative antibody-mediated rejection: A pathologist’s perspective and clinical outcome. Saudi Journal of Kidney Diseases and Transplantation. 2018 Jan 1;29(1):39.
☆The difference between C4d negative and C4d positive AMR:
¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤
☆The DSA profiles:
_____________________
C4d positive:
▪︎Usually of high titre anti- HLA antibodies ▪︎ Fix the complement.
▪︎Preformed DSA
C4d negative:
▪︎Usually of low titre non HLA antibodies ▪︎Don’t fix the complement.
▪︎De novo DSA
☆The onset:
______________
▪︎Both may occur early or late post-transplantation [1].
▪︎C4d -ve AMR can appear in earlier lesions of AMR before becoming C4d +ve AMR.
☆The prognosis:
__________________
C4d-positive and C4d-negative AMR show similar degrees of glomerulitis and peritubular capillaritis, similar frequencies of concurrent cell-mediated rejection [1]
______________________
Ref:
[1] Mark Hass. “Pathology of C4d-negative antibody-mediated rejection in renal allografts”.
Curr Opin Organ Transplant. 2013 Jun.
C4dnegative is due to de novo DSA development class 11
C4d positive. due to preformed DSA, class 1.
The onset:
C4d positive. type appears early in the posttransplant period .
C4dnegative develops late posttransplant .
C4dnegative subclinical presentation with better graft outcome than C4d POSTIVE and
late graft loss.
References:
Rubin Zhang et al.Donor-Specific Antibodies in Kidney Transplant Recipients.
CJASN January 2018, 13 (1)
Studies reported the risk for allograft failure as a function of C4d and DSA. Worthington et al. found that the proportion of allografts failing within 15 years of follow-up in patients with acute allograft dysfunction was highest among patients with both DSA and C4d (75%), compared with patients with C4d alone (23%), DSA alone (0%), or neither of the two (9%). So, the presence of C4d positive is essential for dysfunction associated with DSA.
C4d‑negative AMR morphologically have higher intrarenal endothelial gene expression, alloantibodies expression
While microcirculatory inflamation appeared to be the most important determinant of allograft outcomes, in most instances the presence of C4d increased the risk for allograft loss beyond that observed as a function of DSA or MI alone. So, C4d positive has a worse prognosis in AMR.
REFERENCE:
– A systematic review of the role of C4d in the diagnosis of acute antibody-mediated rejection. Kidney International (2015) 87, 182–194; doi:10.1038/ki.2014.166;
*** The DSA profiles
DSA in the C4d positive ABMR is pre formed antibodies against HLA Class I and itis a complement fixing antibodies IgG1 and IgG3
C4d negative ABMR usually de novo antibodies due to non complement fixing antibodies IgG2 and IgG4 against HLA class1I
*** The onset
C4d positive ABMR Usually occur early posttransplatatio with acute presentation and more aggressive.
C4d negative ABMR Usually occur late may be chronic or subclinical presentation. C4d negative AMR, in association with TCR, can present earlier than C4d positive ABMR.
*** The prognosis
C4d positive ABMR
More responsive to treatment, but with early graft loss.
C4d negative ABMR
Less responsive to treatment but with better prognosis than C4d positive ABMR with late graft loss.
Although C4d negative AMR may not be as severe as C4d positive AMR with regard to potential for causing transplant glomerulopathy, interstitial fibrosis/tubular
atrophy, and graft loss, if not treated C4d negative AMR can definitely result in all of these.
References:
1) Nigam LK, Vanikar AV, Kanodia KV, Patel RD, Suthar KS, Patel HV. C4d-negative antibody-mediated rejection: A pathologist’s perspective and clinical outcome. Saudi J Kidney Dis Transpl. 2018 Jan-Feb;29(1):39-49. doi: 10.4103/1319-2442.225206. PMID: 29456206.
C4d positive ABMR is associated with DSA against class Ⅰ or both class Ⅰ and class Ⅱ. C4d positive ABMRs are usually presented as early acute ABMR within the first month post-TX and are associated with preexisting DSA with worse prognosis. While C4d negative ABMR is associated with class Ⅱ DSA and has late (more than 30 days) presentation. Both of them if untreated, could lead to graft loss. But C4d+ ABMR, especially if is associated with other morphological aspects such as TMA, has worse prognosis even with treatment.
C4d positive AMR
1- Associated with complement-fixing DSA against Class I, preformed.
2- Early-onset AMR, and graft loss
3- Respond to treatment better than C4d negative one
C4d negative AMR
1- Associated with non-complement fixing, de novo, class II, or non- HLA, DSA
2- Late-onset
3- Poor response to treatment
4- Chronic graft loss
In renal allografts, microvascular injury in the presence of DSA but with negative C4d staining in PTC nonetheless is indicative of humorally mediated graft injury that has the potential to cause tubular atrophy/interstitial fibrosis, transplant glomerulopathy, and graft loss.
C4d positive AMR: Due to complement fixing antibodies ( IgG1 and IgG3), usually pre-formed antibodies. Class I DSA
C4d negative AMR: Due to non-complement fixing antibodies (IgG2 and IgG4), usually de-novo antibodies against Class II DSA(DQ)
C4d positive AMR: Usually occur early, acute presentation, more aggressive.
C4d negative AMR: Usually occur late (>1-year post transplant), chronic or subclinical presentation. C4d negative AMR, in association with TCR, can present earlier than C4d positive AMR.
-Out comes
C4d positive AMR: More responsive to treatment, but has early graft loss.
C4d negative AMR: Less responsive to treatment, but has better prognosis than C4d positive AMR, with late graft loss.
REF
1) Zhang R. Donor-Specific Antibodies in Kidney Transplant Recipients. Clin J Am Soc Nephrol. 2018 Jan 6;13(1):182-192. doi: 10.2215/CJN.00700117. Epub 2017 Apr 26. PMID: 28446536; PMCID: PMC5753302.
DSA profiles
C4d + AMR is associated with preformed DSA of class I , II
C4d – AMR is associated with DeNovo DSA class II
Onset
C4d + AMR present early post Tx
C4d – AMR present late post Tx ( may be subclinical and Dx on a protocol Bx )
Prognosis
Both associated with poor graft outcomes ( graft dysfuntion& graft loss ) , although C4d – may have more chronic tissue damage at time of Dx & is less responsive to Rx .
difference between C4d negative and C4d positive AMR
C4d positive ABMR associated with class11 and 1 preformed DSA and c4d negative ABMR associated with class11(de novo) post renal transplant DSA such as endothelial associated transcripts.
the onset
c4d postiveABMR occure early postrenal transplantaion when c4d negative occure late and subclincal
the prognosis
Both c4d positive and c4d negative ABMR are associated with increased graft loss and more information needs to be gathered about the efficacy of intervention in preventing TG and improving graft survival.
References:
1. Hayde N, Bao Y, Pullman J, Ye B, Calder RB, Chung M, Schwartz D, Lubetzky M, Ajaimy M, de Boccardo G, Akalin E. The clinical and genomic significance of donor-specific antibody-positive/C4d-negative and donor-specific antibody-negative/C4d-negative transplant glomerulopathy. Clin J Am Soc Nephrol. 2013 Dec;8(12):2141-8. doi: 10.2215/CJN.04240413. Epub 2013 Sep 12. PMID: 24030736; PMCID: PMC3848403.
2. Haas M. Pathology of C4d-negative antibody-mediated rejection in renal allografts. Current opinion in organ transplantation. 2013 Jun 1;18(3):319-26.
C4d +ve AMR associated with class II and I performed DSA which occur early post transplant while C4d -ve AMR associated with class II and occur late post transplant . Both phenotypes are associated with increased graft loss and thus warrant consideration for intervention .
The DSA profile and onset :
C4d positive usually early in Acute ABM rejection due to the presence of Antibodies in pre-sensitized patient usually
C4d negative usually present late due to De novo DSA mostly against HLA class II
Many studies showed that C4d negative tend to occur later post-transplant with subclinical presentation
and usually due to the non-complement dependent pathway of ABMR
However C4d negative may occur due to :
Technical issues related to the type of fixative used
different methods of C4d detection
poor complement fixation by some DSAs
Prognosis
incidence of C4d negative ABM rejection was 18.2% with less than C4d positive ABMR (72.3%)
with better graft outcome in C4d negative ABMR than C4d- positive ABMR.
The overall graft survival of patients with C4d-negative ABMR was 97.5% as against C4d-positive ABMR which was 95.5%
Although associated with better graft survival, the C4d-negative ABMR does have a poorer graft function as reflected by the higher serum creatinine levels. This proves that although negative for C4d, this immune injury is responsible for graft attrition over time and needs aggressive treatment like ABMR with C4d positive.
C4d-Negative Antibody-Mediated Rejection: A Pathologist’s Perspective and Clinical Outcome Lovelesh Kumar Nigam1 , Aruna V. Vanikar1 , Kamal V. Kanodia1 , Rashmi D. Patel1 , Kamlesh S. Suthar1 , Himanshu V. Patel2
DSA profile: in C4d + AMR the DSA is usually against Class 1 anti HLA and preformed DSA while in C4d –ve mainly against Non-HLA antibodies and de novo DSA.
Several studies have shown several endothelial-associated transcripts in kidney transplants, expression related to the processes of endothelial cell activation, repair, and angiogenesis in cases with chronic AMR. The majority of these cases with chronic AMR features had no C4d staining.
Onset: both may occur early or late post-transplantation.
Prognosis:
Although C4d-positive AMR may represent a more severe form of AMR, Haas M. et al in their data suggest that C4d-positive and C4d-negative AMR show similar degrees of glomerulitis and peritubular capillaritis, similar frequencies of concurrent cell-mediated rejection.
Botermans JM et al found no difference in the occurrence of steroid resistance or graft survival for patients who in retrospect showed a C4d+ or a C4d− graft rejections and he concluded that the C4d staining pattern during an early graft rejections does not predict renal allograft function or survival over time. On the other hand, Batal I et al, found that diffuse C4d was associated with inferior outcomes even in the absence of demonstrable donor-specific antibodies.
Recent studies have found that in patients with DSA, microvascular injury (glomerulitis, peritubular capillaritis) is more strongly associated with graft loss than C4d deposition. A recent study on renal biopsies with AMR has shown that the combination of early C4d positivity and thrombotic microangiopathy confers a significant risk of graft loss when compared to the patients with C4d positivity without thrombotic microangiopathy. These data demonstrate that the association of C4d staining with other morphological aspects has a more prognostic value.
References:
1. Hayde N, Bao Y, Pullman J, Ye B, Calder RB, Chung M, Schwartz D, Lubetzky M, Ajaimy M, de Boccardo G, Akalin E. The clinical and genomic significance of donor-specific antibody-positive/C4d-negative and donor-specific antibody-negative/C4d-negative transplant glomerulopathy. Clin J Am Soc Nephrol. 2013 Dec;8(12):2141-8. doi: 10.2215/CJN.04240413. Epub 2013 Sep 12. PMID: 24030736; PMCID: PMC3848403.
2. Haas M. Pathology of C4d-negative antibody-mediated rejection in renal allografts. Current opinion in organ transplantation. 2013 Jun 1;18(3):319-26.
3. Botermans JM, de Kort H, Eikmans M, Koop K, Baelde HJ, Mallat MJ, Zuidwijk K, van Kooten C, de Heer E, Goemaere NN, Claas FH. C4d staining in renal allograft biopsies with early acute rejection and subsequent clinical outcome. Clinical Journal of the American Society of Nephrology. 2011 May 1;6(5):1207-13.
4. Corrêa RR, Machado JR, da Silva MV, Helmo FR, Guimarães CS, Rocha LP, Faleiros AC, dos Reis MA. The importance of C4d in biopsies of kidney transplant recipients. Clinical and Developmental Immunology. 2013 Jul 9;2013.
DSA PROFILE
*C4d positive AMR is associated with DSA class I, II (preformed DSA)
*C4d negative AMR is associated with class II DSA.( De novo)
ONSET
C4d positive AMR occur mainly in early post transplant period
(acute AMR)
C4d negative AMR occurs in late post transplant time
(Chronic AMR)
PROGNOSIS
Graft outcomes overall were better for the C4d-negative AMR, but this did not reach statistical significance, although both groups were associated with significantly worse graft survival compared with AMR-free patients.
Reference
B. J. Orandi, N. Alachkar, E. S. Kraus, F. Naqvi, B. E. Lonze, L. Lees, K. J. Van Arendonk, C. Wickliffe, S. M. Bagnasco, A. A. Zachary, D. L. Segev, R. A. Montgomery. Presentation and Outcomes of C4d-Negative Antibody-Mediated Rejection After Kidney Transplantation. American Journal of TransplantationVolume 16, Issue 1 p. 213-220
In terms of extent of staining, with IF, Banff Lesion Score C4d ≥ 2 is considered positive and a criterion for antibody interaction with tissue and as equivalent to DSA.
(1) Linear or finely granular peritubular capillary staining was classified as diffuse when it was seen in more than 50% of microscopic fields available for evaluation. It was referred to as focal when present in 10–50% of biopsied tissue, and negative if the staining did not even reach that threshold.
(2) Glomerular basement membrane staining was evaluated according to the most intensely stained glomerulus. It was further classified as global, segmental and minimal when more than 50, 10–50 or less than 10% of glomerular capillaries were stained, respectively. It was considered negative when no glomerular basement membrane staining was observed.
(3) Tubular basement membrane staining was evaluated only within the cortex, as medullary tubules can be difficult to distinguish from the vasa recta by routine light microscopy. In individual tubules, staining was considered to be present if more than half of the tubular basement membrane circumference was stained. Staining was further characterized as diffuse, focal and negative when 450, 10–50 and less
than 10% of the tubules showed C4d deposits, respectively.
(4) Arteriolar staining was classified as diffuse, focal or negative, when 450, 10–50 or o10% of arterioles showed C4d deposits, respectively. Similar criteria were used for arterial staining evaluation. However, when only one artery was available for evaluation, the designations diffuse and focal reflected the percent of circumferential area of that vessel showing C4d deposits.
Circulating Donor-Specific Antibodies:
Donor-specific antibodies were defined as antibodies directed against one or more donor HLA type. diffuse C4d peritubular capillary staining was associated more often with the presence of circulating donor-specific antibodies compared to focally and negatively stained
With regard to the association between C4d staining and detection of donor-specific antibodies, Nadasdy et al found that 9/14 (64%) of diffuse and1/2 (50%) of focal staining in frozen biopsies were associated with donor-specific antibodies, whereas in paraffin-embedded biopsies, 7/10 (70%) diffuse and 2/5 (40%) focal staining reactions were associated with these antibodies.
The absence of detectable circulating donor-specific antibodies in some patients with C4d-positive biopsies has been noted; explanations include technical issues, different
approaches for peritubular capillary C4d staining evaluation and scoring, complete absorbance of high affinity antibodies by allograft tissue and non-HLA antibodies, which would not be detected during routine testing of donor-specific antibody.
Onset:
DSA could be pre-existing(in highly sensitized recipients ), or Denovo (more realated to patients’ nonadherence)
C4D usually late(6 months post tx)
prognosis:
combined both C4D and DSA are of worse diagnosis and least graft survival with less response to treatment.
biopsies
DSA profiles
C4d + AMR is usually due to complement fixing DSA whereas C4d – AMR is due to non complement fixing DSA
DSA is usually against Class 1 , a higher titer and usually anti HLA in case of C4d + AMR however in C4d – it is of lower titer can be against Non HLA antibodies and mostly against class 2 like DQ Ab
As C4d + AMR mostly occurs early so DSA is usually preformed where as in C4d- it is de novo.
The onset :
C4d +ve AMR usually occurs early in post-transplantation more severe in clinical presentation.
C4d -ve AMR usually occurs late in post-transplantation usually 1 year post transplant
The prognosis :
the prognosis of C4d -ve AMR is generally better than C4d +ve AMR regarding graft function and survival
as regard DSA profile
C4d -ve usually associated with anti HLA Class II DSA, mainly formed de novo after transplantation. It cause graft injury by lectin pathway of complement or by Antibody mediated cellular cytotoxicity, hence classical complement pathway (C4d) activation is not seen
C4d +ve are usually positive to anti HLA Class I DSA in significant MFI. They cause complement activation through classical pathway activation and C4d deposition which is seen as the foot print of AMR
Onset:
C4d negative AMR has late onset of presentation after transplant and has low titres of DSA predominantly class II which are formed de novo
C4d positive AMR is associated with pre existing DSA and has an early onset of AMR after transplant
Prognosis:
What is the difference between C4d negative and C4d positive AMR addressing the following points?
The DSA profiles
The onset
The prognosis
C4d is a classical pathway complement degradation product.
C4d positive AMR
Biopsy evidence of deposition of C4d in the peritubular capillaries, morphological evidence of AMR, such as renal injury, allograft dysfunction, & the presence of DSA in plasma.
PTC C4d positivity seen in about 20-50% of indicated transplant biopsies and 2% of protocol biopsies.
starts with the formation of DSA
DSA may or may not lead to active AMR
Not all active AMR will progress to chronic active AMR
Over time, chronic histological features such as TG occur, & the patient develops allograft dysfunction, proteinuria, & poaaibly allograft loss.
Therefore, finding an active vs chronic a-cAMR on the biopsy may be more reflective of the timing of the biopsy rather than the underlying pathological process itself.
Clinical phenotypes of AMR:
Early Posttransplant (<30 Days) Active AMR: Preformed DSA at the time of kidney transplant or H/O sensitizing event. The risk of early AMR increases with growing DSA strength or breadth at the time of transplant as determined by:
– DSA MFI
– Degree of FCM-XM positivity
– The number or breadth of cross-reactive DSA specificities.
Early AMR is generally uncommon, as it is common practice to avoid transplanting patients with known preformed DSA
Early AMR occurs in up to 40% of patients with preformed DSA & a positive FCM-XM
Early AMR is aggressive & presents with an abrupt increase in DSA & allograft dysfunction. C4d is usually positive.
If not recognized & promptly treated, it can lead to cortical necrosis & allograft loss within days.
Histological features of active AMR frequently resolve completely if treated early. Otherwise it can persist & progress to chronic AMR.
Late (>30 Days) posttransplant AMR with pre-existing DSA
An indolent and progressive form of AMR
Usually detected on a protocol biopsy (stable function) or on a for-cause biopsy for mild allograft dysfunction.
Late (>30 Days) AMR Associated With dnDSA
The most common form of AMR is associated with dnDSA.
dnDSA is a new DSA detected after >3 months posttransplant
Occurs in context of inadequate IS due to nonadherence, physician directed, or genetical variability in metabolism of IS drugs.
This form of AMR often presents with allograft dysfunction and concomitant or pre-existing TCMR.
AMR with dnDSA is associated with inferior graft survival compared with AMR from pre-existing DSA.
In renal allografts, MVI in the presence of DSA but with negative C4d staining in PTC is indicative of humorally mediated graft injury that has the potential to cause IF/TA, & graft loss.
So,
The DSA profiles
C4d positive AMR: Due to complement fixing antibodies (IgG1 and IgG3), usually Class I DSA, usually pre-formed antibodies.
C4d negative AMR: Due to non-complement fixing antibodies (IgG2 and IgG4), usually Class II DSA, usually de-novo antibodies.
The onset
C4d positive AMR: Usually occur early, acute presentation, more aggressive.
C4d negative AMR: Usually occur late (>1 year post transplant), chronic or subclinical presentation. C4d negative AMR, in association with TCR, can present earlier than C4d positive AMR.
The prognosis
C4d positive AMR: More responsive to treatment but has early graft loss.
C4d negative AMR: Less responsive to treatment, but has better prognosis than C4d positive AMR, with late graft loss.
Reference
Schinstock, Carrie A. ; Mannon, Roslyn B. ; Budde, Klemens et al Transplantation: May 2020 – Volume 104 – Issue 5 – p 911-922 doi: 10.1097/TP.0000000000003095
DSA profiles:
C4d negative AMR are usually associated with DSA Class II which are formed de novo after years of renal transplantation. These de novo DSA Class II antibodies cause graft injury by lectin pathway of complement or by Antibody mediated cellular cytotoxicity, hence classical complement pathway and C4d activation is not seen
C4d Positive AMR are usually DSA positive to Class I and II in significant MFI. They cause complement classical pathway activation and C4d deposition which is seen as the foot print of AMR
Onset:
C4d negative AMR has late onset of presentation after transplant and has low titres of DSA predominantly class II which are formed de novo
C4d positive AMR is associated with pre existing DSA and has an early onset of AMR after transplant
Prognosis:
C4d positive AMR is associated with worse prognosis and is severe. C4d negative AMR is less severe in nature
C4d positive is a marker of AMR occur due to activation of classical pathway against HLA type class I associated with high titre of DSA level.
C4d is a morphological evidence by presence of C4d staining in peritubular capillarities along basement membrane.
C4d negative is due non HLA antibodies (de novo DSA).
it’s microvascular injury in absence of c4d staining
it’s due to presence of alloantibodies like natural killer cell.
Incidence of c4d positive rejection more than negative c4d
Patient’s with c4d positive have higher serum creatinine levels than those negative c4d.
Onset:
c4d positive is early in coarse (Acute),and aggressive but treatable.
c4d negative is late in coarse after one year of transplant associated with chronic transplant glomerulopathy and loss of graft.
Prognosis:
c4d negative is poor prognosis in term of graft survival rather than C4d positive.
References:
Rosana Rosa et al; The Importance of C4d in biopsies of kidney transplant recipient: Journal of immunology researchers, Volume 2013.
C4d is a marker of complement fixing circulating antibodies.
DSAs with poor complement fixation, complement independent pathway and auto antibodies to angiotensin II type 1 receptor are causes of C4d negative AMR
C4d positive AMR is associated with HLA antibodies against class I and/or II
C4d negative AMR is more likely to develop later post transplant while C4d positive AMR tends to occur early in presensitized patients
Graft outcome is better in patient with C4d negative antibody mediated rejection.
Sapir-Pichhadze R, Curran SP, John R, Tricco AC, Uleryk E, Laupacis A, Tinckam K, Sis B, Beyene J, Logan AG, Kim SJ. A systematic review of the role of C4d in the diagnosis of acute antibody-mediated rejection. Kidney International. 2015 Jan 1;87(1):182-94.
Nigam LK, Vanikar AV, Kanodia KV, Patel RD, Suthar KS, Patel HV. C4d-negative antibody-mediated rejection: A pathologist’s perspective and clinical outcome. Saudi Journal of Kidney Diseases and Transplantation. 2018 Jan 1;29(1):39.
C4d positive AMR is usually due to class I antibodies, usually with complement fixingIgG1 and IgG3 subtype. mostly due to preformed DSAs. the onset is early and more aggressive. response to treatment is better, may lead to graft failure early. On the other hand, C4d negative AMR is mostly due to class and due to de novo DSAs. the onset is late so maybe missed subclinical and less responsive to treatmentDSA class I
In sum:
DSA class I/onset acute/prognosis better in C4D positive AMR
DSA class II/onset late/ worse prognosis. in c4d negative AMR
5. What is the difference between C4d negative and C4d positive AMR addressing the following points?
C4d is a classical pathway complement degradation product.
C4d positive AMR
Diagnosis by:
– Biopsy evidence of deposition of C4d in the peritubular capillaries, morphological evidence of AMR, such as renal injury, allograft dysfunction, & the presence of DSA in plasma.
PTC C4d positivity, a marker for AMR, is seen in about 20-50% of indicated transplant biopsies & in just 2% of protocol biopsies.
The Banff classification has 3 AMR diagnostic categories (including chronic AMR with TG & current or prior DSA but no MVI or C4d).
AMR is frequently a chronic progressive disease process.
This chronic disease process starts with the formation of DSA.
DSA may or may not lead to active AMR.
Not all active AMR will progress to chronic active AMR.
Over time, chronic histological features such as TG occur, & the patient develops allograft dysfunction, proteinuria, & poaaibly allograft loss.
Therefore, finding an active vs chronic a-cAMR on the biopsy may be more reflective of the timing of the biopsy rather than the underlying pathological process itself.
=================================================================
Clinical phenotypes of AMR:
1.Early Posttransplant (<30 Days) Active AMR:Preformed DSA at the time of kidney transplant or H/O sensitizing event.The risk of early AMR increases with growing DSA strength or breadth at the time of transplant as determined by:
– DSA MFI
– Degree of FCM-XM positivity
– The number or breadth of cross-reactive DSA specificities.
Early AMR is generally uncommon, as it is common practice to avoid transplanting patients with known preformed DSA
Early AMR occurs in up to 40% of patients with preformed DSA & a positive FCM-XM
Early AMR is aggressive & presents with an abrupt increase in DSA & allograft dysfunction. C4d is usually positive.
If not recognized & promptly treated, it can lead to cortical necrosis & allograft loss within days.
Histological features of active AMR frequently resolve completely if treated early. Otherwise it can persist & progress to chronic AMR.
2. Late (>30 Days) posttransplant AMR with preexisting DSA
An indolent and progressive form of AMR
Usually detected on a protocol biopsy (stable function) or on a for-cause biopsy for mild allograft dysfunction.
3.Late (>30 Days) AMR Associated With dnDSA
The most common form of AMR is associated with dnDSA.
dnDSA is a new DSA detected after >3 months posttransplant
Occurs in context of inadequate IS due to nonadherence, physician directed, or genetical variability in metabolism of IS drugs.
This form of AMR often presents with allograft dysfunction and concomitant or preexisting TCMR.
AMR with dnDSA is associated with inferior graft survival compared with AMR from preexisting DSA.
=============================================================
In renal allografts, MVI in the presence of DSA but with negative C4d staining in PTC is indicative of humorally mediated graft injury that has the potential to cause IF/TA, & graft loss.
Reference
Schinstock, Carrie A. ; Mannon, Roslyn B. ; Budde, Klemens et al Transplantation: May 2020 – Volume 104 – Issue 5 – p 911-922 doi: 10.1097/TP.0000000000003095
C4d positive AMR
-DSA profile: class 1 DSA is detected with complement fixing IgG subclass 1, 3,
-Onset: it presents early with rapid deterioration of graft function
-Prognosis :early graft loss occurs meanwhile it is more responsive to treatment (1)
C4 d negative AMR
-DSA profile: Class 2 DSA is detected with non complement fixing IgG subclass 2, 4
-Onset: It presents later subclinicaly with slower deterioration of graft function
-Prognosis: late graft loss occurs meanwhile it is less responsive to treatment (1)
C4d-negative ABMR usually occurs >12 months after transplantation but can occur acutely in highly sensitized patients with persistent DSAs (even after desensitization).
C4 d negative AMR could be due to denovo DSA and autoantibodies to the angiotensin II type 1 receptor Fc receptors on NK cells (FcRIIA) can be involved too.
Some studies demonstrated that C4 negative AMR had better graft survival but worse graft function in comparison to C4 d positive AMR.
Loupy et al reported that some patients with ABMR transit between negative C4d staining and positive C4d deposition in the peritubular capillaries
Other studies concluded that C4d-positive and C4d-negative ABMR show similar frequencies of concurrent cell-mediated rejection and both can occur early or late posttransplant. (2)
Non-HLA antibodies anti-endothelial cell antibodies (AECA) has arisen due to reports of antibody-mediated rejection or C4d deposition in the absence of circulating donor specific HLA antibodies.(3)
Reference
1-Rubin Zhang. Donor-Specific Antibodies in Kidney Transplant Recipients .CJASN 2018, 13 (1) 182-192
2- Nigam LK, Vanikar AV, Kanodia KV, Patel RD, Suthar KS, Patel HV. C4d-negative antibody-mediated rejection: A pathologist’s perspective and clinical outcome. Saudi J Kidney Dis Transpl 2018;29:39-49
3- Nicole M. Valenzuela, Elaine F. Reed .Antibodies in Transplantation: The Effects of HLA and Non-HLA Antibody Binding and Mechanisms of Injury. Methods Mol Biol. 2013; 1034: 10.1007/978-1-62703-493-7-2
Difference between C4d negative and C4d positive AMR
Antibody mediated rejection is important cause of allograft dysfunction. The acute antibody mediated rejection is characterised by evidence of circulating DSA and histologically it shows peritubular capillaritis , cell necrosis , thrombotic microangiopathy and glomerulitis. while in Chronic ABMR we can see transplant glomerulopathy which results from inflammatory and thrombotic events leading endothelial injury and graft loss. C4d staining is an important hallmark of ABMR but has low sensitivity.
C4d is an activation product of classical compliment pathway and contains an occult sulfhydral group which forms covalent thioester bond with proteins on activation by C1. C4b and C4d remain in tissues for several days after IG have been released . Follwoing activation the thioester groups are exposed allowing binding of C4d with endothelial cells and matrix components of vascular basement membrane near the C4 activation site. C4d is found in intracytoplasmic vacuoles of endothelial cells. Because of covalent binding it becomes stable molecules and is easily detected by immunohistochemistry thus making it a footprint of antibody response
C4d Positive ABMR
It is usually due to DSA against class 1 HLA antigens. These are compliment fixing DSA usually IgG 1&3. It usually presents s early within 6 months and because of C4d positivity can be detected early and will usually respond well to treatment with better outcome as compared to C4d negative ABMR.
C4d negative ABMR
It usually presents within 6-12 months and is less severe in intensity as compared to C4d Positive ABMR and leads to chronic graft dysfunction i.e. transplant glomerulopathy. TG responds poorly to treatment. The mechanism can be direct endothelial cell injury or Antibody mediated cell cytotoxicity. It is usually due to DSA against class 2 HLA antigens and are non compliment fixing- usually IgG 2&4. These are usually against HLA DQ and can be denovo due to poor compliance , inadequate HLA match or poor drug levels.
Reference.
Lovelish Kumar Negam. et al. C4d-negative antibody-mediated rejection: A pathologist’s perspective and clinical outcome. saudi Journal of transplantation and kidney diseases. 2018 Vol29:39-49.
I summarized the differences in a table and attached it to this comment as a picture.
The difference between C4d negative and C4d positive AMR as per:
C4d positive AMR: Due to complement fixing antibodies (IgG1 and IgG3), usually Class I DSA, usually pre-formed antibodies.
C4d negative AMR: Due to non-complement fixing antibodies (IgG2 and IgG4), usually Class II DSA, usually de-novo antibodies.
C4d positive AMR: Usually occur early, acute presentation, more aggressive.
C4d negative AMR: Usually occur late (>1 year post transplant), chronic or subclinical presentation. C4d negative AMR, in association with TCR, can present earlier than C4d positive AMR.
C4d positive AMR: More responsive to treatment, but has early graft loss.
C4d negative AMR: Less responsive to treatment, but has better prognosis than C4d positive AMR, with late graft loss.
References:
1) Nigam LK, Vanikar AV, Kanodia KV, Patel RD, Suthar KS, Patel HV. C4d-negative antibody-mediated rejection: A pathologist’s perspective and clinical outcome. Saudi J Kidney Dis Transpl. 2018 Jan-Feb;29(1):39-49. doi: 10.4103/1319-2442.225206. PMID: 29456206.
2) Zhang R. Donor-Specific Antibodies in Kidney Transplant Recipients. Clin J Am Soc Nephrol. 2018 Jan 6;13(1):182-192. doi: 10.2215/CJN.00700117. Epub 2017 Apr 26. PMID: 28446536; PMCID: PMC5753302.
C4d positivity means the rejection is complement mediated,which tells many things about the rejection process .
1.C4d positive ABMR-
.Basically by DSA to class 1HLA,and some times
both class 1 and 2 HLA(presensitized patient)
.Normally IgG1 and 3 ab(complement binding)
.Early to appear first 6mnts(as presensitised)
.Very severe form with graft dysfunction
.Response to tpe and ivig is good
.As detected early due to graft dysfunction, so
amenable to treatment without being
undetected like c4d neg abmr.
2.C4d negative ABMR-
.Basically by DSA to class 2 HLA (DQ,DR) due to
formation of denovo Ab (due to incompliant to
immunosuppressive meds,hla mismatch,low
level immunosuppression)
.Normally IgG 2 and 4 ab(noncomplement bind)
.Late to appear mainly after 6-12mnth.
.though less severe than c4d positive but leads
to formation of transplant
glomerulopathy,leading to chronic graft dysfunction.
.response to therapy is very poor.
.Mainly damage by direct endothelial toxicity
Or ab dependant cell cytotoxicity by NK cell.
.As very subtle in action, not detected and licks
out the graft without being unnoticed,so more
dangerous than c4d positive ABMR.
.Without treatment both c4d positive and negative abmr have worse prognosis but even with treatment c4d negative not behave well, though very rare in occurrence.
Acute and chronic definitions of ABMR based on C4d positivity.
As shown in the diagram in the attachment
C4d negative AMR is explained by multiple causes one of them is the type of Noncomplement fixing DSA which is mostly of IgG 2,4 type. it usually develops late after 1st 6m-1 y after kidney transplantation and usually against class II DQ and it usually presents with late graft failure and not respond to treatment
C4d positive AMR is caused by complement-fixing antibodies mostly of IgG 1,3 which usually occurs early post-transplant and leads to rapid deterioration of graft function and usually against class I HLA
It shows more response to treatment and early graft loss
EXCELLENT Ramy
But remember there are many exceptions.
The most recent Banff meeting update high- lights two major phenotypes of ABMR. The first type appears early in the posttransplant period in a pre-sensitized patient and is more likely to be C4d positive.
type develops late post-transplant and is due to de novo DSA development and is likely to be C4d negative. The second phenotype is an important factor in late graft loss. C4d-negative ABMR usually occurs >12 months after transplantation but can occur
acutely in highly sensitized patients with persistent DSAs (even after desensitization).
– DSAs related to C4d negative AMR:
Antigen against the HLA class II antigen., Frequently used against the DR-Q HLA antigen, The majority of DSAs are de novo., IgG DSAs are classified into two classes: class II and class IV., There is no complement-fixing., Associated with an asymptomatic and mild decrease of Allograft function and proteinuria over a long period of time, The symptoms generally appear 6 months after the transplantation.
– AMR is histologically related to both chronic active and chronic inactive disease states. Chronic AMR is represented by Transplant Glomerulopathy (TG) and Chronic Peritubular Capillaritis (PTC) is represented by PTC multilayering in the classic form.
HLA incompatibility, particularly for class II antigen, and non-adherence to anti-rejection drugs are two of the most significant risks.
-It is known that DSAs against HLA antigens of Class I are related to C4d positive AMR;
they are as follows: against class 1(HLA A, B)., DSAs that are already performed. complement-dependent, Induce acute severe clinical AMR in patients. They are often of the IgG antibody type (Class I and Class III). This can occur at any point following the transplantation, although it is most common in the first 6 months. most likely reversible
reference:
C4d-Negative Antibody-Mediated Rejection: A Pathologist’s Perspective and Clinical Outcome.Saudi J Kidney Dis Transpl 2018;29(1):39-49 © 2018 Saudi Center for Organ Transplantation.
Dr\Tareq Abbas’s lecture.
The DSA profiles :
The onset :
The prognosis :
Excellent
1-C4D POSITIVE ABMR
2-C4D NEGATIVE ABMR
C4d -ve ABMR was defined by Banff 13 guidelines as
Presence of microvascular injury as glomeruli this , peritubular capilaritis or TMA associated with DSA and no C4d deposition
Causes
Non complement fixing Ab
Alloantibodies against FC receptors on NK cells
Type of associated DSA : Commonly class II , non complement fixing Ab , de no vo DSA
Clinical presentation: chronic ABMR , less common acute ABMR
Poor graft outcome
C4d + ve ABMR
DSA: Class I, complement fixing , preformed DSA
Clinical presentation: acute ABMR ,shortly after transplantion
Poor graft outcome
The Banff classifies ABMR into :
1. The first type appears early in the posttransplant period in a presensitized patient and is more likely to be C4d positive ABMR.DSA against HLA class I or both class I and II. It is more severe than C4d negative.
2. The second type develops late post-transplant (>12 months after transplantation ) or early,and is due to de novo DSA development and is likely to be C4d negative ABMR. DSA to Class II HLA antigens.
– The endothelial damage in C4d negative ABMR is mediated by NK cells and, to a lesser extent, monocytes and neutrophils; antibody-dependent cell-mediated cytotoxicity.
– C4d ABMR has a subclinical presentation with better graft outcome than C4dpositive.
Reference :
-Lovelesh Kumar Nigam1 etal .Suthar1, Himanshu V. Patel2C4d-Negative Antibody-Mediated Rejection: A Pathologist’s Perspective and Clinical Outcome. Saudi J Kidney Dis Transpl 2018;29(1):39-49.
Well done
Complement Fixing vs Non-Complement Fixing DSA:
Both C4d positive and C4d negative AMR are associated with worse prognosis compared to no AMR.
Complement binding DSAs target class 1 HLA on endothelial cells, activate the classic complement cascade, and deliver complement-dependent cytotoxicity in AMR which occurred early and mainly associated with C4d positive ABMR which ccc by (early onset ,acute, rapid and responsive to treatment).
Complement nonbinding DSAs target the class 2 HLA on endothelial cells and recruit innate immune cells through Fc receptors and lead to antibody-dependent cellular toxicity or direct stimulation effects that cause tissue injury, cellular recruitment, and endothelial proliferation which mainly associated with C4d negative ABMR which ccc by(late onset, chronic or sub-clinical presentation and resistant to treatment)(1).
C4D negative is less common than C4D + cases ,C4D positive ABMR occurs earlier and more severe than C4D -ve.(2).
Graft outcomes: better in c4d –ve and Both C4D +&- require intervention(3).
References:
1-Applied Transplant Immunology; Case-based Discussion (Part 2),lecture of professor: A. Halwa ,(ASNRT).
2-Renal Allograft Rejection (Part 3) lecture By Professor Tarek Abbas(ASNRT).
3-Nigam L., Vanikar A., Kanodia K., Patel R., Suthar K. and et al. C4d-Negative Antibody -Mediated Rejection: A Pathologist Perspective and Clinical Outcome. Saudi J Kidney Dis Transplant, 2018;29(1):39-49.
The link between peri tubular C4d deposition and graft survival was first reported in 1993. It was demonstrated that patients have suspected ABMR and positive C4d staining is associated with impaired graft function.
In 2003, C4d staining was included in the Banff classification for diagnosing ABMR.
Some chronic ABMR rejection related to C4d staining and some are not, which suggests that C4d is specific but not sensitive.
In patients with circulating DSA, deteriorating graft function and long term graft survival have been observed in biopsies with C4d positive versus negative C4d staining, suggesting that C4d is a marker of more significant humoral injury
C4d negative antibody-mediated rejection: The updated Banff Classification included the diagnosis of antibody mediated rejection in the absence of peritubular capillary C4d staining.
Some patients have histopathologic evidence of ABMR with microvascular inflammation and circulating DSA but have no C4d staining in the PTCs.
In C4d negative ABMR, DSA binding to endothelial cells may cause injury through non complement dependent mechanisms like direct endothelial injury. Patients with C4d negative ABMR who were not treated for ABMR had a higher rate of progression to transplant glomerulopathy.
C4d-negative AMR less common in comparison to C4d-positive AMR most likely develop in late post-transplant period and less likely to have a clinical presentation (usually sub clinical course).
The risk of graft loss for C4d negative AMR patients is low in comparison with C4d positive AMR patients. There is no difference in DSA class I vs. class II in terms of the C4d phenotype either C4d positive or negative.
References
Sis B, Jhangri GS, Bunnag S, Allanach K, Kaplan B, Halloran PF. Endothelial gene expression in kidney transplants with alloantibody indicates antibody-mediated damage despite lack of C4d staining. Am J Transplant. 2009;9(10):2312–2323.
C4d positive AMR is more common and DSA is detected early post-transplant and are preformed ,patients usually symptomatic and in acute severe form, and usually class I ,complement fixing DSA.Histologically, microvascular inflammation ( MVI) , glomerulitis and capillaritis ,and or variable degree of arteritis .C4d positive AMR had a higher risk for graft loss and had better response to treatment
C4d negative AMR DSA tends to be subclinical or chronic and occurs late post transplant and are usually denovo but it is non complement fixing and usually class II, it is less severe, less symptomatic , and responsible for late graft dysfunction and loss, no c4d deposition. Histologically associated with Chronic active and chronic inactive AMR. C4d negative AMR less aggressive but poor responsive to the treatment and associated with poor outcome
REFERENCE:
1- Orandi BJ, Alachkar N, Kraus ES, Naqvi F, Lonze BE, Lees L, et al. Presentation and Outcomes of C4d-Negative Antibody-Mediated Rejection After Kidney Transplantation. American Journal of Transplantation 2016; 16: 213–220.
2- Montgomery RA, Loupy A, Segev DL. Antibody-mediated rejection: New approaches in prevention and management. Am J Transplant. 2018 Jan;18 Suppl 3:3-17.
Recent Banff classification update show 2 subtypes of ABMR:
References:
C4d is a degradation of complement cascade which binds covalently with endothelium and the deposits detected by IF or IHC in the peritubular capillary.
Acute or chronic AMR can be c4d negative or positive
C4d positive AMR, DSA is detected and usually class I, it is complement fixing DSA, happens early post transplant , it is more common, acute severe form , and more symptomatic than c4d negative , with c4d deposition peritubular capillary.
C4d negative AMR, DSA is detected but it is non complement fixing and usually class II, it is less severe, less symptomatic , tends to be subclinical or chronic and occurs late post transplant and responsible for late graft dysfunction and loss, no c4d deposition.
Both c4d positive and negative AMR have worse prognosis in comparison to no AMR
references:
lecture of Dr Ahmed Halawa
lecture of Dr Tarek Abass
The DSAs associated with C4d positive AMR are:
1) DSAs against Class I HLA antigen (HLA A,B).
2) usually pre existing DSAs. With positive flow cytometric cross -match and variable FMI.
3) Complement fixing
4) Cause Acute severe clinical AMR.
5) They are usually class I and Class III IgG Antibody type.
6) Can happened any time post transplantation, usually inthe first 6 months.
7) Histologically , presented with Microvascular inflammation ( MVI) glomerulitis and per tubular capillaritis g+ptc >2 according to Banff classification ,and or variable degree of arteritis (intimal to trans-mural ,and fibrinoid necrosis)
Onset:
Early onset ,symptomatic,with Acute AMR and rapid rise of creatinine.
Prognosis:
Is relatively better as it’s
1) reversible with plasma exchange to remove the preformed DSAs,IVIG,and Rituximab to delete B lymphocytes clone that is interacting with the mismatched HLA antigens..Furthermore Bortizomib might have a role in depleting the plasma cells producing DSAs.
2) Frequent follow up of DSAs MFI with flow cytometric assessment and Luminex assay.
3)low threshold for allograft biopsy when clinically indicated or DSAs titer is significantly increasing.
C4d Negative AMR:
DSAs associated with C4d negative AMR:
1) Anti HLA class II antigen.
2) Commonly against DR-Q HLA antigen
3) Mostly De novo DSAs
4) DSAs are class II and class IV IgG DSAs.
5) Non complement fixing .
6) associated with subtle and chronic asymptomatic deterioration of Allograft function and proteinuria
7) usually presented after 6 months post transplantation.
8) Histologically associated with Chronic active and chronic inactive AMR. Classically Chronic AMR represented by Transplant Glomerulopathy TG, and Chronic peritubular capillaritis reflected by PTC multilayring
9) Mechanism of endothelial damage is Antibody dependent Cytotoxicity by Natural killer Cells.
10) Risk factors : HLA incompatibility especially for class II antigen, and non adherence to anti rejection medications.
Onset :
of C4d negative AMR is late with chronic subtle deterioration of allograft function and proteinuria . usually after 6 months to years post transplantation.
Prognosis:
Is poor.
As chronic AMR (TG and PTCML) is the harbinger for chronic Allograft failure.
Reference:
Dr.Ahmad Halawa lecture