3. A 41-year-old CKD 5 male, blood group A1 (Rh +ve) who received a kidney offer from his cousin who is blood group A2 (Rh +ve), cPRA/cRF 97% ( due to many class I and class II antibodies) secondary to previous multiple blood transfusion following cardiac surgery and 101 mismatch. The initial FCXM was postive. He went through a successful desnstization programme (double filteration plasma phesresis , rituximab and IVIg) which renedered the crossmatch negative. Primary function with s Cr 89 µmol/L one week after the operation. As per unit protocol, kidney biopsy was performed at the end of week one. Biopsy showed C4d staining and H&E reported uremarkable (shown below). Tacrolimus level is 9.3 ng/ml (on triple immunosuppression).
- Explain the findings?
- Is any other test required?
- What is your management?
When is biopsy indicated in the index case?
A. Rise of s creatinine by 10% of the baseline
B. The appearance of proteinuria
C. The appearance of DSA is an absolute indication of biopsy
D. Positive urine PCR for BKV
F. CMV viraemia
b,c
Thank you for trying
It is B
B, C, A?
Thank you for trying
It is B
B,C
Thank you for trying
It is, B
A,B,C
Thank you for trying
It is, B
B, C, D
Thank you for trying
It is, B
B
Well done
Yes, B
B
Well done
Yes, B
A- False as an increase in the creatinine by 10 % is not sufficient to indicate acute kidney injury and at least a 15% rise is needed to identify AKI, as a smaller rise may occur due to inter or intra laboratory variability
B- True as a new-onset proteinuria > 500 mg is an indication for renal biopsy
C True as the reappearance of DSA after desensitization is associated with very high probability of ABMR that may be subclinical and needs treatment.
D- False as the presence of PCR without clinical graft dysfunction is an indication for reduction of immunosuppression and not for biopsy, even if graft dysfunction occurs the first step is the reduction of immunosuppression and if no improvement within 1 week or there is suspicion in the diagnosis or suspicions of association with rejection a biopsy is indicated.
E- False as CMV viremia if asymptomatic is treated with antiviral if not responding to reduction of immunosuppression within 1-2 weeks, but if there is graft dysfunction and suspicion of other cause of graft dysfunction is a concern here renal biopsy is indicated.
Thank you for trying
It is B
B & C
Thank you for trying
It is B
B,C
Thank you for trying
It is B
A. No. Rise of serum creatinine above 25% of baseline should be considered for renal biopsy. Or serum creatinine above 115 umol/l serum and urea above 8 mal/l could also be considered if there is associated factors.
B. Yes. Appearance of proteinuria would definitely warrant biopsy. Isolated proteinuria itself would be an indication for renal biopsy in this case. Proteinuria with hematuria would be a definite indication.
C. Yes. DSA appearance would indicate risk of losing the graft and hence renal biopsy is crucial.
D. Yes. BKV viruria and viremia can be seen without renal injury and viral nephropathy and hence diagnosis of BKN must be confirmed by renal biopsy.
E. No. CMV inclusions on renal biopsy are a direct evidence of tissue invasion or CMV nephropathy. However, these inclusions are detected in less than 1% transplant biopsies of patients with CMV disease. CMV viremia level above 90 copies/ml could be considered for renal biopsy if there is association with elevation in serum creatinine or proteinuria. Viremia level above 656 copies/ml has been found to be associated with death.
Note: BKV and CMV can rarely coexist in the patient, and they would mimic cellular rejection. This would require renal biopsy for confirmation.
References :
Thank you for trying
It is B
Only A and B are correct. Rest are dependent on the presentation and case by case evaluation.
Correct Answer is B
A. Rise of s creatinine by 10% of the baseline: False. More than 25% increase needs to be evaluated.
B. The appearance of proteinuria. True. Any new onset proteinuria >500 mg/day should be evaluated.
C. The appearance of DSA is an absolute indication of biopsy. False. A significant proportion of DSA can disappear on its own.
D. Positive urine PCR for BKV. False. BK viruria is common. BK viremia may warrant a kidney biopsy if the graft dysfunction persists despite reduction in immunosuppression
F. CMV viraemia. False. should be initiated in presence of CMV viremia, but kidney biopsy is not a must unless graft dysfunction persists despite treatment of CMV as there may be concomitant rejection
B
C if substitute absolute to some time
_The true answer is ‘B
_Allograft biopsy is indicated in presence of significant protinuria as it may indicated AR or recurrence of the original kidney disease.
_ about rising creatinine and graft dysfunction, it must be significant rise more than 25 % to indicate biopsy
-as regard presence of circulating DSA alone, without evidence of graft dysfunction, it just needs close monitor of it’s titer and close follow up if serum creatinine, biopsy is indicated only if graft dysfunction occurs. As many circulating DSA can disappear without causing graft damage.
-the same in CMV viremia, it just indicated presence of infection in blood, it indicates the adjustment and minimization of immunosupressives but not indicate biopsy except in case of graft dysfunction.
-the postive PCR for BK in urine, can be found normally. But indicates adjustment of immunosupressives and close follow up for any graft dysfunction.
B
B
C
Thank you All
How can you
explain the positive C4d in the index case in one word?
accommodation
accomodation
Accommodation
Accomodation
Accommodation
accommodation.
Accommodation, any maybe due to the desensitization.
Accommodation
Accommodation
Accommodation
Excellent all
Yes, accommodation
accommodation
accomodation
accommodation
Immune accommodation
Acccommodation
Accommodation
Accommodation
Accommodation due to ABOI transplantation occurs within 2 weeks post transplantation
Accomodation
accommodation
due to the ABOI accommodation
Explain the findings?
C4d staining positive. No evidence of allograft rejection. This is due to accomodation.
Is any other test required?
DSA, Anti A2, CMV , BKV PCR
What is your management?
Serial renal profile, DSA and Tacrolimus drug level monitoring.
Positive C4d stain in a normal graft histology it is most likely due to accommodation phenomenon of ABO incompatible transplant.
Other test required were checking for DSA and proteinuria
Regarding management plan we don’t need to add any thing more,just regular follow up for DSA and CNI level.
Normal morphology of glomeruli and no evidence of graft dysfunction
presence of C4d deposition indicates accommodation which occur post transplant.
Iso agglutination test and DSA level
It’s treatment is good fallow up
close adherence to immunosuppressive agents
frequent DSA level
Frequent drug level
Renal biopsy protocol every 3 months
– Explain the findings?
The only positive finding is C4d deposition but no pathological features of AMR so mostly due to accommodation due to transplant a graft from A2 blood group donor to a recipient with blood group A1
– Other tests required
DSA level
Drug level
Monitor proteinuria
– Management plan:
Close monitoring of renal function and drug level along with DSA level
The findings in this case:
Explanation:
Is any other test required?
DSA level is required to rule out HLA-antibody rebound.
Plan of management:
To continue the same plan of management
References:
Mark Haas, Dorry L. Segev, Lorraine C. Racusen, Serena M. Bagnasco, Jayme E. Locke, Daniel S. Warren, Christopher E. Simpkins, Diane Lepley, Karen E. King, Edward S. Kraus and Robert A. Montgomery JASN January 2009, 20 (1) 197-204; DOI: https://doi.org/10.1681/ASN.2008030279
C4d staining in the right slide, no evidence of ABMR
Isolated C4d staining = graft accomodation
DSA, renal graft function, Tacrolimus level and isoagglutinin antibodies.
FOLLOW UP, carry on same treatment, if graft dysfunction, repeat biopsy to rule out ABMR
When is biopsy indicated in the index case?
A. Rise of s creatinine by 10% of the baseline
B. The appearance of proteinuria true
C. The appearance of DSA is an absolute indication of biopsy
D. Positive urine PCR for BKV
F. CMV viraemia
1. The provided biopsy shows normal histology of the graft, no evidence of graft damage. However, 2nd image shows postive c4d staining by immunohistochemistry.
-as the patient now has stable graft function and no evidence of graft dysfunction, in addition to being A2 donor and A1 recipient, so tha postive c4d staining is mostly accomodation. Which is a normal phenomenon occuring 1-2 weeks after transplantation in ABO i compatible transplantation.
2. Other tests required:
_ as any case of ABO incompatible transplant, the monitoring of iso agglutinin titer daily while still admitted, then twice weekly in 1st month_post transplant and monthly therafter, but usually A2 subgroup is less immunogenic and mostly can pass without even desensitization protocol.
_ the problem here is HLA incompatibility , so frequent monitoring of DSA Level and protocol biopsy are essential for early detection of rejection and its treatment.
_ close monitoring of the graft function and TAC trough level are crucial in such highly sensitized patient.
3. Managemnt plan:
_Wait and see , no additional action is required now.
_Close follow up and keep triple maintenance immunosupressives.
_Keep TAC trough level at the higher therapeutic window.
_ no place for steroid withdrawal in such patient.
_ chemoprophylaxis against PJP by SM,TMP and CMV by fanciclovir are essential and also screening for malignancy after aggreesive desensitization protocol and additional powerful maintenance protocol.
1st slide : Normal looking glomerulus , no evidence of tissue injury
2nd slide : C4d staining by IHC
With the state of sensitisation , DSA should be monitored regularly .
isoagglutinin titre for anti A2
having no evidence of tissue injury with stable graft function , such C4d positivity is attributed to accommodation .
keep immunesuppression in the current doses
DSA monitoring at day 4 ( before the biopsy in this case ) , week 1 , 4 , 8 , month 6 , 12 then annualy
protocol / for – cause biopsy as warranted
*Explain the findings
Protocol biopsy with stable graft function 1 week post transplantation shows C4d-positive staining no evidence of vascular or tissue injury,
In patient received ABO incompatible graft
After successful desensitization for HLA mismatch.
this usually happens with accommodation phenomenon which occurs within the first 2 weeks post transplantation
*Is any other test required
Close follow up of the following as he is a high risk patient:
Isoagglutinins level daily during hospital stay then 3 times in the second week
DSA levels
graft function
Tacrolimus trough level
Urine analysis, 24 h urine protein for proteinuria
Protocol biopsies according to the center Protocol.
Or biosy if graft dysfunction occurred .
Cbc.
*What is your management
No evidence of graft injury or AMR so just close monitoring is needed
A2 incompatibility is low immunogenic but the presence of HLA incompatibility and desensitization requires close monitoring of
DSA monthly till 3 months then every year up to 2 years .
Monitor graf function if s creat started to rise to more than 25%of base biopsy should be considered.
CMV prophylaxis.
C4d deposition in the absence of tissue injury is more compatible with accommodation not rejection as mentions in last Banff classifications
Yes, regarding the previous history of the recipient he is considered as high risk so close monitoring of UE1, proteinuria, DSA by SAB, virology screening and maybe protocol biopsy is needed
Conservative management only by
-close monitoring of his IS level and keep it on the higher level
-virology prophylaxis
-more frequent monitoring of his UE1
-DSA monitoring as per center protocol
-protocol biopsy as per center protocol
Explain the findings?
The deposition of C4d without impairment of renal function and in the context of ABO incompatibility suggests the phenomenon of Accommodation.
Is any other test required?
The institutional protocol for monitoring high-risk sensitized patients should remain, including DSA, proteinuria, isoagglutinin titers, serum creatinine, biopsies protocol and CNI measurement
What is your management?
At the moment, there is no need for intervention, and must remain with the follow-up of the institutional protocol
The first slide represents a normal glomerular morphology, while the next slide PAS stain reveals C4D linear deposits yet normal tubular morphology and interstitium (no evidence of rejection).
This case is good reflection of the accommodation phenomenon early post-transplant by the presence of antibodies (isoagglutinins) however they are non-injurious to the renal graft.
So other tests may be required of importance would be:
Monitoring of isoagglutinin titres keeping in mind that A2is considered less antigenic than A1.
DSA levels, drug level, renal profile.
Management plan:
Triple immunosuppression regimen guided by the drug level.
Serial monitoring of renal functions, DSA, Isoagglutinin titres.
This patient is also desensitized so careful attention to infections if existed and prophylaxis is a must.
Monitoring for signs of ABMR if clinically present as his cPRA was already high pretransplant, so keeping his FK level on the higher level would be wise provided that there is no infection.
Protocol biopsy according the transplant center schedule.
1-C4d staining with absence evident of acute rejection so this is accommodation due to ABOi transplant.
ABOI transplant c4d positive 80 to 90% without histological evidence of rejection so due to accommodation and is not consider pathological in absence of HLA donor specific antibodies .
accommodation usually take place 2 week postrenal transplant .
2-lab needed in this case:
kidney function test monitoring any signifience rising for serum creatinine(25%)
CBC,LFT, Virolog, urine c/s,A/CR ratio
DSA monitoring
anti-ABO antibody in the first 2 week
3-no evidence of acute rejection so no specific treatment
protocol biopsy
expression of A2 antigen is weaker than A1
non-A recipient kidney transplant from A2 donor can universally and safely accept the transplant without preconditioning at the time of transplant
References1. Tydén G, Kumlien G, Berg UB. ABO-incompatible kidney transplantation in children. Pediatr Transplant. 2011;15:502–504. [PubMed] [Google Scholar]
2. Takahashi K, Saito K, Takahara S, Okuyama A, Tanabe K, Toma H, Uchida K, Hasegawa A, Yoshimura N, Kamiryo Y. Excellent long-term outcome of ABO-incompatible living donor kidney transplantation in Japan. Am J Transplant. 2004;4:1089–1096. [PubMed] [Google Scholar]
An unremarkable one-week post-transplant graft biopsy showing C4d positivity in presence of an ABO incompatible and post-desensitization HLA incompatible kidney transplant with stable graft function points towards the phenomenon of accommodation.
In view of this being most likely due to accommodation, nothing extra needs to be done except for the routine management including DSA and graft function monitoring with anti ABO isoagglutinin titre evaluation if graft dysfunction ensues, as in the next paragraph.
As this case involves double incompatibility (HLA and ABO), both the aspects need to be dealt with.
HLA incompatibility is more important in this scenario as ABO incompatibility due to A2 is less problematic due to low immunogenicity of A2.
DSA should be monitored monthly for 3 months then annually. A protocol biopsy in first 3 months, and if clinical or subclinical AMR present, then it should be treated.
For ABO incompatibility, anti A2 antibody titres can be checked only if there is graft dysfunction, although samples can be taken thrice a week in first week and then twice a week for next 2 weeks post-transplant.
CBC, creatinine, urine routine examination and urine protein creatinine ratio need to be monitored as in any other transplant recipient.
In view of desensitization, increased risk of infections warrants prophylaxis against CMV and pneumocystis jirovecii.
Reference:
1) Tait BD, Süsal C, Gebel HM, Nickerson PW, Zachary AA, Claas FH, Reed EF, Bray RA, Campbell P, Chapman JR, Coates PT, Colvin RB, Cozzi E, Doxiadis II, Fuggle SV, Gill J, Glotz D, Lachmann N, Mohanakumar T, Suciu-Foca N, Sumitran-Holgersson S, Tanabe K, Taylor CJ, Tyan DB, Webster A, Zeevi A, Opelz G. Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation. Transplantation. 2013 Jan 15;95(1):19-47. doi: 10.1097/TP.0b013e31827a19cc. PMID: 23238534.
Findings
Image 1 Simple squamous epithelium in kidney glomeruli. Unremarkable.
Image 2 Positive C4d staining.
Accommodation of graft
Accomodation is the phenomenon of continuing survival of an ABOi graft in the presence of ABO antibodies, remembering that A and B antigens are expressed on the endothelium of the kidney. One explanation for this could be that the donor endothelium is replaced by host endothelium. Takashi et al states that possible downregulation of glycosyltransferase genes could lead A or B antigens not being activated, with scarce evidence. Other studies hint towards upregulation of protective genes or regulatory genes.
Other tests required :
Management plan
References :
Explain the findings?
Image 1– Normal kidney Glomerulus
Image 2– C4d Staining
H&E reported normal
Donor Blood group A2 and recipient blood group A1.. A2 is less immunogenic.
Renal function is stable
C4d staining represents the process of accommodation
Is any other test required?
Monitor DSA and anti ABO antibody titres
What is your management?
Graft function is stable and no special management is required. Just standard follow up and watch TAC levels
Explain the findings?
– Biopsy showed C4d staining and H&E reported unremarkable .C4d deposition without other abnormalities in ABOi renal transplantation suggests accommodation.
Is any other test required?
-Monitoring of DSA: Day 4, week 2, 4, and 8; 6 months; 1 year; and annually.
-Monitoring anti-ABO for the first 2 weeks.
-TAC level, RFT, CBC.
-urinalysis :for proteinuria
-Screening for infection :BK ,CMV
What is your management?
-No specific treatment but close follow-up for the patient.
Explain the findings?
This is a transplant involve between recipient A1 and Donor A2. A2 is less immunogenic, but has anti-A1 antibody. It is considered ABOi transplant. The patient has cPRA 97%.
Tacrolimus level is acceptable
H&E showed normal Glomerulus
Figure 2 showed C4d positivity
Serum creatinine is normal
This represent accomodation in ABOi.
Is any other test required?
DSA level
BKV PCR
CMV screening
Anti A 1 antibody
What is your management?
Would like to monitor the DSA level and Anti A1 titre
Serial serum creatinine
Repeat Biopsy when there is proteinuria or anti A1 titre is increasing or elevated serum creatinine
Findings
Image 1 reveals simple squamous epithelium in kidney glomeruli. Unremarkable.
Image 2 reveals positive C4d staining.
Other tests required
Management plan
Accommodation in ABO incompatible transplant.
Accommodation refers to a condition in which a transplant appears to resist immune mediated injury and loss of function. In the context of ABOi renal transplant, accommodation of graft is the phenomenon of continuing survival of an ABO incompatible graft facing ABO antibodies. A and B antigens are expressed on the endothelium of the kidney. One thought line went along with the donor endothelium being replaced by host endothelium. However, the Takashi study indicates that there is downregulation of appropriate glycosyltransferase genes such that the antigens A or B are not activated. Other studies indicate upregulation of protective genes or regulatory genes.
References
-The patient has FCX positive and cPRA/cRF 97% initialy then he was desensitised with normal graft function
-first image H and E staining of a normal glomeruli.
– second image ;C4d positivity mean while it can be justified in this case by accommodation occurrence.
Anti ABO ab titer
Monitoring DSA
At the time being patient needs follow up of his creatinine , proteinuria , DSA , screen for viral infection, trace Tac level
Explain the findings?
LRD transplant
ABO: A2 to A1
HLA 101
High cRF (previous SOT)
The initially positive FCXM was rendered negative by successful desensitization using DFPP, rituximab & IVIG.
Excellent primary graft function
The biopsy shows:
Normal histology (H&E staing)
C4d positivity (IH staining)
————————————————
Is any other test required?
· Initial A/B antibody titer not mentioned, but one can assume that it was either not done or was not significantly high.
· Monitor for DSA
· Routine follow up
· For cause biopsy as appropriate
———————————————–
What is your management?
In the view of the current finding, watchful follow up will be sufficient for the time being.
No specific intervention needed, the picture rather looks like accommodation.
N.B
Blood group A2 binds less anti-blood group antibody than blood group A1 and kidneys of blood group A2 rarely undergo hyperacute rejection, but do sometimes exhibit early acute antibody-mediated rejection and graft loss.
Reference
Mayara Garcia de Mattos Barbosa, Marilia Cascalho, Jeffrey L. Platt. Accommodation in ABO-incompatible
organ transplants Xenotransplantation. 2018;25:e12418
https://doi.org/10.1111/xen.12418
Explain the findings?
Slide1 showed normal glomeruli.
Slide 2 showed C4d positivity.
-C4d positive is normally positive in 85% of ABOi transplant due to accommodation .
Is any other test required?
Anti-blood group antibody titer
Drug level
What is your management?
No further treatment apart from regular monitoring of the renal lytes, ABO titer, drug level, CMV& BK.
______________________
** Explain the findings?
# This patient blood group A1, donor blood group A2, cPRA is 97% mainly class 1 &11, history of multiple blood transfusion, one HLA DR mismatch, initial FCXM was positive and after desensitization shift to negative which indicated that, the case is ABO- I kidney transplantation with high immunological risk.
The biopsy showed in slide 1 normal glomeruli
And slide 2 positive C4d without feature of AMR, indicating accommodation.
** Is any other test required?
# DSA serial magerment
Isoagglutinin titer
Renal function
protein urea
CNI trough level
CMV and BKV screening
** What is your management?
# No active treatment with normal graft function and no signs of rejection, just follow up.
Garcia de Mattos Barbosa M, Cascalho M, Platt JL. Accommodation in ABO-incompatible organ transplants.
The patient has normal graft function with successful desensitization management so no rejection.
This phenomenom is called accomodation.
follow up of anti A2 level
TAC level monitoring
There is hypercellularity in the left slide, intense c4d in the right slide with low creatinine is a clue of reasons other than rejection; here accommodation.
Monitoring the DSA level will be good.
At this time, as far as creatinine is stable, I will monitor closely and keep TAC, not below 8-9 (maybe 7-10). later a may repeat the biopsy as indicated by progressive creatinine elevation for example
◇Explain the findings?
Slide1 (H&E) shows normal glomeruli.
Slide 2 shows C4d positivity.
▪︎C4d positive in kidney biopsy with out evidence of rejection goes with ABO-incompatible renal transplants ( in another term accommodation) ( since the donor is Blood group A2 and the Recipient is blood group A1)
◇Is any other test required?
1.DSA level
2. anti-blood group antibody titre
3. Assess proteinuria
4. Drug level
◇What is your management?
Close monitoring of graft function , DSA and drug level.
______________________
Ref:
Raymond J. Lynch and Jeffrey L. Platt. “Accommodation in Renal Transplantation: unanswered questions”
https://dx.doi.org/10.1097/MOT.0b013e32833b9c25
slide showed c4d deposition, no other finding, this may be dt accommodation dt transplantation against ABO
yes, we can consider doing A2 titer , and DSA
management :
just follow up and regular monitoring of A2 titer and DSA
Dear all, is it usual in your practice to check for A1 and A2? Who is practicing ABOi transplantation?
Why do you think they tested for A1 and A2 for this particular patient?
in my practice, we tested for A1 and A2
we transplanted some patients from A2 donor as we considered it O
We do not have ABOi transplantation ever since more than 15 years. Patients
are managed by paired donation. The reason is cost. Government insurance covers all transplants in some way. Even patients who need dialysis are given some type that covers if they have no insurance.
—
I think multiple transfusion history with high DSA levels necessitated control of blood subgroups.
Yes, we do blood group A subgroup typing, as we consider A2 less immunogenic, hence A2 donor can be accepted as donor for A1 recipient. However, the reverse is not accepted.
In addition, in such particular patient with c PRA >90 % and in presence of multiple DSA and frequent blood transfusions, the testing for subgroup A is essential.
The slide show c4d positive in ptc without evidence of microvasular injury
This is considered as accommodation which occurred in ABOI
The antigenic expression of A2 is quantitatively and qualitatively less than that of A1, and the overall immunogenic risk based on antigen expression alone is A1 >B >A2. Given the lower immunogenic risk of the A2 antigen, donor A2 kidneys can generally be successfully transplanted into recipients with low pretransplant anti-A titers without the use of desensitization
Maintenance immunosuppression — In recipients of an ABOI kidney transplant, we administer a triple therapy maintenance immunosuppression regimen that includes a calcineurin inhibitor (tacrolimus), an antimetabolite (mycophenolate), and prednisone.
In ABOI recipients, we target higher whole-blood tacrolimus levels compared with ABO-compatible transplant recipients:
●8 to 12 ng/mL for the first month after transplantation
●5 to 10 ng/mL for subsequent months
Monitoring after transplantation
1-monitor isoagglutinin titers daily while the patient is in the hospital, two to three times per week for the first month posttransplant, weekly for months 2 to 3 posttransplant, and then yearly thereafter. In patients with a posttransplant isoagglutinin titer ≥1:16, a kidney biopsy and/or preemptive plasmapheresis should be performed, particularly if there is evidence of graft dysfunction (eg, delayed/slow graft function or rising serum creatinine).
2-monitor donor-specific antibody (DSA) levels monthly for the first three months posttransplant; then at months 6, 9, and 12; and annually thereafter.
Patients with persistent or de novo DSAs should be evaluated with a renal allograft biopsy to exclude the possibility of ABMR.
Immunologic accommodation
The presence of detectable isoagglutinin titers, AB endothelial antigen expression, and positive peritubular capillary (PTC) C4d staining despite the absence of any histologic evidence of ABMR has been thought to represent ABOI immunologic accommodation
In contrast to transplantation in the HLA-sensitized patient, accommodation appears to be a frequent phenomenon after ABOi kidney transplantations and is often associated with C4d deposition in peritubular capillaries of allograft biopsies. An accommodation phenotype may be achieved by the controlled anti-A/B antibody exposure to antigens in the early phase after kidney transplantation. About 2 weeks after successful transplantation, accommodation is established and even high anti-A/B antibody exposure does not harm the kidney transplant.
1-imageChristian Morath1*, imageMartin Zeier1, imageBernd Döhler2, imageGerhard Opelz2 and imageCaner Süsal2. ABO-Incompatible Kidney Transplantation. Front. Immunol., 06 March 2017.
2-Up to date
Excellent review of the information of both
HLA incompatibility and what to do with that!
And ABO I and how to follow both threats.
Excellent
Very good description of ABO accommodation compared to HLA sensitization .
Very good management and follow up plan.
Very good for follow up of both:
DSA for accommodation assumed for HLA incompatibility
And ABO isoagglutinins for ABO incompatibility.
Correction
Only follow up of DSA is needed
Isoagglutinin follow up will not be needed
The presence of C4d in early post transplant period of an ABOi Tx with normal RFTS and renal biopsy otherwise is suggestive of accomodation.
During early period isoagglutinin titer monitoring is needed and if there is 2 dilution rise in antibody titer biopsy should be done.
I will monitor Anti A2 antibody titer
DSA monitoring
Short cut comprehensive.
Good
This is very interesting case of kidney transplantation among same blood group but different class.
By definition ,this is ABO compatible kidney transplantation. Group A2 to A1.
Approximately 80% of people with blood group A express A1. The remaining express A2.
Anti A1 occurs in 1-8% of A2 individuals, and 22-35% of A2B individuals.This can lead to acute hemolysis in case of blood transfusion or acute rejection in case of organ transplantation. BUT, I couldn’t find the presence of anti-A2 antibodies in A1 recipients. However because of the history of multiple blood transfusion which could be from group A2, the patient could have developed anti-A2 as a consequence.
The first picture shown normal glomerulus, no inflammatory cells inthe tubules or cappilaries, no evidence of injury.
Picture 2 shows positive staining of C4d in the PTC by IHC.
Is any other test required?
1-As the patient is highly sensitized (presence of preformed antibodies before desensitization protocol with positive initial cross match)- DSA screening is required
2- Isoagglutinin antibodies are also required– Anti A2 antibodies
What is your management?
The patient has normal kidney function, no signs of rejection in the kidney biopsy, although C4d staining is positive. Tacrolimus level is within the target. If DSA is negative, and anti-A2 is lower than 1/8, no additional treatment is required. So the picture 2 would be explained as accomodation in the setting of ABOi transplantation.
Well done
Which issue is more worrying here :
The cPRA of 97 due to multiple anti class1,11 due to previous causes of sensitization.
Or A2 donor to A1 recipient ABO incompatibility
Off course you are right to follow up both but priority in this case would be for the first issue.
Excellent. but with this comforting histology it is easy to decide what is needed.
Very good discussion of A2 to A1 recipient although the recipient had also class2 antibodies.
ABO I KTX with significant immunological risk owing to C-RF of more than 97 per cent, DSA to classes I and II, and positive FCXM that required desensitization to become negative.
With a normal renal function test and a protocol biopsy, H&E revealed one glomerulus with normal morphology.
With normal graft function and histology and no indications of acute graft damage after ABOi kidney transplantation (A2 to A1), the result may be explained only by graft accommodation.
Is there any additional examination required?
Follow-up on the isoagglutinin titer.
Follow-up on the DSA serial.
Immunosuppressive medications are being monitored.
protocol biopsy as the patient is at high risk for rejection.
no active treatment, just close monitoring and optimising the immunosuppressive medications.
Excellent
Straight forward excellent
Very good
Also isoagglutinin titre follow up is also essential
The biopsy is clearly showing normal patent glomerular capillaries. Similarly renal tubules are patent with no infiltration.Peritubular capillaries are normal looking with no thrombosis or infiltration.
As far as ABOi transplantation considered, even in the context of A1 recepient and donor of A2 blood group,Anti A2 antibody titer has to be closely monitored post transplantation for the first 2-3 weeks .Although the risk of AMR secondary to rebound of Anti A2 antibodies is minimal as its faintly expressed on the allograft endothelium {its titer is supposed to be less than 1/16 pre transplantation. to have safer transplantation}.monitoring of the antibody titer is mandatory for the first 2-3 weeks post transplantation. and when there is more than 2 dilution rise in the antibody titer , its alarming and kidney biopsy should be contemplated or to start immidiatly the anti AMR if the allograft function is deteriorating.
The presence of C4d staining in the absence of evidence of AMR is consistent with accommodation.
Management is consistent of close follow up anti A2 antibodies.
As of the DSAs , monitoring for rebound is importent to implement is rebound with AMR is commonely encountered especially in the first 6 months post transplant.Threshold for kidney biopsy should be low if there is any significant elevation of DSAs or deterioration of allograft function.
reference:
1]Christian Morath,Martin Zeier and Caner Susal.ABO=Incompatible Kidney Transplantation.frntiers in immunology.2017.
Very good all the information is correct.
But in view of this comforting histology and normal graft function priority will be for DSA.
Excellent
H&E normal glomeruli.
slide 2 Positive C4D in protocol biopsy ,C4d positivity is frequent in allograft biopsies
without acute rejection.
Normal renal function. suggest accommodation.
Is any other test required?
Level OF DSA.
About 0.4% of A2 and 25% of A2B have anti A1 antibodies.
Follow up :
RFT.
DRUG LEVEL.
Very good
The situation here is A2 donor to A1 recipient
So you will monitor A2 antibodies.
Explain the finding This is a case of ABO I transplantation in high risk patient with high c PRA and initial FCXM was positive ( that carries the risk of memory cell activation and rebound antibody formation )
But , zero time biopsy only reveale C4d deposits without associated AMR other features
So it is mostly accommodation response that commonly occur in ABO I transplant
Other tests required:
1- Assess for proteinuria
2- DSA
Management plan
As this C4d deposit are mostly accommodation response , no active intervention is needed only general posttransplantation measures as
1- Monitoring of
IS levels
CMV and BK virus PCR
DSA levels
Kidney function and proteinuria
Excellent you are acknowledging viral threats after desensitization.
A zero hour biopsy can not show accommodation which needs some time this was a 1week biopsy!
You need to follow up isoagglutinin titre as well
Explain the findings?
Case of ABO I KTX from A2 to A1 blood group with high immunological risk due to C-RF more than 97% with DSA to class I and II and positive FCXM which needed desensitization to shift to negative looking for a window for transplantation to avoid hyper acute rejection.
With normal renal function test and protocol biopsy H&E showing one glomerulus with normal morphology and PCT with normal lining epithelium with normal interstitial.
Absence of histological changes of AR with positive C4d staining which mainly due to accommodation process(1)
Is any other test required?
Isoagglutin titer follow up.
DSA serial follow up.
Monitoring of maintained immunosuppressive drugs.
What is your management?
No active treatment at time being with no active histological and biochemical changing.
Strict follow up it the main point as mentioned before.
References:
1- Garcia de Mattos Barbosa M, Cascalho M, Platt JL. Accommodation in ABO-incompatible organ transplants. Xenotransplantation. 2018 May;25(3):e12418. doi: 10.1111/xen.12418. PMID: 29913044; PMCID: PMC6047762.
Excellent
As expected excellent udrestanding and management
Isolated C4D staining with normal graft function and normal histology with no evidence of acute graft injury from ABOi kidney transplantation (A2 to A1 )so the above finding can be explained by graft accommodation only(2).
A2 less immunogenic as compared to A1 but this transplant very high risk as he is sensitized with PRA 97% and historic positive XCM with performed DSAs for both class1,11 with high risk of early memory recall and DSAs rebound despite successful desensitization and high risk for AMR .
for now, will need adequate triple maintenance IS ,his tacrolimus trough level < 10 so suggest to increase the dose of tacrolimus to target higher trough level( 10-12ng )in the first 3 months with full dose MMF 1gm BID and prednisolone tapper dose to 20mg for the first two months
investigation:
1-DSAs level monitoring day 4,then week 2,4,8 ,12 then every 3 months till 12 months then annual .
2-isoagglutinin titer monitoring for the first two weeks then in every OP visit.
3-prefered protocol biopsy (depend on center facility, or once indicated ).
4- tacrolimus trough level and MMF AUC
5-screen for infection like UTI pyelonephritis (intense immunosuppression, so need cmv prophylaxis and antimicrobial prophylaxis for PJP as he underwent desensitization
6-BKV screen, first month then every 3 months till first year
7-control BP and sugar.
References:
1-chinstock CA, Mannon RB, Budde K, Chong AS, Haas M, Knechtle S, Lefaucheur C, Montgomery RA, Nickerson P, Tullius SG, Ahn C, Askar M, Crespo M, Chadban SJ, Feng S, Jordan SC, Man K, Mengel M, Morris RE, O’Doherty I, Ozdemir BH, Seron D, Tambur AR, Tanabe K, Taupin JL, O’Connell PJ. Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus From the Transplantation Society Working Group. Transplantation. 2020 May;104(5):911-922.
2-Barbosa MGM, Cascalho M, Platt JL. Accommodation in ABO-Incompatible Organ Transplants. Xenotransplantation. 2018 May; 25(3): e12418
Excellent
In the following scenario of:
-ABO incompatible transplant from A2 to A1 blood groups.
-History of high sensitization with cPRA 97%
-History of HLA mismatch of 101
-History of DSA against class I and II with previous positive cross match and successful desensitization.
-Primary graft function with stable serum creatinine.
*Honestly it is a very challengeable transplant
Explain the findings?
-positive C4d staining by immunohistochemistry stain in the right side image.
-Unremarkable glomerulus as documented (no histopathological evidence of tissue injury indicating ABMR)
–Isolated C4d staining in peritubular capillaries in iABO transplantation indicating Immunologic accommodation.
Is any other test required?
Regular follow up of isoagglutinin titre is highly needed, follow of DSA and graft function.
What is your management?
No active management for AMR needed at this level.
In case of graft dysfunction proceed for renal biopsy and manage ABMR if there is histologic manifestations of ABMR.
Well done excellent
Challenging is more correct than (challengable).
Allograft biopsy showing positive C4d staining with no other features suggestive of ABMR-This is likely Accommodation.
Is any other test required?
DSA along with other tests like complete blood picture , serum LDH, Creatinine and Retic count.
What is your management?
No treatment is required at present if creatinine is normal and DSA is also negative , just follow-up monitoring with serum creatinine and DSA required.
If DSA is present and rising then it should be treated like ABMR i.e., intensification of immunosuppression (keep Tac trough level between 8-10ng/ml, and Mycophenolate mofetil 2gram daily)daily plasmapheresis followed by IVIG in a dose of 100 mg/kg after each session with or without Rituximab.
REFERENCE:
1- Garcia de Mattos Barbosa M, Cascalho M, Platt JL. Accommodation in ABO-incompatible organ transplants. Xenotransplantation. 2018 May;25(3):e12418
Explain the findings?
Is any other test required?
What is your management?
REFERANCES
1- Collins AB, Schneeberger EE, Pascual MA, et al. Complement activation in acute humoral renal allograft rejection: diagnostic significance of C4d deposits in peritubular capillaries. J Am Soc Nephrol 1999; 10:2208
What is the suggested term for this condition with:
Normal chemistry
Non rising DSA
No evidence of tissue injury in HE
Positive C4d
Still your attempt to exclude ABMR is justified.
graft accommodation
Given the stable serum creatinine level and the absence of histological evidence of rejection, this positive C4d is most likely due to accommodation.
A2 blood group might have anti-A1 antibodies, which react at a low temperature.
Follow-up is currently required for serum creatinine level, DSA level, and Anti-ABO ab level.
References:
Well done excellent
Any explanation why A1 would form antibodies against A2 who are very immunogenitically.
Thank you,,
Realy, I searched for it but didn’t find an explanation, I’ll be so thankful if you can send a paper that explains this case.
C4d positive with a normal H and E in an ABOi transplant is due to accommodation when there is no rise in serum creatinine seen
follow up sr creatinine
DSA and ABO Ig titres if a 30% increase in serum creatinine is seen with tacrolimus in reference range and no other obvious cause.
thrice weekly creatinine for 1 month, twice weekly for second month, once a week for third month.
DSA and ABO Ig titres when there is a 30% increase in serum creatinine along with a renal biopsy.