4. It has been shown that 11% of non-sensitised patient develop de novo DSA. This figure goes up to 25% after 10 years of follow up.
- What is the effect on graft survival?
- What is the most significant prognostic factor?
- What is the most common phenotypic characteristic of these de novo DSA?
- Do you think there is increased risk of TCR with the appearance of de novo DSA?
- Which of these DSA is associated with increased risk AMR?
Dear All
Answer the following question with a justification of your answer (not more than 50 words): De novo DSA
A. Usually, anti-class I antibodies
B. Usually, anti-class II antibodies
C. Anti HLA DQ is the commonest
D. Screening for de novo DSA is not essential in none sensitised patients
E. May disappear without causing graft damage
There is a reward for the correct answer
De novo DSA occurs in about 12% of unsensitized recipient, so screening for DSA post transplantation is important. It classified into class 1 ( IgG1 &IgG3, occur early causing EAR) and class 2 ( IgG2 & IgG4, most common & occur later causing cAMR). Most commonly against HLA-DQ which is difficult in treatment. Some de novo DSA are un harmful & don’t causing graft dysfunction. During follow up of recipients it shown that about 40 % of patients develop persistent denote DSA, & minority of patients develop transient circulating DSA that disappeared during follow up with out affecting graft outcome.
Usually, anti-class I antibodies – F
Usually, anti-class II antibodies-T
Anti HLA DQ is the commonest-T
Screening for de novo DSA is not essential in none sensitized patients – F
Screening for de novo DSA is essential in none sensitized patients in three aspects:
1- Diagnostic: since subclinical and clinical ABMR can occur either due to Planned sub therapeutic immunosuppression (due to malignancy, infection) or conversion to CNI free or CS free protocols or noncompliance on immunosuppressive medication, So all patients with detectable DSA should undergo renal biopsy
2- Therapeutic: immunosuppressive medications can be tailored according to DSA level
3- Prognostic : presence of DSA in the early post-transplant period is associated reduced graft survival when compared to DSA developed later on after 1 year (10 years graft survival 27% vs 80%, respectively), > 40 % of patients with ABMR develop transplant glomerulopathy which reduce significantly graft survival (5 years graft survival in patient with TG is < 50%)
May disappear without causing graft damage – T
1- Biopsy proven ABMR
2- Rapid increase of DSA with normal or near normal biopsy in patients
who received desensitization to render cross match negative
References
1- I.-S. A. Ntokou, A. G. Iniotaki, E. N. Kontou et al., “Long-term follow up for anti-HLA donor specific antibodies postrenal transplantation: high immunogenicity of HLA class II graft molecules,” Transplant International, vol. 24, no. 11, pp. 1084–1093, 2011.
2- Filippone EJ, Farber JL: Humoral immune response and allograft function in kidney transplantation. Am J Kidney Dis 66: 337–347
A false
B true
C true
The majority of de novo DSAs after kidney transplant are class 2 antibodies, especially DQ.
Class 2 de novo DSAs appear later and are commonly noncomplement binding IgG2 or IgG4 sub- class. They tend to be persistent and are associated with chronic antibody-mediated rejection and transplant glomer- ulopathy
D false
The development of de novo DSAs after kidney transplant was reported in 13%–30% of previously nonsensitized patients
E false
de novo developed DSAs after transplant are associated with late acute antibody- mediated rejection, chronic antibody-mediated rejection, and transplant glomerulopathy
de novo, has become a well established biomarker predicting poor transplant out- comes, including high incidence of antibody-mediated re- jection, graft dysfunction, and inferior graft survival.
Reference
Rubin Zhang. Donor-Specific Antibodies in Kidney Transplant Recipients. Clin J Am Soc Nephrol 13: 182–192, 2018. doi: https://doi.org/10.2215/CJN.00700117
De novo DSA
A. Usually, anti-class I antibodies…F
B. Usually, anti-class II antibodies…T
the commonest against DQ
C. Anti HLA DQ is the commonest…T
D. Screening for de novo DSA is not essential in none sensitised patients…F
Developing of donovo DSA post transplant is related to multiple factors like mismatching,race,age and other after classification of the patient into 3 categories
High risk…patient with preexisting DSA and underwent desensitization…dsa monitoring and protocol biopsy in 1st 3m
Intermediate risk…hx of preexisting DSA and not currently…need DSA in 1st month
Low risk patient…non sensitized…DSA at least first 3-12m
DSA Screening is the noninvasive approach for evaluation of humoral response but biopsy still is unreplaceable
DSA is needed for 3 common situations
Diagnostic…. patient underwent proteinuria and elevated kf
Prognostic…fup antibodies titre
Therapeutic…before shifting or decreasing immune suppression medications
E. May disappear without causing graft damage…T
Presence of DSA is strong justified reason to do kidney biopsy
But not always associated with histology proven tissue injury
De novo DSA
A. Usually, anti-class I antibodies—False
B. Usually, anti-class II antibodies—True
C. Anti HLA DQ is the commonest—True
D. Screening for de novo DSA is not essential in none sensitised patients— False
E. May disappear without causing graft damage—True
– Anti-HLA class II DSA are considered the predominant de novo produced antibodies posttransplantation in unsensitized pretransplantation renal transplant recipients
-de novo appearance of DSA was significant in that anti-HLA class II DSA, mostly directed against HLA-DQ molecules, were predominant in HLA class II incompatible grafts
– Some patients with dn DSA would maintain their stable renal function without pathological change toward chronic AMR, just detection of DSA could not be an indication for rejection therapy
-A study by Takayuki Y etal . demonstrated that about 40% of patients with de novo DSA showed biopsy-proven subclinical AMR, leading to progressive graft injury.
Reference
Takayuki Y etal . De Novo Anti-HLA DSA Characteristics and Subclinical Antibody-Mediated Kidney Allograft Injury .Transplantation: October 2016 – Volume 100 – Issue 10 – p 2194-2202
De novo DSA
A_ false
B_ true
C_true
D_fals
E _ true
Its class Ii Ab specific DQ present in 13_30% in non sensitized patients need to frequent screening especially in the first year post transplant by CDC and luminex and single bead antigens techniques ,some of these Ab are detected without significant graft dysfunction.
B,C
De novo DSA usually anti class 2 specially DQ
It also developed in non sensitized recipient
It Not disappeared but may not cause rejection as body of recipient May develop some accommodation ( tolerance)
(B – C – E )>>>>True
(A – D )>>>>>>false
Anti-HLA class II DSA predominant de novo DSA post transplant especially DQ . D evelopment of de novo DSA In unsensitized patients about 13-30% , so screening is essentrial .Presence of DSA is strong indication to do biopsy however not always associated with histology proven tissue injury.
Referances
1. Haas m, mirocha j, reinsmoen nl, et al. differences in pathologic features and graft outcomes in antibody-mediated rejection of renal allografts due to persistent/recurrent versus de novo donor-specific antibodies. Kidney int 2017; 91:729
2. Lefaucheur c, viglietti d, bentlejewski c, et al. igg donor-specific anti-human hla antibody subclasses and kidney allograft antibody-mediated injury. J am soc nephrol 2016; 27:293.
3.A. Ntokou, A. G. Iniotaki, E. N. Kontou et al., “Long-term follow up for anti-HLA donor specific antibodies postrenal transplantation: high immunogenicity of HLA class II graft molecules,” Transplant International, vol. 24, no. 11, pp. 1084–1093, 2011.
4. Filippone EJ, Farber JL: Humoral immune response and allograft function in kidney transplantation. Am J Kidney Dis 66: 337–347
Usually, anti-class I antibodies;false
B. Usually, anti-class II antibodies ;true
C. Anti HLA DQ is the commonest true
The majority of de novo DSAs after kidney transplant are class 2 antibodies, especially DQ. Class 1 de novo DSAs are usually detected sooner after transplant and more likely IgG1 and IgG3 subclasses. They are associated with acute antibody-mediated rejection and early graft loss (1). Class 2 de novo DSAs appear later and are commonly noncomplement binding IgG2 or IgG4 subclass. They tend to be persistent and are associated with chronic antibody-mediated rejection and transplant glomerulopathy(2).
D. Screening for de novo DSA is not essential in none sensitised patients ;false High percentage of non sensitized patients were found to develop de novo DSA in the first year after transplantation and or even later .
E.May disappear without causing graft damage ;true the correlation between DSA strength and clinical outcome is far from perfect. DSAs with similar mean fluores-cence intensity do not always activate the complement cascade. There are patients with transplants with high levels of circulating DSAs who escape rejection or graft dysfunction (2).
The ability of DSAs to bind on beads maynot be the same as that to bind on HLA antigens of endothelial cells. there are also “benign” DSAs that may not be clinically relevant, because they are not associated with antibody-mediated rejection or graft failure (3).
Reference:
1 Valenzuela NM, Reed EF: Antibodies in transplantation: The effects of HLA and non-HLA antibody binding and mechanisms of injury. Methods Mol Biol 1034: 41–70, 2013.
2 Filippone EJ, Farber JL: Humoral immune response and allograft function in kidney transplantation. Am J Kidney Dis 66: 337–347, 2015
3 KumbalaD, ZhangR: Essential concept of transplant immunology for clinical practice. World J Transplant 3: 113–118, 2013.
Rubin Zhang. Donor-Specific Antibodies in Kidney Transplant Recipients. Clin J Am Soc Nephrol 13: 182–192, 2018
A. Usually, anti-class I antibodies False
B. Usually, anti-class II antibodies True
Anti-HLA class II DSA are considered the
predominant de novo produced antibodies posttransplantation in unsensitized pretransplantation renal transplant recipients
C. Anti HLA DQ is the commonest True
de novo appearance of DSA was significant in that anti-HLA class II DSA, mostly directed against HLA-DQ molecules, De novo DQ-DSA may be a biomarker for chronic damage and/or AMR, while an isolated DSA determination appears clinically insignificant.
D. Screening for de novo DSA is not essential in none sensitised patients False
routine posttransplant DSA monitoring identifies recipients at risk for graft damage or loss. Persistent de novo DSAs correlated with inferior graft outcomes and AMR. With or without AR, DSA persistence was associated with worse outcomes, possibly warranting intervention.
E. May disappear without causing graft damage
False
formation of de novo DSA after kidney transplantation is associated with antibody-mediated graft injury that may lead to graft failure
De novo DSA
A. Usually, anti-class I antibodies
B. Usually, anti-class II antibodies
C. Anti HLA DQ is the commonest
D. Screening for de novo DSA is not essential in non sensitised patients
E. May disappear without causing graft damage
True: B, C, E
False: A, D
Most common anti-HLA antibodies are class II, especially Anti DQ antibodies. Class I anti HLA antibodies are very rare.
Even in low risk patients, screening for DSA is recommended at least once in 12 to 24 months. (1)
Kidney biopsy in a patient with DSA may not show graft damage.There is a category of de-novo DSA, known as transient do-novo DSA which disappear after sometime, hence the importance of monitoring of DSA level.
Reference:
1) Crespo M, Zarraga S, Alonso A, et al. Monitoring of Donor-specific Anti-HLA Antibodies and Management of Immunosuppression in Kidney Transplant Recipients: An Evidence-based Expert Paper. Transplantation 2020;104:S1-S12.
De novo DSA
A-usually ,anti-class 1 antibodies? false
B- usually , anti-class 11 antibodies? True
Anti-HLA class II DSA are considered the predominant de novo produced antibodies post transplantation .
Ntokou I-SA, Iniotaki AG, Kontou EN, et al. Long-term follow up for anti-HLA donor specific antibodies postrenal transplantation: high immunogenicity of HLA class II graft molecules. Transplant International. 2011;24(11):1084–1093.
C-anti HLA DQ is the commonest? True
De novo DQ donor-specific antibodies (DSAbs) are the predominant HLA class II DSAb after transplantation. DQ DSAbs are associated with inferior allograft outcomes.
Willicombe M, Brookes P, Sergeant R, et al. De novo DQ donor-specific antibodies are associated with a significant risk of antibody-mediated rejection and transplant glomerulopathy. Transplantation. 2012;94(2):172–177.
D- screening for de novo DSA is not essential in none sensitized patients? False
DSA were proven to have a strong adverse impact on graft survival. These results indicate that a post transplant HLAab monitoring routine could be appropriate to improve long-term results.
Lachmann N, Terasaki PI, Budde K, et al. Anti-human leukocyte antigen and donor-specific antibodies detected by luminex posttransplant serve as biomarkers for chronic rejection of renal allografts. Transplantation. 2009;87(10):1505–1513.
E- may disappear without causing graft damage ? true
Interestingly, the presence of de novo DSA within the first post-transplant year but cessation of their production in the subsequent years predicts a good prognosis regarding long-term allograft function and survival.
Banasik M, Boratynska M, Koscielska-Kasprzak K, Mazanowska O, Krajewska M, Zabinska M, et al. The impact of de novo donor-specific anti-human leukocyte antigen antibodies on 5-year renal transplant outcome. Transplant Proc 2013;45:1449-1452
De novo DSA
Answer the following question with a justification of your answer (not more than 50 words):
De novo DSA
A. Usually, anti-class I antibodies- false
• Usually is associated with anti-class 2 . Study by Aubert et al showed De novo DSA associated with 25.5% class 1 and 74.5% class 2 HLA
• Pre-existing DSA ABMR are more class one than De novo DSA
B. Usually, anti-class II antibodies- true
• De novo DSA production is associated with HLA class 2 and stimulate the ABMR
C. Anti HLA DQ is the commonest- true
• Anti HLA DQ has the high incidence probably due to high number of polymorphic epitopes that are expressed on both alpha and beta chains of HLA-DQ molecules
D. Screening for de novo DSA is not essential in none sensitised patients-false
• De Novo DSA can appear in any transplantation patients including non-sensitised and low risk patient.
• De Novo DSA appearances as early as 6 months and as late as 6-8 years. Monitoring DSA will detect early rejection and interpret it with protocol biopsy will guide ABMR therapy.
E. May disappear without causing graft damage-false
• De novo DSA has worse allograft survival compared wot pre-existing DSA
• De novo DSA plays a major role in formation of double contour membrane (transplant glomerulopathy) , tubulitis, more arteriolar hyalinosis and more atrophy fibrosis
so my answer will be
TRUE -B,C
FASLE – A,D,E
De novo DSA
A. Usually, anti-class I antibodies
false
B. Usually, anti-class II antibodies
True
C. Anti HLA DQ is the commonest
True
The majority of de novo DSA are class-II antibodies especially DQ
D. Screening for de novo DSA is not essential in none sensitised patients
False
Post transplant screening for de novo DSA is recommended for all patients in early post operative period, in non sensitized recipients, screening at least once in period from 3-12 months after transplant
E. May disappear without causing graft damage
True
Some recipients with de novo DSA and have no evidence of rejection in graft biopsy, not all DSA are equal in the pathogenic potential of DSA
Zhang, R., 2018. Donor-specific antibodies in kidney transplant recipients. Clinical Journal of the American Society of Nephrology, 13(1), pp.182-192.
Morath, C., Opelz, G., Zeier, M. and Süsal, C., 2014. Clinical relevance of HLA antibody monitoring after kidney transplantation. Journal of immunology research, 2014.
Garg, N., Parajuli, S., Mandelbrot, D.A. and Djamali, A., 2020. Donor-specific antibodies in kidney transplantation: the University of Wisconsin experience. Current Opinion in Organ Transplantation, 25(6), pp.543-548.
De novo DSA:
A. Usually, anti-class I antibodies. False
B. Usually, anti-class II antibodies.True
Anti-HLA class II are considered the predominant de novo produced antibodies in unsensitized patients of renal transplant.
C. Anti HLA DQ is the commonest True
-The high incidence of anti-HLA DQ DSA is probably related to a high number of polymorphic epitopes that are expressed on both the α and β chain of the HLA- DQ molecules.
D. Screening for de novo DSA is not essential in none sensitized patients. False
-post-transplant Antibodies increase the risk of rejections and poor patient and graft survival.
E. May disappear without causing graft damage. True
– some recipients have a stable renal function in the allograft with no graft dysfunction, in whom DSA was detected by routine surveillance.
Referrence:
Konstantinos Panagiotellis, Aliki Iniotaki, and John N. Boletis. Incidence and Clinical Significance of De Novo Donor Specific Antibodies after Kidney Transplantation.Journal of Immunology reseach. Published 21 Nov 2013
Usually, anti-class I antibodies F
B. Usually, anti-class II antibodies T
C. Anti HLA DQ is the commonest T
D.Screening for de novo DSA is not essential in none sensitised patients
F also.
Dsa screening in three aspects
1 . Diagnostic if there is signs of rejectio n.
2 ..therapeutic .
In adjusting dose of immunosuppression
3.. prognostic..
In prognosis of graft survival
E. May disappear without causing graft damage
True ..
Answer the following question with a justification of your answer (not more than 50 words): De novo DSA
A. Usually, anti-class I antibodies — false
B. Usually, anti-class II antibodies — true
C. Anti HLA DQ is the commonest — true
D. Screening for de novo DSA is not essential in none sensitised patients — false
as a new dnDSA may appeare after month or years post transplant .
E. May disappear without causing graft damage– false
It affects graft survival as it can cause transplant glomerulopathy and late antibody mediated rejection .De novo DSAs most commonly appear in the 1st year post transplantation
Mainly directed against class II HLa
Risk factors for developing Denovo DSA include :
HLA mismatch ,Inadequate immunosuppressive drugs ,Non adherence to medication
Inflammation of the graft either due to viral infection or ischemia injury
Usually it is develops against class II HLA and IgG4 type caries worst prognosis
Yes can cause TCR if DQ
Increased risk of AMR is DQ ,IgG4
-Donor denovo DSA are associated with transplant glomerulopathy and chronic AMR.
-Majority of them are elated to HLA class II and are IgG2 or IgG4 subclasses and non-complement binding causing chronic AMR.,MFI titer of DSA are associated with more graft loss because of complement – fixing properties.
-The most significant prognostic factor: but if de no go DSA is IgG4 phenotype e carries the worst prognosis and if MFI >3000.
– DQ and IgG 4
A. False( de no DSA is class II )
B. True ( de no DSA is class II )
C. True, Anti-HLA DQ is the commonest DSA
D. False , DSA still seen in11% of non-sensitised patients for that you may need screening.
E. True , DSA is dynamic, and it may present without clinical significance
De novo DSAs most commonly appear in the 1st year post transplantation
Mainly directed against class II HLa antigens
They are associated with development of late acute antibody mediated rejection and chronic antibody mediated rejection and transplant glomerulopathy
Risk factors for developing Denovo DSAs include :
High Degree of HLA mismatch
Inadequate immunosuppressive drugs
Non adherence to medication
Inflammation of the graft either due to viral infection or ischemia injury
Being directed against class II , and the value of their MFI may form poor prognostic factor
The most common phenotypic feature is that they are against class II and IgG type
Yes denovo DSAs can cause TCR as both forms of immunity interact
DSAs directed against HLA antigens , that are of more that 3000 MFI , that are complement fixing , are associated with increased risk of AMR
Non-Complement-Binding De Novo Donor-Specific Anti-HLA Antibodies and Kidney Allograft Survival.Guidicelli G, Guerville F, Lepreux S, Wiebe C, Thaunat O, Dubois V, Visentin J, Bachelet T, Morelon E, Nickerson P, Merville P, Taupin JL, Couzi L J Am Soc Nephrol. 2016 Feb; 27(2):615-25.
2. Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Wiebe C, Gibson IW, Blydt-Hansen TD, Karpinski M, Ho J, Storsley LJ, Goldberg A, Birk PE, Rush DN, Nickerson PW Am J Transplant. 2012 May; 12(5):1157-67.
1- De novo DSA negatively affecting graft survival as it is associated with late onset AB mediated graft rejection
2- Mismatch of class II is associated with de novo DSA formation ;MFI more than 3000 and DSA IgG4 have worse prognostic outcome
3- Those de novo DSA are of class IIDQ phenotype.
4- There is increased risk of TCR with preformed de novo DSA; Class II DQ and DRB and those reacting with C1q
usually associated with late onset antibody mediated graft rejection.
Class II mismatch is associated with De novo DSA development.
both MFI of DSA (> 3000)and class of DSA (IgG4) have poor prognostic outcome.
Class II DQ type.
Yes, TCR is more common with preformed and de novo DSA.
Class II DQ
Donor DSA are associated with transplant glomerulopathy and chronic AMR. Majority of them are elated to HLA class II and are IgG2 or IgG4 subclasses and non-complement binding causing chronic AMR.
MFI titer of DSA are associated with more graft loss because of complement – fixing properties. Complement-binding DSA for example C1q or C3d and c4d have the worst outcome. IgG1 and IgG 3 subclasses are complement-binding but IgG2 and IgG4 are less or no complement-binding properties. IgG 4 DSA, were associated with transplant glomerulopathy. Donor DSA simultaneous with T cell rejection shows worse outcome. ÌgG3 complement binding DSA are associated with high risk of AMR.
To evaluate correlation of preformed DSA with graft outcome, 462 patients were investigated. Among them 95 patients (20.6%) had positive anti-H LA antibodies and 40 (8.7%) had DSA. AMR was significantly higher in patients with DSA.
DSA with MFI >3000 were associated with AMR and more graft loss even with a negative CDC-XM or FCXM. Majority of induction therapy in sensitized patients without AMR was performed with ATG vs Basiliximab.
What is the effect on graft survival
Despite the variation in reported estimates of DSA prevalence, the literature clearly
illustrates that DSA adversely affect the survival of a transplanted organ .
Numerous studies have linked the presence of preexisting or de novo antibodies to poorgraft outcome. For example, renal recipients with positive panel reactive antibodies (PRA
recognizing >10 % of HLA alleles) or with DSA have lower graft survival at 3 and 5 years
post-transplant . Accordingly, patients diagnosed with antibody mediated
rejection are likely to have donor specific HLA antibodies , and episodes of AMR
predispose recipients to lower renal allograft survival , regardless of whether antibodies
were preexisting or produced late after transplantation (from 83 % survival without HLA
antibodies to 49 % with HLA antibodies) . In a study with more than 1,000 patients, half
of those with failed grafts had HLA antibodies, and 21 % had donor specific HLA
antibodies . If desensitization or other therapy effectively reduced DSA levels, long-term
survival was significantly superior than if the DSA was persistent
the most significant prognostic factor is it of anti HLA class II ( DQ, DRB ) .the intensity ( MFI ) level also is important. it reflect bad prognosis in regard of ABMR and transplant glomerulopathy .
these antibodies usally are of class II type ( especially DQ,DR )
No , it is usually associated ABMR ,
CLASS II ( DQ, DRB ) and those wich react with C1q .
●What is the effect on graft survival?
Major risk factor for acute rejection .
●
What is the most significant prognostic factor?
Mfi levels
●What is the most common phenotypic characteristic of these de novo DSA?
Class 1
Ig g1
IG G 3
Class II dp Dr DQ it the most common
type .
●Do you think there is increased risk of TCR with the appearance of de novo DSA?
Yes ..
●Which of these DSA is associated with increased risk AMR?
IGG3
Answer the following question with a justification of your answer (not more than 50 words): De novo DSA
A. Usually, anti-class I antibodies false
B. Usually, anti-class II antibodies (True)
C. Anti HLA DQ is the commonest(true)
D. Screening for de novo DSA is not essential in none sensitised patients false
E. May disappear without causing graft damage (true)
Justification:
A and B: I am not sure about the meaning of the word usually, however Class II de novo DSA are the predominant, non complementbut appear later, Class I de novo DSAs are detected early and complement fixing..
C- true
D- screening is essential for diagnostic purposes (clinical and subclinical rejections), therapeutic (IS according to level of DSAs), prognostic.
E- they may disappear, but likely to persist if Class II.
4. It has been shown that 11% of non-sensitized patient develop de novo DSA. This figure goes up to 25% after 10 years of follow up.What is the effect on graft survival?
De novo DSA were associated with an increased risk of ABMR (hazard ratio [HR] 2.2) but were not an independent risk factor for DCGS. 1
De novo DSA were more frequent in transplant recipients of higher immune risk and associated with an increased risk of ABMR. 1
De novo DSAs against class I HLA antigens are usually detected early after transplant, commonly complement fixing and usually IgG1 and IgG3 (more powerful than IgG1) subclasses. They are associated with acute ABMR and early graft loss.
De novo DSAs against class II HLA antigens usually appear later, AB against DQ are the predominant ones, commonly non-complement binding IgG2 or IgG4 subclass. They are persistent and associated with chronic ABMR and TG.
De-novo DSA associated AMR has poorer graft survival as compared to pre-existing DSA associated AMR (34% versus 63% at 8 years post rejection).1
What is the most significant prognostic factor?
The most important prognostic factor is complement binding ability, since complement fixing DSAs are associated with significantly lower graft survival than non-complement binding DSAs.2
rejection rate was higher in dnDSA +ve group (62 .5％) than HLA -ve group (8 .57％) and dnDSA -ve group (8 .69％) . The difference was statistically significant (P=0 .013).2
De novo +ve group revealed more frequent histopathological findings like microcirculatory inflammation (glomerulonephritis & trichodangiitis) and damage (multilayer change of capillary basement membrane) and C4d remained positive.2
However, scar, arterial fibrosis or tubulointerstitial inflammation was not correlated with dnDSA . 2
HLA mismatch is correlated with dnDSA positivity.2
dnDSA may reduce graft survival and enhance rejection rate. 2
What is the most common phenotypic characteristic of these de novo DSA?
The majority of de novo DSAs are class 2 antibodies, especially DQ. 3
Class 1 de novo DSAs are usually detected sooner after transplant and more likely IgG1 and IgG3 subclasses (more powerful than IgG1). They are associated with acute AMR and early graft loss.3
Class 2 de novo DSAs appear later and antibodies against DQ are the predominant ones, are commonly non-complement binding IgG2 or IgG4 subclass. They tend to be persistent and are associated with chronic AMR and TG.3
Do you think there is increased risk of TCR with the appearance of de novo DSA?
Yes, the risk of developing TCMR such as planned sub-therapeutic immunosuppression (due to malignancy, infection) or conversion to CNI free or CS free protocols or non-compliance on immunosuppressive medication. 4
for B-cell activation in absence of preformed immune memory, cognate T-cell help is required thus, previous de novo T-cell allo-immune priming (dnDST) against donor antigens might also occur, subsequently driving anti-donor humoral immune activation.4
it has recently been reported the impact of HLA class-II mismatching predicting not only the advent of dnDSA and ABMR but also TCMR. 4
the study findings support a mechanistic explanation of incompatibility at the DR and DQ molecules being especially associated to the risk of de novo T-cell activation. 4
up to 50% of transplant recipients with pre-DST maintained a strong DST response after kidney transplantation, which seems to be mainly influenced by pre-transplant anti-donor T-cell frequencies and the absence of T-cell depletion induction therapy.4
Which of these DSA is associated with increased risk AMR?
Complement fixing AB are more clinically significant than non-complement fixing AB since it is associated with ABMR and C4d staining which reduce graft survival, moreover it is correlated well with cross matching but not with intensity of DSA this means there may be a DSA with high intensity but is not complement fixing.5
Clinical phenotypes of AMR are determined by the complex characteristics of DSAs, including HLA classes, specificity, strength, IgG subclasses, and complement binding capacity. 5
IgG subclasses have various abilities to activate complement and recruit effector cells through the Fc receptor. 5
C1q binding DSAs are associated with acute AMR more severe graft injuries, and early graft failure. 5
C1q binding IgG3 DSA is associated with acute AMR, more severe graft injury, and early graft loss.
C1q nonbinding DSAs correlate with subclinical or chronic AMR and late graft loss. 5
Complement binding IgG3 DSAs are frequently associated with acute AMR and severe graft injury. 5
non-complement binding IgG4 DSAs are more correlated with subclinical or chronic AMR and TG. 5
Hyper-acute rejection is mediated by high titer of preformed anti-donor antibodies: anti-HLA, anti-ABO, or other non-HLA antibodies.5
The development of de novo DSAs in previously non-sensitized patients is associated with late acute AMR, chronic AMR, and TG. 5
References:
1) Wan SS, Chadban SJ, Watson N, Wyburn K. Development and outcomes of de novo donor-specific antibodies in low, moderate, and high immunological risk kidney transplant recipients. Am J Transplant. 2020 May;20(5):1351-1364. doi: 10.1111/ajt.15754. Epub 2020 Jan 22. PMID: 31867849.
2) De novo DSA affect the prognosis of kidney transplant recipients: retrospective study
Zejia SUN; Xiaodong ZHANG; Xinuo ZHANG; Peng CAO; Xing LI; Xiang ZHENG; Baozhong YU; Wei WANG.
3) Donor-Specific Antibodies in Kidney Transplant Recipients: Rubin Zhang CJASN January 2018, 13 (1) 182-192; DOI: https://doi.org/10.2215/CJN.00700117
4) Maria Meneghini et al study: Front. Immunol., 10 March 2021 | https://doi.org/10.3389/fimmu.2020.623276
Donor/Recipient HLA Molecular Mismatch Scores Predict Primary Humoral and Cellular Alloimmunity in Kidney Transplantation
5) Donor-Specific Antibodies in Kidney Transplant Recipients Rubin Zhang CJASN January 2018, 13 (1) 182-192; DOI: https://doi.org/10.2215/CJN.00700117
The presence of antibodies directed against antigens expressed on donor organs attacks the immune system on the transplanted organ and increases the risk of graft loss or rejection. In addition, DSA attacks the endothelium of the allograft, resulting in subsequent AMR. Repeated attacks of such alloantibody-mediated injury result in distinct changes in the microvasculature of the allograft and development of chronic rejection and have been associated with a higher graft failure rate.
The development of de novo antibodies during and after the first year post-transplant has been shown to significantly reduce the 15-year graft survival in cardiac allografts recipients. Moreover, it was associated with a higher incidence of sub-clinical AMR, leading to long-term graft dysfunction. Similarly, de novo DSA is associated with poor outcomes in renal transplant patients, liver, lungs (leading to Bronchiolitis Obliterans Syndrome (BOS)), and pancreas recipients.
Significant factors for poor graft survival, including HLA mismatches, delayed graft function with or without recovery, and antibody-mediate rejection (AMR). Additionally, the persistence of donor-specific anti-HLA antibodies, as well as specific histological markers, is indicative of poor prognosis and might lead to further therapeutic modifications. Tacrolimus trough level during the first 0–2 month’s post-KT was also an independent predictor of DSA development.
The common de novo DSA was against class II antigens.
Yes, there might be an increased incidence of TCMR in patients with HLA-DR/DQ mismatches.
The common de novo DSA in AMR were against class II antigens, and the anti-HLA DQ was the commonest
Reference:
1- McCaughan JA, Tinckam KJ. Donor specific HLA antibodies & allograft injury: mechanisms, methods of detection, manifestations and management. Transplant International. 2018 Oct;31(10):1059-70.
2- Lee CY, Yang CY, Lin WC, Chen CC, Tsai MK. Prognostic factors for renal transplant graft survival in a retrospective cohort of 1000 cases: The role of desensitization therapy. J Formos Med Assoc. 2020 Apr;119(4):829-837. doi: 10.1016/j.jfma.2019.11.008. Epub 2019 Dec 6. PMID: 31818714.
3- Lefaucheur C, Nochy D, Hill GS, Suberbielle‐Boissel C, Antoine C, Charron D, Glotz D. Determinants of poor graft outcome in patients with antibody‐mediated acute rejection. American journal of transplantation. 2007 Apr;7(4):832-41.
4- Jung HY, Kim SH, Seo MY, Cho SY, Yang Y, Choi JY, Cho JH, Park SH, Kim YL, Kim HK, Huh S, Won DI, Kim CD. Characteristics and Clinical Significance of De Novo Donor-Specific Anti-HLA Antibodies after Kidney Transplantation. J Korean Med Sci. 2018 Jun 28;33(34):e217. doi: 10.3346/jkms.2018.33.e217. PMID: 30127706; PMCID: PMC6097072.
5- Matsuda Y, Sarwal MM. Unraveling the role of allo-antibodies and transplant injury. Frontiers in immunology. 2016 Oct 21;7:432.
-Renal transplant recipients may develop de novo antibodies against donor HLA or non-HLA-like MICA molecules.
-De novo DSA, direct against HLA, is a major risk factor for acute mediated rejection, transplant glomerulopathy, and reduced allograft survival.
-Anti-HLA class II are considered the predominant de novo produced antibodies post-transplant in the renal transplant recipient.
-Antigen mismatches were associated with the anti-HLA DQ DSA and associated with AMR, while patients mismatched at the HLA –DR locus were at significant risk for developing DQ DSA.
-The high incidence of anti-HLA DQ DSA is probably related to a high number of polymorphic Epitopes that are expressed on both the α and β chain of the HLA- DQ molecules.
-Time to development of de novo DSA is a critical factor in determining allograft survival. Antibodies that developed within the first year of transplantation result in graft failure of the meantime of 5.1years while antibodies developed after the first year of transplantation are associated with a slow rate of failure and 80% of patients had functioning grafts one decade after transplantation.
-De novo DSA +ve TCMR had a worse chronicity score and was associated with poor allograft function and histology.
References
1.Konstantinos Panagiotellis, Aliki Iniotaki, and John N. Boletis. Incidence and Clinical Significance of De Novo Donor Specific Antibodies after Kidney Transplantation.Journal of Immunology reseach. Published 21 Nov 2013
2. A. Cherukuri, A. Sharma, M. Mangiola, P. Sood, P. Randhawa, A. Zeevi, R. Mehta, S. Hariharan.UPMC, Pittsburgh.De Novo DSA with T Cell Mediated Rejection (TCMR) Leads to Early Allograft Scarring and Dysfunction. 2017 American Transplant Congress.
Answer the following question with a justification of your answer (not more than 50 words): De novo DSA
A. Usually, anti-class I antibodies False
B. Usually, anti-class II antibodies True
C. Anti HLA DQ is the commonest True
D. Screening for de novo DSA is not essential in none sensitised patients False
E. May disappear without causing graft damage False
Preformed DSA with high MFI levels at the time of transplantation and the persistence of preformed DSAs were related to acute or chronic ABMR as well as poor graft survival.
Preformed DSA that disappeared after transplantation did not significant affect the prognosis of renal allograft, although memory B cells may contribute to the development of chronic ABMR due to preformed DSA.
The timing of presentation and type of DSA (preexisting or de novo) with the histological classification: early posttransplant (<30 days) active ABMR, late (>30 days) posttransplant ABMR with preexisting DSA, and late (>30 days) ABMR associated with de novo DSA (dnDSA).
ABMR with dnDSA usually occurs 3 months or later after transplantation and the majority is associated with anti-HLA class II. De novo DSA is a significant risk factor for TG and allograft failure.
T cell-mediated rejection may be more often encountered in ABMR with dnDSA than ABMR with preformed DSA.
Chronic active ABMR mainly shows the phenotype of late posttransplant ABMR with dnDSA, particularly class II dnDSA. However, chronic active ABMR can develop in recipients with preformed DSA.
In chronic active ABMR, DSA is mainly non-complement binding IgG2 and IgG4.
De no DSA is a major cause of chronic ABMR and is associated with poor allograft outcomes.
In a study by Schinstock et al., the mean time to dnDSA detection was 1.8 years after transplant, and only 3.2% of patients developed dnDSA within 1 year after the transplant. In one study after dnDSA development, graft loss occurred in 24% within 3 years, whereas renal allograft survival was 76% in recipients with high levels of preformed DSA.
Insufficient immunosuppression from nonadherence and reduction of the immunosuppressive agents, cellular rejection, young age, deceased-donor transplant recipients, pretransplant HLA antibodies, HLA mismatch, especially including HLA DQ mismatch, were independent factors for dnDSA formation.
Cellular rejection may be a predictor of dnDSA formation. Inflamed renal microcirculation during TCMR may contribute to the development of dnDSA.
Mismatching at HLA A, B, or DR loci are risks for dnDSA, but mismatching at HLA DQ is currently emerging as a greater cause of dnDSA.
Discrepancies at both DR and DQ increase the risk of developing a de novo class
II DSA compared to discrepancy at either DR or DQ alone. Moreover, DQ DSA has been associated with risk not only for ABMR, but also for transplant glomerulopathy, and graft failure.
HLA-DR/DQ eplet mismatch and tacrolimus less than 5 ng/mL increase the risk of the development of dnDSA.
Non-HLA antibodies against genetically mismatched peptides identified in patients with chronic ABMR were associated with an increased risk of graft loss independently of HLA incompatibility. These autoantibodies may be detected pretransplantation or develop de novo posttransplantation.
However, in a study by Sun et al, only de novo non-HLA antibodies, not preformed non-HLA antibodies, were associated with rejection, especially C4d negative ABMR.
The presence of DSA, especially dnDSA, is associated with a high risk of ABMR and graft loss. The higher the level of DSA at baseline, the higher the incidence of active ABMR and graft loss. Monitoring for dnDSA is recommended in the event of reduced immune suppression, medication, nonadherence, or rejection.
Several alloantibody characteristics have been associated with outcome, including the presence of C1q DSA positive and anti-class II DSA.
Haas, M., Mirocha, J., Reinsmoen, N. L., Vo, A. A., Choi, J., Kahwaji, J. M., et al. (2017). Differences in pathologic features and graft outcomes in antibodymediated rejection of renal allografts due to persistent/recurrent versus de novo donor-specific antibodies. Kidney Int. 91 (3), 729–737. 2016. 10.040
De novo DSA are associated with poor transplant outcome, associated with high incidence of acute AMR, chronic AMR and transplant glomerulopathy
It is a predictor of graft dysfunction and poor graft survival.
complement binding assay is a prognostic factor as it determine C1q binding DSA which are associated with significant high risk of AMR, severe graft injury and tissue loss
The majority of de novo DSA are class-II antibodies especially DQ.
There may be an increased risk of TCR as there is independent correlation between HLA class-II mismatch and Banff Borderline TCMR with increased incidence of TCMR and recurrent TCMR in patients with HLA-DR/DQ mismatches. (1)
The majority of de novo DSAs after kidney transplant are class II antibodies, especially DQ.
Class-I de novo DSAs are usually detected early after transplant and more likely IgG1 and IgG3 subclasses. They are associated with acute antibody-mediated rejection and early graft loss.
Class II de novo DSAs appear later and are commonly non complement binding IgG2 or IgG4 subclass. They are mostly persistent and associated with chronic AMR and transplant glomerulopathy.
Viglietti D, Loupy A, Vernerey D, et al. Value of donor-specific an-ti-HLA antibody monitoring and characterization for risk stratifica-tion of kidney allograft loss. J Am Soc Nephrol. 2017;28(2):702-715.
Djamali A, Kaufman DB, Ellis TM, Zhong W, Matas A, Samaniego M: Diagnosis and management of antibody-mediated rejection: Current status and novel approaches. Am J Transplant 14: 255–271, 2014
Ramon DS, Huang Y, Zhao L, Rendulic T, Park JM, Sung RS, Samaniego M: Use of complement binding assays to assess the efficacy of antibody mediated rejection therapy and prediction of graft survival in kidney transplantation.Hum Immunol 78: 57–63, 2017
Zhang, R., 2018. Donor-specific antibodies in kidney transplant recipients. Clinical Journal of the American Society of Nephrology, 13(1), pp.182-192.
(1) Wiebe, C., Rush, D.N., Gibson, I.W., Pochinco, D., Birk, P.E., Goldberg, A., Blydt‐Hansen, T., Karpinski, M., Shaw, J., Ho, J. and Nickerson, P.W., 2020. Evidence for the alloimmune basis and prognostic significance of Borderline T cell–mediated rejection. American journal of transplantation, 20(9), pp.2499-2508.
De novo DSA
Answer the following question with a justification of your answer (not more than 50 words):
De novo DSA
A. Usually, anti-class I antibodies- false
• Usually is associated with anti-class 2 . Study by Aubert et al showed De novo DSA associated with 25.5% class 1 and 74.5% class 2 HLA
• Pre-existing DSA ABMR are more class one than De novo DSA
B. Usually, anti-class II antibodies- true
• De novo DSA production is associated with HLA class 2 and stimulate the ABMR
C. Anti HLA DQ is the commonest- true
• Anti HLA DQ has the high incidence probably due to high number of polymorphic epitopes that are expressed on both alpha and beta chains of HLA-DQ molecules
D. Screening for de novo DSA is not essential in none sensitised patients-false
• De Novo DSA can appear in any transplantation patients including non-sensitised and low risk patient.
• De Novo DSA appearances as early as 6 months and as late as 6-8 years. Monitoring DSA will detect early rejection and interpret it with protocol biopsy will guide ABMR therapy.
E. May disappear without causing graft damage-false
• De novo DSA has worse allograft survival compared wot pre-existing DSA
• De novo DSA plays a major role in formation of double contour membrane (transplant glomerulopathy) , tubulitis, more arteriolar hyalinosis and more atrophy fibrosis
so my answer will be
TRUE -B,C
FASLE – A,D,E
What is the effect on graft survival ?
The presence de novo DSA significantly correlated with lower graft survival, poor transplant function, and proteinuria.
What is the most significant prognostic factor ?
AMR-related factors were ΔMFI greater than 50%, DSA-MFI values greater than 3000, C1q-binding dn DSA, class II DSA, especially DR-associated DSA (DR + DQ and DR alone), history of acute T cell–mediated rejection and younger (<40 years) recipients.
What is the most common phenotypic characteristic of these de novo DSA ?
The phenotype of de novo DSA induced AMR is different from that of preformed DSA associated AMR .
Do you think there is increased risk of TCR with the appearance of de novo DSA ?
De novo DSA were significantly more frequent in patients with TCMR than in patients without , and patients with preformed and de novo DSA had a significantly higher rate of TCMR than patients without any DSA .
Which of these DSA is associated with increased risk of AMR ?
Production of post transplantation antibodies directed against donor HLA-A, -B, -Cw, -DR, and -DQ mismatches are all strongly predictive of AMR transplant failure.
.
Reference ;
Hourmant M, Cesbron-Gautier A, Terasaki PI, et al. Frequency and clinical implications of development of donor-specific and non-donor-specific HLA antibodies after kidney transplantation. Journal of the American Society of Nephrology. 2005;16(9):2804–2812.
Worthington JE, Martin S, Al-Husseini DM, Dyer PA, Johnson RWG. Posttransplantation production of donor HLA-specific antibodies as a predictor of renal transplant outcome. Transplantation. 2003;75(7):1034–1040.
Hidalgo LG, Campbell PM, Sis B, et al. De novo donor-specific antibody at the time of kidney transplant biopsy associates with microvascular pathology and late graft failure. Am J Transplant. 2009;9:2532–2541.
A. Usually, anti-class I antibodies False
B. Usually, anti-class II antibodies True
Anti-HLA class II DSA are considered the
predominant de novo produced antibodies posttransplantation in unsensitized pretransplantation renal transplant recipients
C. Anti HLA DQ is the commonest True
de novo appearance of DSA was significant in that anti-HLA class II DSA, mostly directed against HLA-DQ molecules, De novo DQ-DSA may be a biomarker for chronic damage and/or AMR, while an isolated DSA determination appears clinically insignificant.
D. Screening for de novo DSA is not essential in none sensitised patients False
routine posttransplant DSA monitoring identifies recipients at risk for graft damage or loss. Persistent de novo DSAs correlated with inferior graft outcomes and AMR. With or without AR, DSA persistence was associated with worse outcomes, possibly warranting intervention.
E. May disappear without causing graft damage
False
formation of de novo DSA after kidney transplantation is associated with antibody-mediated graft injury that may lead to graft failure
What is the effect on graft survival?
the effect is attributed to the HLA class , the number ,intensity and the ability to fix complement and start immune response
de novo,has become a well established biomarker predicting poor transplant outcomes
Class 1 de novo DSA cause acute antibody-mediated rejection and early graft loss.
Class II are mostly non-complement binding and they cause chronic antibody-mediated rejection and transplant glomerulopathy
However, there are also “benign” DSAs that may not be clinically relevant, because they are not associated with antibody-mediated rejection or graft failure
Patients with high DSA had worse 1-year GFR compared to patients wothout DSA.
Some DSA can have agood effect as
they can upregulate protective mechanisms .
What is the most significant prognostic factor?
Number ,strength and type of DSA
The type of DSA whether complement fixing or not (C1q binding DSA , C3d or C4d binding DSA). C3d binding DSA was a better predictor of graft loss than C1q binding DSA .
IgG3 iDSA lead to acute rejection , increased microcirculation injury, and positive C4d deposits
IgG4 iDSA lead to later graft injury.
What is the most common phenotypic characteristic of these de novo DSA?
class II de novo DSA antibodies are more common and persistent after transplant the most common id HLA DQ.
Do you think there is increased risk of TCR with the appearance of de novo DSA?
Yes,
Occurrence of TCMR together with presence of de novo DSA is associated with worse Serum Creatinine level and a higher chronicity scores than DSA alone .
but they did not appear to impact the frequency or severity of TCMR or graft survival.
Which of these DSA is associated with increased risk AMR?
C1q binding DSAs are associated with significantly higher risk of antibody-mediated rejection, severe tissue injury, and graft loss .
In the large cohort study from Loupy et al., C1q binding DSA detected at 1 year after kidney transplant or during antibody-mediated rejection was an independent factor of graft loss.
Recently, Guidicelli et al. compared the long-term effects of C1q binding versus C1q nonbinding DSAs on graft survivals. They found that both are associated with graft loss. However, C1q binding DSAs were associated with graft loss occurring quickly after their appearances, and C1q nonbinding DSAs led to graft loss in the long term.
The incidences of chronic antibody-mediated rejection were also significantly higher in patients with C1q-positive DSAs .
Positive C1q binding DSA is an independent risk of antibody-mediated rejection and graft loss beyond the traditional DSA mean fluorescence intensity.
There are preliminary data suggesting C3d or C4d binding DSA as a predictor of antibody-mediated rejection.
Sicard et al. compared both C1q and C3d binding DSA assays at the time of rejection diagnosis. They found that presence of C3d binding DSA was associated with a higher risk of graft loss independent of mean fluorescence intensity.
C3d binding DSA was a better predictor of graft loss than C1q binding DSA .
It was found that acute antibody-mediated rejection was mainly driven by IgG3 iDSA (91%), whereas subclinical antibody-mediated rejection was driven by IgG4 iDSA (76%).
Reference
Rubin Zhang,Donor-Specific Antibodies in Kidney Transplant .Clin J Am Soc Nephrol 13: 182–192, 2018.
De novo DSA usually anti-class ll against DR, DQ, will cause acute and chronic antibody-mediated rejection.
De novo donor-specific HLA antibodies (dn DSA) are associated with chronic antibody-mediated rejection (AMR) which leads to poor outcome. Effective immunosuppressive treatment and sensitive HLA antibody testing have reduced the incidence of acute T cell–mediated rejection and acute AMR, improving short-term graft survival.
de novo DSA with TCMR is associated with worse Serum Cr & chronicity scores.
Denovo DSA is responsible mainly for acute AMR ,chronic AMR and transplant glomerulopathy . There are 2 sub classes of these Ab class I with presence of IgG 1 and 3 and class 2 with IgG2 and 4 .
Risk factors related to denovo DSA development are mainly HLA _DQ mismatch so it’s class II Ab drug related causes like toxicity or compliance and increase graft immunogenicity.
These Ab usually appears in the first year post transplant causing AMR and also it can affect on graft function even after many years and it can associated with ACR (mixed rejection).
The prognostic factors are IgG classes , specifity
and complement binding capacity .
Reference
_DONOR SPECIFIC ANTIBODIES IN KIDNEY TRANSPLANT RECIPIENTS.(2018,1,13).CJASN,p 182_192.
de novo DSA:
de novo DSA has been shown to be associated with poor graft survival, with upto 50% graft loss within 5 years of detecting DSAs. (1) Another study showed that presence of de novo DSA reduced the graft survival by 40% 10 years later.(2)
The most significant prognostic factor is the type of DSA. Class II de novo DSA are mainly responsible for rejection, hence class II (DR, DQ) mismatch increase risk of graft loss. (2,3)
The phenotype of de-novo DSA induced AMR is different from that of pre-existing DSA associated AMR. (4)
de-novo DSA usually occur in the first year post transplant, can be class I or class II. Class I de novo DSA develop earlier, are associated with acute AMR and graft loss. Class II antibodies, especially DQ are the predominant ones, appear later and are usually associated with chronic AMR and transplant glomerulopathy. (5)
Yes. It has been shown that de novo DSA associated rejection is usually a mixed T cell mediated and antibody mediated rejection. (6)
Class II DSA are associated with increased risk of AMR. (5)
References:
1)Hidalgo LG, Campbell PM, Sis B, et al. De novo donor specific antibody at the time of kidney transplant biopsy associates with microvascular pathology and late graft failure. Am J Transplant 2009;9:2532-2541.
2) Wiebe C, Gibson IW, Blydt-Hansen TD, et al. Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant 2012;12:1157-1167.
3) Everly MJ, Rebellato LM, Haisch CE, et al. Incidence and impact of de novo donor specific allontibody in primary renal allografts. Transplantation 2013;95:410-417.
4) Djamali A, Kaufman DB, Ellis TM, et al. Diagnosis and management of antibody-mediated rejection:current status and novel approaches. Am J Transplant 2014;14:255-271.
5) Valenzuela NM, Reed EF. Antibodies in transplantation: the effects of HLA and non-HLA binding and mechanisms of injury. Methods mol biol 2013;1034:41-70.
6) Nickerson PW. What have we learned about how to prevent and treat antibody-mediated rejection in kidney transplantation? Am J Transplant 2020;20:12-20.
A-Usu,ani-class 1 antibody. False . Early AMR episodes were characterized by DSA that
were of similar frequencies with respect to class I and class II.
B- True .DSA in late AMR episodes were almost exclusively Class II in general.
C- Anti HLA DQ is the commonest .True with the vast majority being DQ specific.
D- Screening for de novo DSA is not essential in none sensitized patients. False .it
develop in most transplant patient and posttransplant DSA monitoring strategies may
reduce the risk of AMR in sensitized patients.
E- May disappear without causing graft damage.True Post-transplant with a
decrease/removal of DSA within one month will lead to a low rate of AMR.
Reference:
Maha Mohammed et al. post-transplant DSA monitoring may predict antibody-mediated
rejection in sensitized kidney transplant recipients. Clin Transpl. 2011;389-94.
Walsh, R. Carlin1; Brailey, Paul .Early and Late Acute Antibody-Mediated Rejection Differ
Immunologically and in Response to Proteasome Inhibition.
Transplantation: JuNE15.2011- Volume 91-issue -p1218-1226 .
The true answer B, C, E
-De novo DSA usually anti-class ll, will cause acute and chronic antibody-mediated rejection. Chronic allograft nephropathy is the leading cause of short-term transplant survival.
-The DSA titre and type are crucial. (high titre and complement-dependent and HLA-specific antibodies) associated with poor graft outcomes.
-HLA-specific antibodies target major and minor HLA antigens.
-Non-HLA anti-bodies directed against donor cell antigens.
–the detection of de novo DSA is associated with destructive consequences, as the pathogenic capacity of de novo DSA is not equal. it is well known that the complement binding capacity of DSA is a crucial factor that influences the pathogenic capacity of DSA.
–De novo DQ-DSA may be a biomarker for chronic damage and/or AMR, while an isolated DSA determination appears clinically insignificant.
–DSA may go away, but they are likely to endure, particularly against class II or high MFI.
Donor-specific antibodies (DSA), against human leucocyte antigens (HLA), are associated with increased risk for graft rejection .
Several studies have shown the relationship between presence of anti-HLA antibodies and the reduction of graft survival in renal transplant recipients and with an increased risk of acute antibody-mediated rejection
Anti-HLA antibodies detection by Luminex present high sensitivity and accuracy
Class II antibodies, either alone or in combination with class I antibodies, are reported to be related to an increased risk of graft immune damage than class I antibodies (1)
Independent predictors of de novo DSA production were HLA-DRB1 and nonadherence .
In a study by Lionaki S et al demonstrated that the presence of detectable anti-HLA antibodies, either DSA or non-DSA, was the only independent predictor for graft loss (2)
Pheotypic charecteres are DSA-MFI values over 3000, class II DSA,DR-DSA. Variability in DSA response, can be related to differences in expression levels of targeted antigen (eg, HLA class I > DR > DQ) in the graft and complement fixing activity of DSA (eg, IgG1, 3 > IgG2, 4).
De novo donor-specific HLA antibodies (dn DSA) are associated with chronic antibody-mediated rejection (AMR) which leads to poor outcome. Effective immunosuppressive treatment and sensitive HLA antibody testing have reduced the incidence of acute T cell–mediated rejection and acute AMR, improving short-term graft survival.
-DSA-class II, especially DR-associated DSA (DR + DQ and DR alone), MFI values of DR-DSA, ΔMFI (>50%), DSA-MFI values greater than 3000, and C1q binding dn DSA are associated with increased AMR risk.
it might be possible that some patients with dn DSA would maintain their stable renal function without pathological change toward chronic AMR, just detection of DSA could not be an indication for rejection therapy.(3)
Reference
1-De Sousa MV etal . Effect of Preformed or De Novo Anti-HLA Antibodies on Function and Graft Survival in Kidney Transplant Recipients. Ann Transplant. 2018; 23: 457–466.
2- Lionaki S et al .Incidence and Clinical Significance of De Novo Donor Specific Antibodies after Kidney Transplantation.Journal of immunology 2013. Article ID 849835, 9 pages
3- Takayuki Y etal . De Novo Anti-HLA DSA Characteristics and Subclinical Antibody-Mediated Kidney Allograft Injury .Transplantation: October 2016 – Volume 100 – Issue 10 – p 2194-2202
Recent data indicate that > 60% of late kidney graft losses are due to antibody-mediated rejection, with growing evidence that HLA antibodies are responsible for kidney graft and also in other solid organ transplantations (1).
Risk factors for the de novo development of DSA.
precense of HLA antibodies pre -transplantation, DR, DQ HLA mismatch, denovo DSA s, second KTX, DD TX with DGR, younger age of recipient, inflammation (infection with minimazation of IS), subclinical TCMR, nonadherence to IS (1).
in general the DSA effect on the graft depend on its specificity, intensity, antigen class and IgG subclasses, complement binding capacity, and its presence is required for the diagnosis as well as monitoring of the response to treatment of both acute and chronic active ABMRT (2).
DSA Characteristic and association with poor graft outcome
HLA DSAs with MFI with peak > 6000 had more than 100-fold risk of developing AMR. graft survival was lower in patients with SAB DSA MFI > 3000 however in the absence of histological evidence of rejection with acute active inflammation HLA DSAs alone may not associated with increased risk of graft failure.
DSA complement binding capacity:
all Complement pathways are involved in ABMR, leading to recruitment and activation of leukocytes such as Natural Killer cells, monocytes/macrophages, and lymphocytes, C4D deposition indicating activation of Classical pathway and it considered one of golden criteria for the diagnosis of AMR which associated with poor graft survival (4). C4d -SAFB is potentially a powerful tool for risk stratification prior to transplantation and may allow identification of unacceptable donor antigens, or patients who may require enhanced immunosuppression (3).
C1q, DSA HLA binding AB increasing the risk of AMR and poor 5 years graft survival 3).
DSA types and subclasses and its impact on graft survival
HLA class II-mismatches (not only HLA-DR but also HLA-DQB, DQA,and DP mismatches) are associated with late AMR and increased risk for late graft loss in most of the studies (1).
DSA response to therapy
In one study involved 174 patients with second kidney transplantation between years 2007 and 2012. With 62 recipients with preformed DSA-SPA detected by Luminex at the time of transplantation, how had higher rejection rates (54.8% vs. 34.8%, P=0.01), including higher rates of antibody-mediated rejection (AMR) (32.3% vs. 7.1%, P<0.001(1).after 2 years of close FU, they found more AMR among DSA-SPA-positive patient so they conclude that the graft survival not affected in early time of FU and rejection can be treated but upon FU the recurrence of AMR was more in DSA positive group (3).
Do you think there is increased risk of TCR with the appearance of de novo DSA?
Early TCMR may trigger persistent alloimmune response with denovo DSA expression and increase the risk of AMR (4). Recently, El Ters et al, showed that early acute cellular rejection was not a single acute event but triggered a persistent alloimmune response that might result in long-term graft injury and graft loss years after the acute event (4).
Denovo DSA and graft survival:
–Class 1 B-DSA, class2 DR-DSA, and DQ-DSA were associated with AMR (6)
-DQ-DSA associated with higher incidence of AMR (15.5%)) with worse graft survival in the non-sensitized subgroup compared to the no DSA group (P < 0.05) (6).
– DQ-DSA exhibited, more histological vascular damage including more microvascular inflammation and glomerulitis with ci and Tc pathological scoring more resistance to antirejection treatment with more chronic AMR which emphasized the importance of early detection and monitoring. (6)
Chronic AMR is again more with DQ- DSA as compared with DR- DSA and associated with worse graft outcome.
The correct answer:
B, C, E
References:
1-Review Article Clinical Relevance of HLA Antibody Monitoring after Kidney Transplantation: Christian Morath,1 Gerhard Opelz,2 Martin Zeier,1 and Caner Süsal2, Journal of Immunology Research Volume 2014, Article ID 845040, 5 pageshttp://dx.doi.org/10.1155/2014/845040.
2-Preformed donor-specific antibodies and risk of antibody-mediated rejection in repeat renal transplantation, Transplantation. 2014 Mar 27;97(6):642-7.
3-Preformed complement-activating low-level donor-specific antibody predicts early antibody-mediated rejection in renal allografts
Christopher Lawrence 1, Michelle Willicombe, Paul A Brookes, Eva Santos-Nunez, Retesh Bajaj, Terry Cook, Candice Roufosse, David Taube, Anthony N WarrensTransplantation. 2013 Jan 27;95(2):341-6.
4-Impact of acute rejection episodes on long-term renal allograft survival:
Jianyong Wu 1, Jianghua Chen, Yimin Wang, Jianguo Zhang, Zong Zhu, Zhangfei Shou, Suya Wang, Ping Zhang, Hongfeng Huang, Qiang HeChin Med J (Engl). 2003 Nov;116(11):1741-5.
5-Recent Advances on Biomarkers of Early and LateKidney Graft DysfunctionMarco Quaglia 1, Guido Merlotti 1, Gabriele Guglielmetti 1, Giuseppe Castellano 2 andVincenzo Cantaluppi 1, *international journal of molecular science, Published: 29 July 2020.
6-Clinical Significance of HLA-DQ Antibodies in theDevelopment of Chronic Antibody-Mediated Rejectionand Allograft Failure in Kidney Transplant Recipients:Hyeyoung Lee, MD, Ji Won Min, MD, Ji-Il Kim, MD, In-Sung Moon, MD, Ki-Hyun Park, MS,Chul Woo Yang, MD, Byung Ha Chung, MD, and Eun-Jee Oh, MD, Medicine [1] Volume 95, Number 11, March 2016.
What is the effect on graft survival?
Denovo DSA associated with poorer graft survival than preexisting Dsa
(8years graft survival 34% and 60% respectively)
But outcomes of donovo DSA are much related to 5 factors
1) strength….MFI more than 6000
2) complement fixing…. although one study showed complement fixing activity of antibodies are related to it’s strength
3)Subtype IG g3 and g1 are mostly against class 1 HLA and develop early post transplant and they are complement fixing and associated with poorer graft survival than late denovo DSA which usually IG g2,g4 and usually non complement fixing and associated with IFTA and TG (10year graft survival between early donovo DSA and late 27%to 80%)
4) response to treatment… decrease MFI of Dsa post treatment is associated with better outcomes but still no obvious cutoff.
What is the most significant prognostic factor?
Subclass and complement fixing
What is the most common phenotypic characteristic of these de novo DSA?
Most common of donovo DSA is DQ class 2
Do you think there is increased risk of TCR with the appearance of de novo DSA?
Yes,Denovo DSA mostly formed after underimmune suppressed or non compliance and associated with TCR.
Which of these DSA is associated with increased risk AMR?
class 1 DSA mostly develop early and associated with acute ABMR and subclass usually IG g1/g3 which is complement fixing
Class 2 DSA mostly develop late and associated with IFTA and TG and subclass is IG g2/g4 which is non complement fixing.
De novo DSA
A. Usually, anti-class I antibodies…F
B. Usually, anti-class II antibodies…T
the commonest against DQ
C. Anti HLA DQ is the commonest…T
D. Screening for de novo DSA is not essential in none sensitised patients…F
Developing of donovo DSA post transplant is related to multiple factors like mismatching,race,age and other after classification of the patient into 3 categories
High risk…patient with preexisting DSA and underwent desensitization…dsa monitoring and protocol biopsy in 1st 3m
Intermediate risk…hx of preexisting DSA and not currently…need DSA in 1st month
Low risk patient…non sensitized…DSA at least first 3-12m
DSA Screening is the noninvasive approach for evaluation of humoral response but biopsy still is unreplaceable
DSA is needed for 3 common situations
Diagnostic…. patient underwent proteinuria and elevated kf
Prognostic…fup antibodies titre
Therapeutic…before shifting or decreasing immune suppression medications
E. May disappear without causing graft damage…T
Presence of DSA is strong justified reason to do kidney biopsy
But not always associated with histology proven tissue injury
Referances
1. Haas m, mirocha j, reinsmoen nl, et al. differences in pathologic features and graft outcomes in antibody-mediated rejection of renal allografts due to persistent/recurrent versus de novo donor-specific antibodies. Kidney int 2017; 91:729
2. Lefaucheur c, viglietti d, bentlejewski c, et al. igg donor-specific anti-human hla antibody subclasses and kidney allograft antibody-mediated injury. J am soc nephrol 2016; 27:293.
3-S. A. Ntokou, A. G. Iniotaki, E. N. Kontou et al., “Long-term follow up for anti-HLA donor specific antibodies postrenal transplantation: high immunogenicity of HLA class II graft molecules,” Transplant International, vol. 24, no. 11, pp. 1084–1093, 2011.
4- Filippone EJ, Farber JL: Humoral immune response and allograft function in kidney transplantation. Am J Kidney Dis 66: 337–347
De novo DSA
A. Usually, anti-class I antibodies T
B. Usually, anti-class II antibodies T
C. Anti HLA DQ is the commonest F
D. Screening for de novo DSA is not essential in none sensitised patients F
E. May disappear without causing graft damage T
In many patients with late antibody-mediated graft loss, even when HLA class I alloantibodies
are detectable, HLA class II de novo DSAs are considered to be mainly responsible for rejection.
de novo DSAs appeared at a mean of 4.6 years after transplantation, and the prevalence of de novo DSAs after 10 years was 20% in adherent to the immunosuppressive regimen, compared with 60% in nonadherent graft recipients. De novo DSAs that were
directed against HLA class II antigens had an especially strong association with strongly impaired graft survival. solid-phase assays into a clinical routine enable detection and distinction of complement binding (C1q assay) HLA antibodies, that are more harmful, from antibodies that do not bind complement.
The higher risk for graft loss in patients with complement-binding
DSAs was attributable to a higher risk for chronic antibody-mediated
rejection. Recent preliminary data also suggest that DSAs of different.
immunoglobulin G subclasses may be associated with different distinct injury phenotypes in kidney allograft biopsies.
Other antibodies that may contribute to chronic antibody-mediated
rejection are MHC class I–related chain A antibodies, angiotensin II
type 1 receptor–activating antibodies, and other anti-endothelial cell
antibodies.
the knowledge of the patient’s alloantibody status before and after transplantation is a requirement for early diagnosis of allograft injury
and early and targeted treatment to prevent antibody-mediated rejection and ensure long-term graft survival. HLA alloantibodies should be tested at least once after transplantation in all patients. In immunologically high-risk patients, desensitized patients, patients with suspected rejection, and during therapy of antibody-mediated rejection and patients who receive reduction, withdrawal, or change of immunosuppressive drugs
1- What is the effect on graft survival?
2- What is the most significant prognostic factor?
3- What is the most common phenotypic characteristic of these de novo DSA?
4- Do you think there is increased risk of TCR with the appearance of de novo DSA?
5- Which of these DSA is associated with increased risk AMR?
What is the effect on graft survival?
De novo DSA is associated with ABMR and graft loss.
What is the most common phenotypic characteristic of these de novo DSA?
De novo DSAs are predominantly directed to donor HLA class 2 especially DQ bind to noncomplerment {IgG2 orIgG4 } occur during the first year of kidney transplant, but They tend to be persistent and are associated with chronic antibody-mediated rejection and transplant glomerulopathy .
Class 1 de novo DSAs are usually detected sooner after transplant and more likely IgG1 and IgG3 subclasses. They are associated with acute antibody-mediated rejection and early graft loss .
What is the most significant prognostic factor?
Those with C1q-binding DSAs within a year after transplantation had lower 5-year allograft survival and higher AMR rates compared with patients with non-C1q-binding . C1q binding DSA detected at 1 year after kidney transplant or during antibody-mediated rejection was an independent factor of graft loss. and acute and chronic AMR in renal transplant recipients with C1q-binding DSAs.
think there is increased risk of TCR with the appearance of de novo DSA?
Studies found that DSA is associated with greater incidence and severity of TCMR and graft loss .
Which of these DSA is associated with increased risk AMR?
DSAs are the main risk factors for ABMR and graft loss but could have variable pathogenicity according to their IgG subclass composition. A study found that IgG3 DSA is associated with ABMR occurrence and severity and with poor outcome independent of DSA MFI level . Binding to C1q also associated with increased risk and severity .
.
JASN February 2016, 27 (2) 615-625; DOI: https://doi.org/10.1681/ASN.2014040326
by S Calp-Inal · 2016 · Cited by 53 — In Group 1 patients, who were monitored prospectively, 31 (11%) developed de novo DSA during a median follow-up of 2.5 (1.9, 3.6) years. Of these, 11 (4%) …
What is the effect on graft survival?
Class 1 de novo DSA cause acute antibody-mediated rejection and early graft loss
Class II are mostly non-complement binding and they cause chronic antibody-mediated rejection and transplant glomerulopathy 1
Patients with DSA MFI > 6000 had worse 1-year GFR (p = 0.022) and 2-year graft survival (p = .026) compared to DSA (-ve ) patients
Once acute rejection occur , it will magnify the effect of de novo DSA on graft survival. 29 months post transplantation the presence of the two classes DSA and MFI > 6000 is associated with poor graft survival only in association with acute rejection episodes .2
DSA more than 10,000 MFI are associated with C4d deposition and complement fixation 3
Furthermore, DSA are associated with accelerated arteriosclerosis in renal biopsies 1 year post transplant and their graft survival is less after 8 year compared with those without DSA 4
Not all DSA affect graft as DSA can affect the graft negatively through endothelial injury and positively they can upregulate protective mechanisms . the effect is attributed to the HLA class , the number and intensity 7
What is the most significant prognostic factor?
The type of DSA whether complement fixing or not (C1q binding DSA , C3d or C4d binding DSA). C3d binding DSA was a better predictor of graft loss than C1q binding DSA .
IgG3 iDSA lead to acute rejection , increased microcirculation injury, and positive C4d deposits
IgG4 iDSA lead to later graft injury with more transplant glomerulopathy and interstitial fibrosis/tubular atrophy 1
What is the most common phenotypic characteristic of these de novo DSA?
class II de novo antibodies are more common and persistent after transplant (esp DQ) and are IgG2 or IgG4 subclass. Class I are usually IgG1 and IgG3 subclasses. 1
Do you think there is increased risk of TCR with the appearance of de novo DSA?
Yes,
de novo DSA with TCMR is associated with worse Serum Cr & chronicity scores than DSA alone . this suggest the possibility of DSA being a marker for a heightened cellular alloresponse .5 Although associated with the development of TCMR, they did not appear to impact the frequency or severity of TCMR or graft survival. Instead, de novo DSA may suggest a state of insufficient IS.6
Which of these DSA is associated with increased risk AMR?
IgG3 iDSA (91%), C1q binding DSAs (acute graft loss) . 1
1-Rubin Zhang,Donor-Specific Antibodies in Kidney Transplant Recipients,CJASN Jan 2018, 13 (1) 182-192; DOI: 10.2215/CJN.00700117
2-Cooper JE, Gralla J, Chan L, Wiseman AC. Clinical significance of post kidney transplant de novo DSA in otherwise stable grafts. Clin Transpl. 2011:359-64. PMID: 22755431.
3-James C. Cicciarelli, Nathan A. Lemp, Youngil Chang, Michael Koss, Katrin Hacke, Noriyuki Kasahara, Kevin M. Burns, David I. Min, Robert Naraghi, Tariq Shah, “Renal Transplant Patients Biopsied for Cause and Tested for C4d, DSA, and IgG Subclasses and C1q: Which Humoral Markers Improve Diagnosis and Outcomes?”, Journal of Immunology Research, vol. 2017, Article ID 1652931, 14 pages, 2017. https://doi.org/10.1155/2017/1652931
4-Lefaucheur, C.; Vernerey, D.; Duong, J.; Aubert, O.; Rabant, M.; Jouven, X.; Glotz, D.; Legendre, C.; Loupy, A. Post Transplant DSA: Independent Factor of Accelerated Arteriosclerosis in Kidney Transplant Population., Transplantation: July 15, 2014 – Volume 98 – Issue – p 78
5- To cite this abstract in AMA style:Cherukuri A, Sharma A, Mangiola M, Sood P, Randhawa P, Zeevi A, Mehta R, Hariharan S. De Novo DSA with T Cell Mediated Rejection (TCMR) Leads to Early Allograft Scarring and Dysfunction. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/de-novo-dsa-with-t-cell-mediated-rejection-tcmr-leads-to-early-allograft-scarring-and-dysfunction/. Accessed December 12, 2021
6- Schluckebier D, Cousin VL, Petit LM, Belli D, Wildhaber B, Rougemont AL, Villard J, Ferrari-Lacraz S, McLin VA. Preformed and de novo DSA are associated with T-cell-mediated rejection in pediatric liver transplant recipients requiring clinically indicated liver biopsy. Pediatr Transplant. 2020 Feb;24(1):e13611. doi: 10.1111/petr.13611. Epub 2019 Nov 4. PMID: 31682057.
7- Malheiro J, Tafulo S, Dias L, Martins LS, Fonseca I, Beirão I, Castro-Henriques A, Cabrita A. Analysis of preformed donor-specific anti-HLA antibodies characteristics for prediction of antibody-mediated rejection in kidney transplantation. Transpl Immunol. 2015 Mar;32(2):66-71. doi: 10.1016/j.trim.2015.01.002. Epub 2015 Feb 7. PMID: 25661873.
Very impressive Hinda
1- What is the effect on graft survival?
De novo DSA is a major risk factor for graft loss and antibody-mediated rejection in renal tx., however, the outcome of de novo DSA in renal Tx is variable, which means that the effect of de novo DSA range from no effect on the graft to rapid graft function decline which means that these DSA have different pathogenicity depending on their level which is MFI detected by Luminex, and ability to bind to C1 q
2- What is the most significant prognostic factor?
DSA level detected by MFI and ability to bind to C1q
3- What is the most common phenotypic characteristic of these de novo DSA?
The most common phenotypic type is IgG 3 followed by IgG1thats because IgG 3 and IgG 1 have the greatest potential to activate the complement. Moreover, IgG 3 and IgG 1 have the best affinity for FcyIIIa which is an activating receptor for natural killer cells.
4- Do you think there is an increased risk of TCR with the appearance of de novo DSA?
Hee-Yeon Jung demonstrated in their study that de novo DSA is significantly associated with AMR, but not TCMR
5- Which of these DSA is associated with increased risk AMR?
The same answer as question 2 and question 3 IgG 3 is the most commonly associated with risk AMR followed by IgG 1
References
1- Lefaucheur C, Loupy A, Hill GS, Andrade J, Nochy D, Antoine C, et al. Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation. J Am Soc Nephrol. (2010) 21:1398–406. doi: 10.1681/ASN.2009101065
2- Loupy A, Lefaucheur C, Vernerey D, Prugger C, Duong van Huyen JP, Mooney N, et al. Complement-binding anti-HLA antibodies and kidney-allograft survival. N Engl J Med. (2013) 369:1215–26. doi: 10.1056/NEJMoa1302506
3- Michaelsen TE, Garred P, Aase A. Human IgG subclass pattern of inducing complement-mediated cytolysis depends on antigen concentration and to a lesser extent on epitope patchiness, antibody affinity and complement concentration. Eur J Immunol. (1991) 21:11–16. doi: 10.1002/eji.1830210103
4- Bruhns P, Iannascoli B, England P, Mancardi DA, Fernandez N, Jorieux S, et al. Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses. Blood. (2009) 113:3716–25. doi: 10.1182/blood-2008-09-179754
5- Jung HY, Kim SH, Seo MY, et al. Characteristics and Clinical Significance of De Novo Donor-Specific Anti-HLA Antibodies after Kidney Transplantation. J Korean Med Sci. 2018;33(34):e217. Published 2018 Jun 28. doi:10.3346/jkms.2018.33.e217
What is the most common phenotypic characteristic of these de novo DSA?
is it class 1 or class 2?
It is phenotype class II
At 18 months, the incidence of de novo DSA is 12.5% among renal allograft recipients, and has no significant graft dysfunction.
In the presence of chronic AMR, there is no significant difference in the graft outcome between the patients have de novo DSA and those patients with no de novo DSA , also there is no significant difference between the patients with positive c4d stain and the patient with negative stain. So the role of de novo DSA and its impact on graft outcome is controversial. The presence of chronic AMR negatively affects graft survival, and its treatment is debatable.
Presence of Complement binding is most significant factor to find AMR lesion on protocol biopsy, C1q is the most important phenotype, also there is IgG3 and IgG4 phenotypes.
There is increased risk of appearance of de novo DSA in the patients with borderline changes in protocol biopsy or acute T cell mediated rejection if untreated or treated insufficiently. So early detection and sufficient immunosuppressive treatment will suppress development of de novo DSA.
references:
Ravi Kumar Singh, Ashwani Gupta, Vinant Bhargava, Anurag Gupta, Vaibhav Tiwari, Manish Malik, AK Bhalla, DS Rana, Monika Jain Effect of De novo donor-specific antibodies on graft function in renal allograft recipients. 2020, vol 14, P130-135.
Woo Yeong Park, Yaerim Kim, Jin Hyuk Paek, Kyubok Jin, Seungyeup Han. Clinical significance of de novo donor-specific antibody in kidney transplant recipients with chronic antibody-mediated rejection. Korean J Transplant 2021; 35(1): 33-40.
Gabriel M. Danovitch. Handbook of Kidney Transplantation
Tsuji T. · Iwasaki S. · Makita K. · Imamoto T. · Ishidate N. · Mitsuke A. · Fukuzawa N.· Harada H.· Fukazawa Y. Preceding T-Cell-Mediated Rejection Is Associated with the Development of Chronic Active Antibody-Mediated Rejection by de Novo Donor-Specific Antibody. Nephron 2020;144(suppl 1):13–17.
Try reading the subject again
Try addressing each question seperatly
What is the effect on graft survival?
De novo DSA is a major risk factor for ABMR ang graft loss. (1)
What is the most significant prognostic factor?
Complement binding and the MFI level of DSA. 2
What is the most common phenotypic characteristic of these de novo DSA?
Class I de novo DSA: usually detected sooner after transplant and more likely IgG1 & IgG3 subclasses with strong complement binding, They are associated with ABMR and early graft loss.
Class II de novo DSA: appear later and are non-complement binding IgG2 or IgG4 subclasses, they tend to be persistent and associated with chronic ABMR and transplant glomerulopathy.
The majority of de novo DSA are class II antibodies especially DQ. (2)
Do you think there is increased risk of TCR with the appearance of de novo DSA?
Studies found that DSA is associated with greater incidence and severity of TCMR and graft loss despite immunosuppression and anti-rejection therapy, and despite the use of protocol biopsies to detect early rejection, DSA was detected at or before the onset of TCMR indicating a temporal relationship.
The presence of DSA is indicative of a more mature immune response with contribution from both humoral and cellular immunity.
Other studies found that 54% of patients with de novo DSA had a prior TCMR. (3)
Which of these DSA is associated with increased risk AMR?
DSAs are the main risk factors for ABMR and graft loss but could have variable pathogenicity according to their IgG subclass composition. A study found that IgG3 DSA is associated with ABMR occurrence and severity and with poor outcome independent of DSA MFI level. (1)
References:
Well done
Agree, it class 2 mostly. Which one of class 2?
Thank you
I mentioned in my comment class II mostly DQ .
Now I want to arrange them as follows:
DQ ( mostly), followed by DR , and to lesser extent DP.
Renal graft loss or failure is mainly caused by AMR. Preformed DSA referred to presence of anti-HLA Abs before transplantation, while denovo DSA developed after transplantation & benign DSA mean clinically non significant Abs which is not associated with AMR.
Both performed & denovo DSA area associated with high rate of AMR, graft failure & decrease graft survival. Denovo DSA was reported in 12-30 % of unsensitized recipients.
There are several risk factors for developing of denovo DSA including:
Denovo DSA can be classified into :
class 1 DSA which occur early post transplantation period, its subclasses include IgG1 & IgG3. It associated with AMR & early graft failure
class 2 DSA : is the most common class of denote DSA, occurs late post transplantation, usually non complement binding. Subclasses include IgG2 & IgG4 which associated with cAMR.
Elimination of class 2 denovo DSA is difficult especially DQ DSA & put the recipient under high risk of aggressive immunosuppression with out much benefit.
Patients with denovo DSA can be classified depending on clinical syndrome in to :
Likewise Devos et al report show that denovo DSA associated with increase risk of AR, higher serum creatinine, & worse graft outcome, & persistent DSA had high rate of rejection & graft failure.
Andrade-Sierra et al shows that patients with early steroid withdrawal had risk of development of denovo DSA class II Abs. Also TCMR was more in patients with class II denovo DSA development compared to patients with out denovo DSA.
References:
You missed the relation with TCMR
Otherwise very well explained
Which one of class 2?
Class II DR-associated DSA ( DQ+DR & DR alone )
What are the phenotypes of these DSA and how they affect graft survival?
De novo DSAs against class I HLA antigens are usually detected early after transplant, commonly complement fixing and usually IgG1 and IgG3 (more powerful than IgG1) subclasses. They are associated with acute ABMR and early graft loss.
De novo DSAs against class II HLA antigens usually appear later, AB against DQ are the predominant ones, commonly non-complement binding IgG2 or IgG4 subclass. They are persistent and associated with chronic ABMR and transplant glomerulopathy .
De-novo DSA associated AMR has poorer graft survival as compared to pre-existing DSA associated AMR (34% versus 63% at 8 years post rejection).(1)
Additionally, another study that involved 125 recipients who had DSA detected in the first year had found an association between the DSA IgG subclass and the outcome. IgG3 dominant DSA was associated with a shorter time to rejection, increased microvascular injury, C4d capillary deposition, and graft failure. While IgG4 dominant DSA was associated with later allograft injury, increased allograft glomerulopathy, and interstitial fibrosis/tubular atrophy (IF/TA) (2)
What is the most significant prognostic factor?
The most important prognostic factor is complement binding ability, since complement fixing DSA are associated with significantly lower graft survival than non-complement binding DSA
Do you think there is increased risk of TCR with the appearance of de novo DSA?
Yes as some of risk factors for developing denovo DSA increase the risk of developing TCMR such as planned subtherapeutic immunosuppression (due to malignancy, infection) or conversion to CNI free or CS free protocols or non compliance on immunosuppressive medication
Which of these DSA is associated with increased risk AMR?
Complement fixing AB are more clinically significant than non-complement fixing AB since it is associated with ABMR and C4d staining which affect badly graft survival, Moreover it is correlated well with cross matching but not with intensity of DSA this means there may be a DSA with high intensity but is not complement fixing.
REFERANCES
1. Haas M, Mirocha J, Reinsmoen NL, et al. Differences in pathologic features and graft outcomes in antibody-mediated rejection of renal allografts due to persistent/recurrent versus de novo donor-specific antibodies. Kidney Int 2017; 91:729
2. Lefaucheur C, Viglietti D, Bentlejewski C, et al. IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury. J Am Soc Nephrol 2016; 27:293.
IgG3 is the type with complement binding and ABMR with C4d
Well done Sherif
Pretransplantation unsensitized kidney transplant recipients may develop de novo antibodies against donor HLA or non-HLA. De novo formation of donor specific antibodies (DSA), directed against HLA, is associated with poor allograft survival, and even independent of the baseline biopsy, as reported by some studies.
In one study evaluating the effect of de Novo antibosies, graft biopsies performed during protocol biopsies were studied.Post-transplantation screening consisted of Luminex solid-phase assays performed at 1 month, 3 months, 6 months, 9 months, 12 months and annually. We observed that 54. 5% recipients with positive de Novo DSA had a diagnosis of acute ABMR, chronic ABMR or mixed rejection. 59.1% received a therapeutic regimen that included a steroid pulse, plasma exchange , IVIG and/or rituximab. Evaluation of the overall effect of any treatment versus no treatment at the time of dnDSA on the histopathological appearancein the follow-up biopsy revealed no statistically significant difference.
They found that the two independent predictors of dnDSA were a mismatch for HLA-DRβ1 > 0 non-adherence (1).
Another study showed very strong association between the production of HLA antibodies after transplantation and graft failure indicates the importance of monitoring for posttransplant HLA antibodies (2).
More on the effect of de Novo antibodies was evaluated in a study done in Greece demonstrated that Anti-HLA class II DSA are the predominant de novo produced antibodies post-transplantation in unsensitized pre-transplantation renal transplant recipients.
HLA antibody tests have moved from CDC to solid phase assays, which show increased sensitivity and specificity to detect anti-HLA antibodies even with a negative flow cytometry crossmatch.
Patients in this study had low immunological risk with de novo DSA were classified according to the clinical findings at the time of detection:
1- acute allograft dysfunction
2- Indolent allograft dysfunction,
3- stable renal function, in whom DSA were detected by routine surveillance.
Results from a study showed that independent predictors of de novo DSA production were HLA-DRB1 and nonadherence. de novo appearance of DSA was significant in that anti-HLA class II DSA, mostly directed against HLA-DQ molecules, were predominant in HLA class II incompatible grafts. The presence of detectable antiHLA antibodies, either DSA or non-DSA, was the only independent predictor for graft loss in the study coming from our center (3).
In a study ,to clarify the relationship between TCMR and dnDSA-positive CAABMR showed that Preceding T-Cell-Mediated Rejection was associated with the development of Chronic Active Antibody-Mediated Rejection by de Novo Donor-Specific Antibody. In summary, the higher frequency of Borderline chnges/ATMR in the CAABMR group suggests that, preceding BLC/ATMR may be a trigger for dnDSA production.
The relationship between de novo DSA and subsequent TCMR and its impact on allograft survival was studied in prospective study published in the American journal of transplantation concluded that de novo DSA with TCMR is associated with worse renal function and chronic allograft injury than DSA alone, suggesting that DSA is a marker for a heightened cellular alloresponse and early detection may preserve graft function. In KTRs with de novo DSA, variables such as young age and DGF are important risk factors for the occurrence of TCMR940.
References
1-Yassine Bouatou , Olivia Seyde , Solange Moll , Pierre-Yves Martin , Jean Villard, Sylvie Ferrari-Lacraz and Karine Hadaya. Clinical and histological evolution after de novo donor-specific anti-human leukocyte antigen antibodies: a single centre retrospective study.Bouatou et al. BMC Nephrology (2018) 19:86.
2-Q Mao , P I Terasaki, J Cai, K Briley, P Catrou, C Haisch, L Rebellato. Extremely high association between appearance of HLA antibodies and failure of kidney grafts in a five-year longitudinal study.Am J Transplant 2007 Apr;7(4):864-71.
3-Sophia Lionaki, Konstantinos Panagiotellis, Aliki Iniotaki, and John N. Boletis. Incidence and Clinical Significance of De Novo Donor Specific Antibodies after Kidney Transplantation .Clinical and Developmental Immunology Volume 2013, Article ID 849835, 9 pages.
4-A. Cherukuri, A. Sharma, M. Mangiola, P. Sood, P. Randhawa, A. Zeevi, R. Mehta, S. Hariharan..De Novo DSA with T Cell Mediated Rejection (TCMR) Leads to Early Allograft Scarring and Dysfunction.2017 American Transplant Congress
In quoting from a reference please don’t put your pronoun WE in the text.
Please read the studies again and summarize the answers to the given questions.
However the answer to the relationship with TCMR was very good.
Thank you Dr for your comment and your Right. “WE”This is by mistake.
Agree, anti-HLA class II DSA are the predominant de novo produced antibodies post-transplantation in unsensitized pre-transplantation renal transplant recipients.
Effect of dnDSA on graft survival:
According to an important study in this aspect:
Wan SS, Chadban SJ, Watson N, Wyburn K. Development and outcomes of de novo donor-specific antibodies in low, moderate, and high immunological risk kidney transplant recipients. Am J Transplant. 2020 May;20(5):1351-1364. doi: 10.1111/ajt.15754. Epub 2020 Jan 22. PMID: 31867849.
Prognostic factor in dnDSA:
According to Zejia SUN et al study :
Objective To explore the relationship between positive rate of de novo donor specific antibody (dnDSA ) and human leukocyte antigen (HLA ) mismatch after kidney transplantation and explore the impact of dnDSA upon long-term graft survival and rejection .
Methods Retrospective analysis was conducted for clinical data of 101 kidney transplant recipients .Based upon HLA antibody and dnDSA ,they were divided into three groups of HLA-(n=70) ,dnDSA- (n=23) and dnDSA+(n=8).
Rejection and graft survival were recorded for evaluating the impact of dnDSA on rejection and graft survival and observing the differences among all groups.
Results The mismatchs of HLA-A/B and HLA-DR were more frequent than HLA-and dnDSA-groups(P=0 .047 , P=0 .010)and graft survival was lower in dnDSA+ group than HLA-and dnDSA-groups (P=0 .001).
De novo donor specific antibody affect the prognosis of kidney transplant recipients:retrospective study
Zejia SUN; Xiaodong ZHANG; Xinuo ZHANG; Peng CAO; Xing LI; Xiang ZHENG; Baozhong YU; Wei WANG.
The most common phenotypic characteristic of de novo DSA:
DSA Classes and Specificity
Donor-Specific Antibodies in Kidney Transplant Recipients
Rubin Zhang CJASN January 2018, 13 (1) 182-192; DOI: https://doi.org/10.2215/CJN.00700117
The risk of TCR with the appearance of de novo DSA:
In Maria Meneghini et al study:
Front. Immunol., 10 March 2021 | https://doi.org/10.3389/fimmu.2020.623276
Donor/Recipient HLA Molecular Mismatch Scores Predict Primary Humoral and Cellular Alloimmunity in Kidney Transplantation
DSA and association with increased risk AMR:
Donor-Specific Antibodies in Kidney Transplant Recipients
Rubin Zhang CJASN January 2018, 13 (1) 182-192; DOI: https://doi.org/10.2215/CJN.00700117
Please try to rephrase this massive information in your own words
Some statements are repeated which looses the impact of the particular message.
Your copied information is correct but needs downsizing in your own words. Off course you can quote some with their respective references.
What is the effect on graft survival?
Is associated with worse graft outcomes only in association with AR episodes.
What is the most significant prognostic factor?
High titer of DSA h.as been correlated with complement binding capability and more severe tissue injuries.
Complement binding or not.
DSA Ig subclass.
What is the most common phenotypic characteristic of these de novo DSA?
De novo DSAs are predominantly directed to donor HLA class 2 mismatches, especially DQ.
Do you think there is increased risk of TCR with the appearance of de novo DSA?
There is a significant connection between a past history of acute T cell–mediated rejection
(<6 months) and de novo DSA leading to subclinical AMR.
Which of these DSA is associated with increased risk AMR?
Complement binding IgG3 donor-specific antibodies are frequently associated with acute antibody mediated rejection and severe graft injury, whereas noncomplement binding IgG4 donor-specific antibodies are more correlated with subclinical or chronic antibody-mediated rejection and transplant glomerulopathy.