5. A 41-year-old CKD 5 Afro-Caribbean male, who moved to UK 3 years ago. His blood group is B (Rh – ve) and received a kidney offer from his cousin who is blood group A1 (Rh – ve). The recipient anti-A antibody IgG titre is 1/128. 120 mismatch. There are DSA (anti HLA-A36 with MFI 10,000) due to previous multiple blood transfusion during childhood.
- Will you go ahead?
- If yes, what is your immunosuppression plan?
- If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
- If no, what are your other options?
Dear All
I have gone through your replies. There is a
consensus that this transplantation is very high risk due to ABOi and HLAi.
There is a tricky question with a reward for the
best answer (Comprehensive Nephrology – Sixth Edition).
What is the chance of this recipient to have a
kidney offer either from the paired exchange scheme or on the cadaveric waiting
list given his high anti HLA 36 DSA level and why?
He will have a better chance to get a kidney in paired exchange scheme or cadaveric waiting list as he has anti-HLA-A36 DSA.
HLA-A36 is a rare HLA serotype, limited largely to Africa, central and east central Asia. He received multiple blood transfusions in his childhood (before migrating to UK), hence the presence of anti HLA-A36 antibodies.
HLA-A36 is not present in natives of Europe, so he has higher chance to get a compatible donor (without HLA-A36) in UK.
Excellent, well done. You are a winner
Thanks for brief concise answer..
thanks for this convenient reply
the data support the view that antibodies to both HLA and blood group substance may be tolerated once the graft is in situ and it is only the critical early post transplant days and weeks that can not be accommodated.
comprehensive nephrology 6th edition
According to The Allele Frequency Net Database – I found that HLA 36 is a very rare antigen worldwide and in Europe frequency of this HLA antigen is not exceeding 0.5 %, while in the frequency may reach 17% in Nigeria
This means that although the patient has high MFI and cannot be transplanted to his cousin (of same descent) but in the new country there is a very high probability to find a compatible donor either deceased or living donor through KPD, cPRA is 0% new country
Excellent, well done. You are a winner
HLA 36 is an extremely uncommon antigen around the world, with the frequency of this HLA antigen being very low in Europe. While the patient has a high MFI against A36 and so cannot be transplanted to a cousin (of the same ancestry), there is a very high possibility of finding a suitable donor, either deceased or living, in the new country, as shown by KPD.
Excellent, well done. You are a winner
# A36 is largely limited to Africa.
# Outside Africa, >50% of the populations have no A36 & the majority that do, have only trace levels.
# The index case is not native to UK. Assuming that most of available donors in PKD & deceased donation programs are natives, the chances of this patient to an organ in this country are high.
# HLA A36 is one of the MM with low immunogenicity & frequency (<25% immunogenicity & MM frequency<8) that do not usually lead to the formation of dnDSA.
# ABO type B recipients who meet their center’s criteria for titer levels are eligible to receive kidneys from donors with ABO A2 or A2B.
# Sensitized recipients have increased priority through a sliding scale points system for cPRA (those with cPRA >98%).
# So the a/m points make the chances of this candidate high in both programs
N.B:
# A36 has a high false serotyping rate to A1.
# A1 is more common in Europe than elsewhere
Reference
1. The new kidney allocation system that became effective on December 4, 2014
2. Arce-Gomez B et al (February 1978). “The genetic control of HLA-A and B antigens in somatic cell hybrids: requirement for beta2 microglobulin”. Tissue Antigens. 11 (2): 96–112. doi:10.1111/j.1399-0039.1978.tb01233.x. PMID 77067.
Excellent but can you elaborate more on high false serotype rate with A1.
HLA A36(largely limited to africa)has a high (16%)false serotyping rate to A1,which is is more common in Europe than elsewhere.
They share a common epitope,thus considered a CREG
HLA A36 is more common in Africa (North and East) and Central Asia. A36 is rare HLA-A allele group.
Outside Africa, more than half of the populations have no HLA A36.
So he has a good chance for paired kidney exchange or deceased donor in view of high possibility of no HLA A36 antibodies.
Successful ABO and HLA incompatible renal transplantation in children in the united kingdom over the last decade:
There is a good evidence of good short and medium term outcomes for ABO incompatible (ABOi) and HLA incompatible (HLAi) with pre-transplant positive crossmatches in paediatric patients. In spite off there are concerns regarding the higher risks of infections and antibody mediated rejections from desensitization and strong immunosuppression.
The short and medium term outcomes are due to the strong IS against concerns of infections and coagulation problems of IA
HLA A36 is largely limited to Africa. More than half of the populations outside Africa have no A36 and the majority that do, have only trace levels. The exception is in Central/East Central Asia.
A36 has a high false serotyping rate to A1.
So for this patient being Afro Caribbean male moving to UK increases his chance of finding a more compatible donor in UK due to rarity of HLA A36 in UK
Reference
-Arce-Gomez B, Jones EA, Barnstable CJ, Solomon E, Bodmer WF (February 1978). “The genetic control of HLA-A and B antigens in somatic cell hybrids: requirement for beta2 microglobulin”. Tissue Antigens. 11 (2): 96–112
-Sasazuki, Takehiko; Tsuji, Kimiyoshi; Aizawa, Miki (1992). HLA 1991: proceedings of the eleventh International Histocompatibility Workshop and Conference, held in Yokohama, Japan, 6-13 November, 1991. Oxford [Oxfordshire]: Oxford University Press.
Excellent, well done. You are a winner
27% chance.
Acceptable mismatch program (EUROSTAM) it is 27% % of patients listed on the AM
waiting list receive an offer within the first 7 months of listing. increased chance for
patients to be transplanted in the AM program comes from the addition of the acceptable antigens to the HLA phenotype of the patient, thereby creating an ‘extended’ HLA type on the basis of which allocation takes place.
A36 is more common in Africa (North and East) and Central Asia. A36 is rare HLA-A allele group.
A36 is largely limited to Africa. Outside Africa, more than half of the populations have no A36 and the majority that do, have only trace levels. The exception is in Central/East Central Asia.
So his relative carry the same antigen
And this patient will have a better chance to find doner without this HLA DSA in Uk population so its better to join Kidney Paired Donation system or cadaveric Donation
Excellent, well done. You are a winner
_ HLA A36, is one of the rare antigens especially in the UK, estimated to be in 0.5 % of the population. So it is better for him to wait for ABO compatible donor from UK. In addition, the DSA against HLA A 36 will be negligable.
The chance of this recipient to get matched donor will be higher in the new county.
Excellent, well done. You are a winner
he is from minor ethnicity with HLA-A36 which rare antigen more in black race so he will get better chance to get access to matched donor from paired exchange program or deceased donor waiting list in white ethnicity the HLA-A2 predominate antigen .
Excellent, well done. You are a winner
50% ,
As the HLA A36 antigen is largly limited to Africa, and 50 %of the population outside of africa have no HLA A36 antigen. and in those who do , they have only trace level.
He is of Afro- Carribbean origin , had multiple transfusion, therefore has high titer of anti HLA A36 antibody, But being an immigrant to UK, he will be having very good chance of getting a donor with acceptable Antigen, and being among UK population, means 50 % chance of getting an acceptable mismatch.
reference
Paul Sikoriski et al.characterization of an antibody specific for HLA A 36 and with HLA A1.human immunology Jan 2011.
Excellent, well done. You are a winner
He has high chance to get suitable donor by allocation system and PKD program because he has rare HLA A36
Excellent, well done. You are a winner
What is the chance of this recipient to have a
kidney offer either from the paired exchange scheme or on the cadaveric waiting
list given his high anti HLA 36 DSA level and why?
The HLA 36 is common in the African ethnicity. However, it is considered a rare antigen in western countries like UK and Canada. Therefore, bring currently living in the UK, the patient has a good chance of having a compatible allograft either through a paired kidney exchange scheme or a deceased donor program.
Excellent, well done. You are a winner
Very tricky question to learn. The patient will probably have great chanse to get a better kidney offer with less immunological risk if get involved in Paired e change program. As we already learned, that some alleles that are common in some population could be rare in another. So having anti-HLA-A36 DSA in this case could be of no effect if engaged in PKE programme.
Excellent, well done. You are a winner
HLA-A36 is a rare antigen in Europe countries, although it is a frequent antigen in Africa. So, the chance of finding a compatible HLA-TX in UK is very high either from a KPD or waiting for a compatible deceased donor.
Excellent, well done. You are a winner
HLA-A36 is largely limited to Africa and it is a rare serotype.
So, if he gets a donor from Europe where the HLA-A36 is rare, there will be a great chance to have a compatible donor.
1)Will you go ahead?
No
2)If yes, what is your immunosuppression plan?
Desensitization with cycle of plasmapheresis and IV IG +/- IV Rituximab
Induction : ATG.
Maintenance : Tacrolimus MMF Prednisolone
3)If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
Yes.
4)If no, what are your other options?
Paired kidney exchange program.
Will you go ahead?
No due to high risk of ABM rejection as these incompatible blood groups with presence of anti-A antibody IgG titer of 1/128 also the presence of DSA against HLA 36 with a high risk of rejection
If yes, what is your immunosuppression plan?
First desensitization protocols to decrease the load of DSA and risk of rejections including plasma exchange or plasma adsorption in addition to Rituximab and IVIG.
with monitoring of DSA before kidney transplantation and confirming negative flowcytometry cross matches.
Induction ATG
With mainatince Steroids + MMF + Prograf with high level with a target of 10-15 in the first 3 months .
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
Yes, we need to Follow up Anti A antibodies 2 weeks post kidney transplantation and follow DSA post-transplantation in addition to biopsies protocol for early detection of ABM rejection with early intervention.
If not, what are your other options?
Kidney paired kidney donation
waiting for compatible living or deceased donor
Will you go ahead?
I wouldn’t go ahead. The donor is ABOi plus HLAi, with high anti-A IgG titer and high anti-HLA DSA level.
If yes, what is your immunosuppression plan?
The plan will be:
· Desensitization treatment before transplant( DFPP or IA + IVIG + RTX).
· Induction with ATG.
· Intense IS regimen(TAC, MMF, Prednisolone)
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
Yes, we need to monitor both HLA DSA and anti-ABO IgG antibody titer as high level and rebound is associated with the risk of rejection and poor graft and patient survival.
If no, what are your other options?
Other alternatives:
· Kidney paired donation; the chance for finding a suitable and compatible donor is high as HLA-A 36 is very rare in Europe and common in Africa and central
Asia
· Altruism
· Waiting list for deceased donation.
* Will you go ahead?
No, I will not go ahead , this is highly risk transplantation due to HLA-i (1-2-0), ABO-i (A1 and B) with IgG titre 1/128 and positive DSA ,anti-HLA-A36 with MFI (10000)
And we should know the result of crossmatch.
* If yes, what is your immunosuppression plan?
Plasma exchange,IVIG, Rituximabeto to reduce the level of antibody, ATG and maintenance triple therapies (tac, MMF, steroid)
* If yes, do we need to monitor the anti-A antibody titre and the DSA post -transplantation?
Yes, we need serial monitoring of anti- A antibody in the first month then monthly and DSA monitoring for 2 weeks, one month, 2 month, 3 month and one year also we need to do protocol biopsy.
* If no, what are your other options?
Kidney paired exchange donation and DD programming
I would decline this transplnattaion as high risk one.
plasma pharesis sessions before transplantation to clear the antibody titre.
regarding induction, i would use ATG
regarding maintenance , I would use MMF, Tacrolimus + steroids.
regular monitoring of graft function and denovo DSA titre
Sure, both have to be closely monitored
search for better matched donor
paired exchange program
Will you go ahead?
I would prefer not to proceed because it is high risk; ABOi, DSA with MFI> 10000, MM 120
If yes, what is your immunosuppression plan?
Densitization: plasma exchange, IVIG, Rituximab
Induction: ATG
Maintenance: tacrolimus/mmf/steroids
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
yes
If no, what are your other options?
DKE, wait for another donor
Dear All
What is the chance of this recipient to have a
kidney offer either from the paired exchange scheme or on the cadaveric waiting list given his high anti HLA 36 DSA level and why?
Chance is higher, because HLA 36 IS RARE IN EUROPE and UK, it is common in Nigeria.
This case pertains to combined ABO incompatibility and HLA incompatability.
The anti-A antibody titres are 1:128 in this patient, suggesting a difficult-to-cross ABO barrier (requiring higher number of plasmapheresis sessions and increased chances of rebound) and having high risks of AMR. In addition, A1 is highly immunogenic.
Presence of DSA: DSA (anti HLA-A36 with MFI of 10000). The DSA-RIS score for this patient is 5, which is low and can be taken up for desensitization. (1)
But in presence of high anti-A antibody titres, this transplant should be avoided.
We also need to know about the HLA-typing of the donor and the recipient, as well as the crossmatch results.
No. I will not accept this donor.
If we take up this patient for transplant, then the patient will require desensitization with Plasmapheresis and IVIG and rituximab to achieve a negative crossmatch, as well as anti-A IgG antibody titre of ≤1:8 before proceeding with the transplant.
Injection Rituximab 200 mg IV 2 weeks prior to the tentative date of transplantation.
Since this patient is a high immunological risk category patient, the patient will require induction immunosuppression and tacrolimus based triple drug maintenance immunosuppression.(2)
1) Induction therapy: Injection Anti Thymocyte Globulin (ATG) in dose of 1-1.5 mg/kg per day for 4-6 days (total dose 6 mg/kg).
2) Maintenance immunosuppression: Triple drug therapy including
a. Tacrolimus: Target trough level of 8-10 ng/ml
b. Mycophenolate mofetil (MMF): 1000 mg twice a day
c. Corticosteroids: Injection methylprednisolone 500 mg intravenous on the day of surgery, followed by tablet prednisolone 1mg/kg/day for 3 days and then 20 mg/day, to be tapered to 5 mg/day over next 6 to 8 weeks.
Steroid-free regimen should not be used in this case.
CMV and pneumocystis prophylaxis should be given.
Post-transplant, patient requires close follow-up with clinical and laboratory evaluation.(2)
i) Complete blood count, urine examination and serum creatinine. Tacrolimus trough levels to be monitored.
ii) Anti-A antibody titres monitoring: daily for first 2 weeks, then twice a week for next 2 weeks.
iii) To look for proteinuria: Spot urine protein-to-creatinine ratio.
iv) DSA testing: Once in first three months, then annually or whenever there is any graft dysfunction, alteration in immunosuppression or suspicion of non-adherence.(3,4)
v) Protocol biopsy: Once in first three months.(3) If the biopsy shows features of AMR, it should be treated.
Yes. We do need to monitor Anti-A antibody titres post-transplant.
Initially daily for 2 weeks and then twice a week for next 2 weeks. After 1 month, no need to monitor anti-A antibody titres.
The other options available in this scenario include:
a) Change the donor to someone who is compatible (ABO and HLA)
b) Enroll in kidney paired exchange program to get a better match kidney, both regarding anti-HLA and anti-blood group antibodies.
c) Wait for a better matched offer through the deceased donor program
References:
1) Sethi S, Choi J, Toyoda M, Vo A, Peng A, Jordan SC. Desensitization: Overcoming the Immunologic Barriers to Transplantation. J Immunol Res. 2017;2017:6804678. doi: 10.1155/2017/6804678. Epub 2017 Jan 3. PMID: 28127571; PMCID: PMC5239985.
2) Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x. PMID: 19845597.
3) Tait BD, Süsal C, Gebel HM, Nickerson PW, Zachary AA, Claas FH, et al. 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.
4) Crespo M, Zárraga S, Alonso Á, Beneyto I, Díaz Corte C, Fernandez Rodriguez AM, et al; GREAT Study Group and Spanish Network for Research in Renal Diseases (REDINREN, RED16/0009). Monitoring of Donor-specific Anti-HLA Antibodies and Management of Immunosuppression in Kidney Transplant Recipients: An Evidence-based Expert Paper. Transplantation. 2020 Aug;104(8 Suppl 2):S1-S12. doi: 10.1097/TP.0000000000003270. PMID: 32658025.
Will you go ahead?
No this is a high risk transplant both in terms of HLA incompatibility and ABO incompatibility…Although the anti A titre is 1:128 which is amenable to antibody removal by Rituximab and Immunoadsorption, the presence of anti HLA A36 wit MFI >10,000 poses a risk of desensitization. In general MFI>5000 desensitization is not successful.
If yes whats the immunosuppression protocol?
This transplant is ideally contraindicated due to the presence of very high MFI…I would do CDC if negative proceed with HLA desensitization… I would do a FCXM B cell and T cell cross match..I would proceed only if the T cell FCXM is negative and the MCS<250….I would then do DSA SAB…Here in this case the MFI is 10,000. I would calculate the RIS..If the score <17, I will then proceed for desensitization..
I would give Inj Rituximab 375mg/m2 2 doses starting 2 weeks before with triple immunosuppression namely tacrolimus (to maintain trough level 10-12ng/ml), MMF, steroids…Patient needs plasmaphresis to reduced the anti A titre and HLA MFI DSA…I would do alternate day plasmaphresis and HD….I would repeat the FCXM T cell and B cell cross match and HLA SAB…I would proceed with transplant only if the T cell cross match is negative (B cell CXM can be false positive due to rituximab) and the HLA SAB MFI<500 with CDC being negative… I would use Inj ATG as induction in this case due to high risk sensitization history of transfusion in a dose of 1.5mg/kg BW for 4 to 5 days starting from day 0 of transplant…
We need to monitor the anti A titre and HLA DSA after transplant. Anti A titre needs to be monitored every alternate day for 2 weeks after transplant. HLA DSA needs to be monitored every month after transplant to detect ongoing AMR
the other options are to get listed in the deceased donor renal transplant program or find another suitable donor
• Will you go ahead?
I´m imagining that the patient has been on the list for 3 years and has been participating in PKD, without success for 3 years. In this situation, I would accept the offer.
The presence of Anti-HLA 36 antibody (common in patients undergoing multiple blood transfusions) is highly prevalent in the blood transfused population.
• If yes, what is your immunosuppression plan?
Desensitization would be necessary to decrease titres of anti-A antibody IgG and to DSA (anti HLA A 36). I would try plasmapheresis to decrease titres, associated with Rituximab to decrease the chance of Novo DAS. Induction would be with ATG, due to the high risk classification and maintenance with CNI + MFI + Corticosteroid.
• If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
Yes, monitoring would be necessary due to the risk of an increase in titles or the emergence of a Novo DSA.
1- will you go ahead?
No, it is high-risk transplantation, and the patient can have a better chance with paired kidney exchange. although; it is possible after aggressive immunosuppression
2- if yes, what is your immunosuppression plan?
a- desensitization
DFPP or IA with Rituximab 1 month before the operation + IVIG before surgery aim to reduce the isoagglutinin titer to < 1:16 and DSA level to 500 MFI
CDC and FCXM before operative within 1 week and should be negative
b- induction with ATG +methyprednisolone
c- Maintenance Tac+mmf+steroids
c- prophylaxis against CMV and PJP
3- if yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
yes, both Isoagglutinin titer and DSA
4- If no, what are your other options?
PKD or waiting deceased donor or dialysis
No, I won’t proceed .
If yes, what is your immunosuppression plan?
Desensitisation with plasmapheresis , IVIG and Mabthera till lowering anti A Ig G from 1/8 to 1/32
Induction with ATG and triple maintenance therapy Tac based .
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
Yes we need to monitor both.
If no, what are your other options? Waiting for more compatible living or deceased donor.
Kidney exchange transplant program.
2.Ideally we should not proceed,but if patient cant find a donor through KPD and long waiting time of deceased donor is there,i will consider crossing DSA and ABoi barrier. I Will do a CDC crossmatch and Flow cytometry crossmatch.If CDC cross match is positive, i will not proceed further. If CDC is negative and flow positive with median channel shift of <250, withh RIS value of <17( here 10)–we can proceed for Desensitization.If Median channel shift of >250 ,i will not proceed. I will give Rituximab at higher dose to cross both barrier ,375mg/m2 14 days before transplant, will do plasmapheresis to bring titre of Anti A antibody to <1/8,I will start triple immunosuppression atleast 14 days before of transpalnt day,,. Before proceeding to transplant, I will again do A CDC crossmatch anf flow crossmatch–if either CDC positive ,or Flow with median channel shift of >250, we will not proceed. IF CDC negative and Flow wth median channel shift of <250, transplantation should be done within 1 week.I will give IVIG 0.5 g/.kg ,1 day before transplant, Will give ATG ,A total of atleast 6 mg/kg,followed by triple immunosuppression.
3.Yes,this is the case of very high chance of ABMR and we should follow both Anti A titre as well as DSA.
4.KPD And Deceased kidney transplant are other options.
Desensitization
Rituximab single dose 375 mg /m₂ 4 weeks before transplantation Immunoadsorption Using Anti-A column to reduce anti-A antibody titres to ≤1:8 prior to transplant 2-3 times till the titer reaches the target 1/8.
Induction therapy with basiliximab (Simulect) 20 mg given intravenously preoperatively and on day 4, and peri-operative methylprednisolone 500 mg intravenously
Maintenance therapy tacrolimus, MMF and prednisolone
Q3 /If yes, do we need to monitor the anti-A antibody titer post-transplantation?
· Yes Ab titer need to be monitored post transplantation specially in the first 2 weeks
Q4/ If no, what are your other options?
1.Waiting for a more suitable living donor
2.Other options could be paired kidney exchange program.
3.Waiting for a more compatible deceased donor
Will you go ahead?
No as it’s ABOi transplant with high isoagglutinin titer , plus 120 mismatch. There are DSA (anti HLA-A36 with MFI 10,000)
If yes, what is your immunosuppression plan?
First desensitization with DFPP, IVIG, Rituximab to achieve antibody titer of less than 1:8, induction with ATG, basiliximab on day 1 and day 4 , triple immunosuprrisive medications of tacrolimus, MMF, and steroids. monitoring of IgG levels in the early post-transplant period
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
Yes sure
If no, what are your other options?
Best option would be to be part of paired exchange program (PKD) if available in his country
or deceased donor program or waiting list for living donor and continuation on RRT
The transplantation from his cousin is high risk because of ABO incompatibility with the combination of DSA. I will prefer paired kidney donation as many of my colleagues offered. still can be considered after desensitization as the titer of anti-A is 1/128 and can be reduced by plasmapheresis. there is one HLA/2 HLA b mismatch. If no suitable pair is found I would transplant him after desensitization wth repetitive plasmapheresis till a titer of no more than 1/16 preferably. I will prefer ATG and monitor for DSA ant Anti- A titer especially in the first month then according to renal function and planning renal biopsy when needed
Will you go ahead?
No,I will not accept to preccd with this transplantion because it considered as ahigh risk for AMR
Due to HLA mismatch ,high titer of DSA (HLA-A36 with MFI 10,000) . although the ABOI present in low titer but it is considered a double hit
If yes, what is your immunosuppression plan?
Desensitization should be done by plasmapharesis,IVIG,ritiximab to achieve DSA titer MCS less than 250 and Isoagglutinin antibody titerstiters ≤1:8 to 1:32,
Induction by ATG
Maintenance by TAG,MMF,steroid
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
If no, what are your other options?
Yes,we need to do monitoring
* we 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).
*monitor DSA levels at months 1, 3, 6, and 12 posttransplant and then annually
In patients with a significant rise in DSA we perform a renal allograft biopsy.
If No
I will wait for another more compatible donor
Or paired kid exchange
Reference
Up to date 2022
Desensitization with aphresis till titer of anti-A antibod reaches 1/8, IVIG and Rituximab
Induction with ATG ,maintenance immunosuppression with tacrolimus, MMF and steroids
Yes, need close monitor of DSA and anti-A Ab titre to detect any rebound of isoagglutinin.
Will you go ahead?
No as it is high risk due to ABOi ,120 mismatch. DSA with anti HLA-A36 with MFI 10,000
If yes, what is your immunosuppression plan?
Desensitization : Rituximab 375mg\m2 1month before Transplantation , DFPP and IV IG just before transplant to achieve antibody titer of less than 1:8,
induction with ATG
Maintainance therapy : triple immunosuprrisive medications of tacrolimus, MMF, and steroids.
follow up DSA and igG , anti A Antibodies titer early post transplant
protocol biopsy
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
Yes sure
If no, what are your other options?
paired exchange program (PKD)
Q1: No. I won’t.
Q2: Because of both HLA-incompatible with high MFI and ABO incompatible donor, risk of hyper-acute rejection is high and need an aggressive desensitization and aggressive immunosuppression to reach a negative cross-match (if possible).
Q3: Yes, we need frequent monitoring of DSA by Luminex-SAB and isoagglutinin titer especially during the first weeks (daily) and then 2-3 times per week.
Q4: Another options are KPD and waiting for HLA and ABO compatible deceased donor.
_Will you go ahead?
No,there is high immunological risk due to ABO and HLA incompatibility
_If yes, what is your immunosuppression plan?
Desensitization with PE till titer of anti-A antibody reach 1:8, IVIG and Rituximab
Induction with ATG maintenance immunosuppression with Tac, MMF and steroids
_If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
Yes, close monitor of DSA and anti-A antibody titer are needed to predict post transplant rebound of isoagglutinin.
-If no, what are your other options?
Kidney paired donation ,searching for more compatible donor from deceased donor waiting list.
HLA-A36 is a rare HLA serotype; mainly limited to Africa, central and east central Asia. Multiple blood transfusions in this patient childhood resulted in development of anti HLA-A36 antibodies.
There is higher chance to get a compatible donor in UK as HLA-36 is absent in natives of Europe.
This patient has ABO incompatible and HLA incompatible and highly sensitised patient because previous blood transfusion
He has rare HLA A36
It’s better to avoid transplant from his cousin and refer patient to donor allocation system or PKD because has rare HLA A36 and has high chance to get donor from non African population
If yes patient will undergo to desensitisation therapy of removal of antibodies by double filtration plasma exchange plus intravenous immunoglobulin and rituximab for B cell depletion and inhibition of complement activation by eculizumab and triple immunosuppressive agents with MMF and steroid and tacrolimus
Serial monitoring of anti A/B antibodies before and post transplant
Monitoring of DSA level and checking by cPRA
serial monitoring by schedule renal biopsy
Yes will monitoring anti A/B antibodies and DSA level post transplant
Another option is donor allocation system and PKD program
No,this patient has both HLA incompatible and ABOi, although the titer of amenable to desensitization but A1 antigen is highly immunogenic.
If yes, Induction with ATG, RIT and DFPP before transplant and continue with TAC triple therapy.
Both DSA and anti-A antibody titer should be monitored in the first 2 to 4 week post-transplantation and I prefer protocol biopsy.
Other options PKDE or go through accepted antigens for deceased donor waiting list.
1-Will you go ahead?
ABO incompatible (recipient is blood group B and the donor is blood group A1) with a recipient antibody IgG titre 1/128 (very high ,need desensitization ). The HLA mismatches are 120 (3/6).There are DSA against HLA-36 ( default antigen –A1) with MFI 10,000. No reported data about cross match . The recipient has high immunological risk for hyper acute rejection.
.
I will not go ahead before desensitization
2-If yes, what is your immunosuppression plan?
a-Desensitization using plasmapheresis, IVIG and rituximab .
b-Induction with ATG .
c-maintenance triple TAC
d- prophylaxsis against opportunistic .
Monitoring of both DSA and anti A IgG with protocol biopsy .
3-If yes, do we need to monitor the anti-A antibody titre and the DSA post transplantation?
Yes we need to monitor both DSA using SAB ,for 2 weeks then 4 weeks then 8 weeks then 3 months , 12 months. Anti-agglutinin ABs titer need to be frequently monitored for first 4 weeks then monthly
4-If no, what are your other options?
-Kidney exchange transplant program.
-Combined desensitization and PKT .
-Waiting for more compatible living or deceased donor.
Reference ;
1- Al Meshari K, Pall A, Chaballout A, El Gamal H, Al Mana H, Humaidan H, Alzayer F, Al Talhi M. Outcome of desensitization in human leukocyte antigen- and ABO incompatible living donor kidney transplantation: a single-center experience in more than 100 patients. Transplant Proc. 2013 May;45(4):1423-6. doi: 10.1016/j.transproceed.2013.01.081. PMID: 23726587
yes, but it is considered a high risk procedure then.
this procedure has two main problems to be solved as much as we can ,namely blood group incompatibility which necessitates plasmapheresis or immunoadsorption with concomitant use of IVIG , and Rituximab in advance prior to Tx till anti A titer goes down to 1 l 8 , the other problem is to achieve a negative cross match in the presence of high DSA and elevated MFI levels will be benefited from plasmapheresis and IVIG.
yes it would be wise to monitor them ,and protocol biopsy as well.in case of suspected rejection plasmapheresis and rituximab may be needed to manage this.
kidney paired donation and deceased donor programs would be other options.
Will you go ahead?
1- he is ABO incompatible with his donor.
2- he has DSA with very high titre.
If yes, what is your immunosuppression plan?
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
If no, what are your other options?
Will you go ahead?
This is high risk for kidney transplantation as there is HLA mismatch 120, Anti HLA-A36 positive with MFI 10,000. Also there is ABO incompatibility with IgG titres 1/128.
If yes, what is your immunosuppression plan?
I will like to know result of FXCM and mean channel shift value. If there is no other option desensitization will be required with Plasmaphresis followed by IVIG and Rituximab. Plasmaphresis to achieve negative cross match and IgG titres less than 1/8. Rituximab 3 weeks pre transplant. Induction with ATG and maintenance with Tacrolimus, MMF and ATG. Prophylaxis for CMV and
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
Yes . Monitoring will be require for DSA and anti A antibody titres. DSA needs to be checked with Luminex SAB at day 4, week2, 4, week 8, and then accordingly. Anti A antibodies need to monitored daily in first two weeks and then accordingly. Protocol biopsy as per protocol
Protocol biopsies as per protocol.
If no, what are your other options?
Kidney paired donation
Enrol in deceased donor programme
Find a suitable compatible donor and continue on dialysis
No ,This is high risk transplant, better not to put patient on risk of both rejection and
sensitization. We knew Blood group B waiting time for match donor is long and
allocation also take long time but having both HLAi AND ABOI is high risk.
Desensitisation:
Rituximab.
plasmapheresis.
IVIG.
Induction therapy: ATG.
Maintenance therapy:
MMF.
TAC.
Prednisolone.
Yes monitor anti-A antibody titer :
Daily while the patient is in the hospital.
First month posttransplant Two to three times per week .
weekly for months 2 to 3 posttransplant.
yearly thereafter.
Wait for suitable donor.
Kidney Paired donation.
Matched decease donor.
1. This offer is very highly immunogenic as it involves ABO incompatibility in addition to HLA 3 mismatch which put him at inevitable risk of acute rejection.
So, I will not proceed to transplant, the high MFI DSA against HLA A36 is of significance in such offer from related donor of that same ethnicity.
The best option is to wait for another offer from UK when the rare antigens A36 will be neglected, it’s of 0.5 % prevalence on UK. In addition, ABO compatible donor will be the best.
2. If I proceed in such offer, it will need aggressive desensitization by 3_7 sessions of PEX or IA (better selectivity ) as it avoids wash out if coagulation factors which increases risk of peri-operative hemorrhage Ina addition to wash out if all immunoglobulins that increase risk of serious infections.
_ the PEX should be prior to transplant till reach target isoagglutinin titer of 1/16.
_ additional use of PEX may be needed if still high titer.
_ induction with basilixamab can be used followed.
_ solumedrol pulses and early start of tacrolimus based triple maintenance therapy can be started one week before operation.
3. Post transplant follow up of DSA titer, isoagglutinin titers especially more frequently in 1st 4 weeks by flow cytometry in addition to protocol biopsy.
_chemoprophylaxis against CMV and p. Jirovecii are essential is such high risk transplantation due to use of aggressive desensitization protocol for 6 months post transplant.
4. Other options will be PKD or deceased donor via KAS.
_ this high risk transplant must not be carried out except after failure to find better offer of ABO compatible and low c PRA when searching an offer from UK with very low incidence of the rare antigen which differs greatly between different ethnic groups.
Will you go ahead?
No , both recipient and donor are ABO-incompatible and the recipient’s anti-A antibody IgG titer is 1/128 so he needs desensitization to lower IgG titre˂1/8.
-Crossmatch is not mentioned and the recipient has DSA.
If yes, what is your immunosuppression plan?
-Desensitisation of the recipient with plasma exchange followed by IVIg and rituximab
-Induction with rATG , maintenance immunosuppression with Tac,MMF ( MMF was taken7-14 d pretransplant to inhibit antibody production.), and prednisolone.
– Prophylaxis for PJP & CMV infection.
-Follow-up posttransplant for :
-Anti-A antibodies , DSA.
-Tac level, CBC, RFT, urine analysis
-Protocol biopsies.
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
-Yes, because an increase in Anti A or DSA levels is the risk of AMR.
-DSA monitoring: day 4, week 2, 4, and 8; 6 months; 1 year; and annually.
-Anti-A antibody titre daily in the first 2week and then according to follow up.
If not, what are your other options?
-Search for another living compatible donor
– deceased compatible donor.
– Kidney Paired Donation
· Will you go ahead?
No I won’t advice to proceed as it is considered a high risk transplantation due to the presence of HLA mismatch 120 anti HLA-A36 with MFI 10,000 and ABO mismatch with Ig G titer 1/128
· If yes, what is your immunosuppression plan?
Considered highly sensitised case
Desensitisation with plasmapheresis , IVIg and Rituximab can be applied till lowering
Anti A Ig G to less than1/18 and decreasing Pretransplant DSA level to MFI <500
Induction with r ATG and maintenance therapy using Tac ,MMF , steroids
With prophylaxis against CMV ,PJP
Post transplant protocol biopsy will be needed
· If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
Yes we need to monitor both DSA using SAB ,for 2 weeks then 4 weeks then 8 weeks then 3 months , 12 months.
Anti-agglutinin ABs titer need to be frequently monitored for first 4 weeks then monthly
· If no, what are your other options?
Kidney exchange transplant program
Waiting for more compatible living or deceased donor
Excellent decision
A 41-year-old CKD 5 Afro-Caribbean male, who moved to UK 3 years ago. His blood group is B (Rh – ve) and received a kidney offer from his cousin who is blood group A1 (Rh – ve). The recipient anti-A antibody IgG titer is 1/128. 120 mismatches. There is DSA (anti HLA-A36 with MFI 10,000) due to previous multiple blood transfusion during childhood.
Will you go ahead?
No this is very high risk for ABMR and graft loss due to double hit, ABOI and HLA i- kidney transplant from minor ethnicity, black race with high DSA anti-HLA- A 36 which is more in black race, i preferred to search for another donor as he is high immunological risk for rejection in addition to the desensitization protocol complication and intense immunosuppression therapy with associated surgical complications coagulopathy and opportunistic infections, malignancy so we should always individualized such decision taken in consideration he is young if he lost this graft then will be more difficult to get access for another transplantation
If yes, what is your immunosuppression plan?
If yes we need to know about the FXCM and the MCS value if positive with > 250 and no other alternative donor from KPD or DD then he should go for desensitization protocol as ABOI KTX and here the desensitization should be 1 month prior to surgery date to target the isoagglutinin AB titer TO < 1.8with combination of therapeutic plasma exchange 3-5 sessions Followed by IVIG ,and B cell depleting agent rituximab (nowadays using low doses 200mg /m2) followed by induction with ATG 1.5mg /KG for 4 doses, PMP 500mg and triple maintenance IS with tacrolimus 0.15mg/KG with target trough level 10-12 ng first three months then 7-9ng , MMF , prednisolone , with CMV Prophylaxis and PJP prophylaxis
If yes, do we need to monitor the anti-A antibody titer and the DSA post-transplantation?
yes need frequent monitoring for DSA by Luminex SAB , 2.4 .8 weeks then 3 months , 12 months, frequent anti-agglutinin ABs titer first 2-4 weeks then monthly
Protocol biopsy as per center policy or once indicated
If no, what are your other options?
Paired kidney donation
DD
References:
1- Al Meshari K, Pall A, Chaballout A, El Gamal H, Al Mana H, Humaidan H, Alzayer F, Al Talhi M. Outcome of desensitization in human leukocyte antigen- and ABO-incompatible living donor kidney transplantation: a single-center experience in more than 100 patients. Transplant Proc. 2013 May;45(4):1423-6. doi: 10.1016/j.transproceed.2013.01.081. PMID: 23726587.
2- up to date ,kidney transplantation in adult: Induction immunosuppressive therapy. accessed 2022.
Excellent
the data support the view that antibodies to both HLA and blood group substance may be tolerated once the graft is in situ and it is only the critical early post transplant days and weeks that can not be accommodated.
If yes, what is your immunosuppression plan?
desensitization protocol
1-plasmphresis followed by IVIG as to achive cross matching negative and IgG antibodies titre less than 1:8.
2-Rituximab 375 mg/m2 3 week pretransplant.
3- induction therapy by ATG 1 to 1.5 mg /kg daily for 4 to 6 days.
4-triple immunosupression therapy
Tacrolimus trough level 8 to 10
MMF1 gm po BID
methylpredisolone500mg for 3 days and predinslone 1mg /kg then taper to 5 mg po od over 8 weeks.
prophylaxies for CMV and pnumocystic pneumonia.
moniter
DSA in the first 3 month
protcol biopsy in the first 3 month
anti A antibodies dialy for 2 weeks and then twice for next 2 week then acommdation will take place no need to monitor
If no, what are your other options?
wating for ABOc and HLA compitable donor .
PKD program
waiting list for deceased compatible donor
references
1-Comprehensive Nephrology -six Edition
2- Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x. PMID: 19845597.
Very good
No, as the transplantation is associated with high immunological risk due to ABO incompatibility and HLA incompatibility
He will need intense immunosuppression which will increase the risk of infection
Desensitization with Plasmapheresis till titer of anti-A antibody reach 1:8, IVIG after sessions of plasmapheresis and Rituximab
Induction with ATG
maintenance immunosuppression with tacrolimus, MMF and steroids
Yes, need close monitor of DSA and anti-A antibody titer to detect post transplant rebound of isoagglutinin.
Kidney paired donation to find a more compatible donor
waiting for a kidney offer from deceased donor waiting list.
Salvadori M, Tsalouchos A. Current protocols and outcomes of ABO-incompatible
kidney transplantation. World J Transplant 2020; 10(7): 191-205
Very good
Will you go ahead and do it?
No, patients with considerable incompatibility of both ABO (A1 donor, which is highly antigenic and exhibits extremely high antibody levels) and HLA incompatibility with DSA against A36, most likely will have a positive crossmatch.
If you answered yes, what is your immunosuppressive strategy?
To attain an anti-A ab titer of less than 1:8 and negative cross-match, desensitization should be performed with PP, IVIG, and Rituximab.
Treatment with ATG for induction.
Tac-based triple IS treatment is used for maintenance ( Tac, MMF, steroids).
Monitoring the level of DSA and Anti-A antibody are mandatory in the early post-transplant. In addition to protocol biopsy.
Do we need to monitor the anti-A antibody titre and the DSA after the transplantation, if the answer is yes?
Yes, during the early stages of the disease since there is a danger of antibody rebound.
If this is the case, what are your alternative options?
PKD Donation or wait for a cadaveric with better compatibility.
This case pertains to combined ABO incompatibility and HLA incompatability.
The anti-A antibody titres are 1:128 in this patient, suggesting a difficult-to-cross ABO barrier (requiring higher number of plasmapheresis sessions and increased chances of rebound) and having high risks of AMR. In addition, A1 is highly immunogenic.
Presence of DSA: DSA (anti HLA-A36 with MFI of 10000). The DSA-RIS score for this patient is 5, which is low and can be taken up for desensitization. (1)
But in presence of high anti-A antibody titres, this transplant should be avoided.
We also need to know about the HLA-typing of the donor and the recipient, as well as the crossmatch results.
No. I will not accept this donor.
If we take up this patient for transplant, then the patient will require desensitization with Plasmapheresis and IVIG and rituximab to achieve a negative crossmatch, as well as anti-A IgG antibody titre of ≤1:8 before proceeding with the transplant.
Injection Rituximab 200 mg IV 2 weeks prior to the tentative date of transplantation.
Since this patient is a high immunological risk category patient, the patient will require induction immunosuppression and tacrolimus based triple drug maintenance immunosuppression.(2)
1) Induction therapy: Injection Anti Thymocyte Globulin (ATG) in dose of 1-1.5 mg/kg per day for 4-6 days (total dose 6 mg/kg).
2) Maintenance immunosuppression: Triple drug therapy including
a. Tacrolimus: Target trough level of 8-10 ng/ml
b. Mycophenolate mofetil (MMF): 1000 mg twice a day
c. Corticosteroids: Injection methylprednisolone 500 mg intravenous on the day of surgery, followed by tablet prednisolone 1mg/kg/day for 3 days and then 20 mg/day, to be tapered to 5 mg/day over next 6 to 8 weeks.
Steroid-free regimen should not be used in this case.
CMV and pneumocystis prophylaxis should be given.
Post-transplant, patient requires close follow-up with clinical and laboratory evaluation.(2)
i) Complete blood count, urine examination and serum creatinine. Tacrolimus trough levels to be monitored.
ii) Anti-A antibody titres monitoring: daily for first 2 weeks, then twice a week for next 2 weeks.
iii) To look for proteinuria: Spot urine protein-to-creatinine ratio.
iv) DSA testing: Once in first three months, then annually or whenever there is any graft dysfunction, alteration in immunosuppression or suspicion of non-adherence.(3,4)
v) Protocol biopsy: Once in first three months.(3) If the biopsy shows features of AMR, it should be treated.
Yes. We do need to monitor Anti-A antibody titres post-transplant.
Initially daily for 2 weeks and then twice a week for next 2 weeks. After 1 month, no need to monitor anti-A antibody titres.
The other options available in this scenario include:
a) Change the donor to someone who is compatible (ABO and HLA)
b) Enroll in kidney paired exchange program to get a better match kidney, both regarding anti-HLA and anti-blood group antibodies.
c) Wait for a better matched offer through the deceased donor program
References:
1) Sethi S, Choi J, Toyoda M, Vo A, Peng A, Jordan SC. Desensitization: Overcoming the Immunologic Barriers to Transplantation. J Immunol Res. 2017;2017:6804678. doi: 10.1155/2017/6804678. Epub 2017 Jan 3. PMID: 28127571; PMCID: PMC5239985.
2) Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x. PMID: 19845597.
3) Tait BD, Süsal C, Gebel HM, Nickerson PW, Zachary AA, Claas FH, et al. 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.
4) Crespo M, Zárraga S, Alonso Á, Beneyto I, Díaz Corte C, Fernandez Rodriguez AM, et al; GREAT Study Group and Spanish Network for Research in Renal Diseases (REDINREN, RED16/0009). Monitoring of Donor-specific Anti-HLA Antibodies and Management of Immunosuppression in Kidney Transplant Recipients: An Evidence-based Expert Paper. Transplantation. 2020 Aug;104(8 Suppl 2):S1-S12. doi: 10.1097/TP.0000000000003270. PMID: 32658025.
1.I will not go ahead with transplant, due to
A.ABOi tx.
B.DSA positive with high value.
As both ABOi and HLAi transplant has very bad outcome with high rejection and infection rate.
2.If very much desperation for tx,then desensitize till crossmatch negative and antibody titre less than 1/8.
Rtx 200mg day-14
Tacrolimus 0.15mg/kg day-14
Mmf 1g/day day-14
Therapeutic plasma exchange alternate with ivig.
ATG induced .
3.yes we have to monitor
Anti-A titre daily 1st wk,twice 2nd wk
Once wkly for 3mnth
DSA 1,3,6,12mnth
4.kidney paired donation
References:
I will not proceed with this transplant straightaway for two reasons
1 ABOi with anti A IgG 1/128
2. HLA incompatibility with DSA of 10000 MFI against HLA-A36.
If some how we proceed with transplant the immunosupression protocol should at least start 1.4 weeks prior to transplant with Rituximab 2 00 mg.
2. Intiate Mycophenolate 500 mg twice daily 4 weeks prior
3. At two weeks prior to the scheduled transplant surgery date, we should obtain an isoagglutinin titer and a final crossmatch. Based upon the isoagglutinin titer results, we plan for pretransplant plasmapheresis to achieve a goal isoagglutinin titer of ≤1:8 by the time of transplant surgery.
4. Patient should be admitted at least 5 days before surgery and depending upon isoagglutinin titer plasma exchange should be initiated.
In general, the titer can be expected to decrease by one dilution with each session of plasmapheresis. This can be used to estimate the number of plasmapheresis sessions necessary to achieve the target titer.
IVIG 10 grams after each plasmapheresis session, except after the final session prior to transplant, At the last plasmapheresis session prior to transplant, IVIG is administered as 500 mg/kg, rounded to the nearest 10 grams. This is given to correct the preoperative hypogammaglobulinemic state induced by plasmapheresis.
We would require to monitor anti HLA A antibody titer and DSA post transplant.
Paired donor exchange program is a better option
▪︎Will you go ahead?
I will not accept this donor as there are both ABO and HLA incompatibility with high and significant MFI which is associated with risk of hyperacute rejection.
isoagglutunin titer is less than 1:256 which would be acceptable if no HLA incompatibility .
▪︎If yes, what is your immunosuppression plan?
No data about CDC-XM and FCXM ,
Desensitization until crossmatch becomes negative and isoagglutinin antibody titer of less than 1/8
with plasmapheresis, IVIG and rituximab
Rituximab in the dose of 200 mg 2 weeks prior to transplant. Triple immunosuppression to be given starting 2 weeks before transplantation. Tacrolimus was given in the dose of 0.1 mg/kg twice a day, mycophenolate sodium in the dose of 360 mg 3 times daily, and Prednisolone 20 mg once daily.
The volume of plasma exchanged 30 ml/kg body weight. Replacement fluid used was Ringer’s lactate and 0.9% normal saline. Fresh frozen plasma with blood group of the donor
Each session of plasmapheresis followed by IVIG in the dose of 5 gm, with a total of 8 sessions.
Induction with ATG as he is high risk patient.
Maintenance immunosuppression with triple immunosuppression tacrolimus, MMF and steroids.
Tacrolimus trough level: 8-12ng/ml for first month.
▪︎If yes, do we need to monitor the anti-A antibody titer and the DSA post-transplantation?
monitoring of isoagglutinin titers daily till discharge from the hospital, then 3 times per week for the first month then weekly till 3 months post-transplant then yearly.
Follow up of DSA in 1,3,6,12 months .
Protocol biopsy wil also help to detect early and subclinical AMR
▪︎If no, what are your other options?
The paired kidney donation program.
Deepak Shankar Ray and Sharmila Thukral.ABO-Incompatible Renal Transplantation with High Antibody Titer: A Case Report.Am J Case Rep. 2017; 18: 1073–1076.
Will you go ahead?
Patient has both ABOi and HLAi with DSA MFI of 10,000
double hit – no transplantation
If no, what are your other options?
Paired kidney exchange program or compatible deceased donor kidney
this patient is obviously having two issues:
1} ABOi with donor, anti A antibodies titer is significant at 1/128.
2} HLAi at 120 with Anti A36 of 10000 MFI.
plan:
I would consider flow cytometry cross match and CDC cross match.
if CDC cross match is positive, then there is high risk of hyperacute rejection.will not proceed with transplant, will offer PKD program. or KAS to avoid unacceptable antigens.
if flow cytometry cross match positive and CDC negative then depending median channel shift MCS and Relative intensity score RIS,
MCS less than 250 and RIS less than 17 {like in this patient},then will offer desensitization. and proceed with transplant, with follow up of DSAs post transplant. and having ABOi with titer of 1/128 is another indication for desensitization program which will consider double filter plasma pheresis, IVIG and Rituximab,
i would suggest rATG for induction and Tac. based immunosuppressant with MMF and prednisolon.
Anti A antibodies has to be monitored closely on daily basis during the first 2 weeks. After that less frequently as the accommodation phenomina of allograft will be supervened.
If MCS is more than 250,or RIS more than 17,then Desensitization is not advisable ,
will recommend PKD program.
reference:
Edmond huang, and Stanley C.Jordan .Kidney transplantation in Adult, HLA Desensitization.www.uptodate.com
5. A 41-year-old CKD 5 Afro-Caribbean male, who moved to UK 3 years ago. His blood group is B (Rh – ve) and received a kidney offer from his cousin who is blood group A1 (Rh – ve). The recipient anti-A antibody IgG titre is 1/128. 120 mismatch. There are DSA (anti HLA-A36 with MFI 10,000) due to previous multiple blood transfusion during childhood.
Will you go ahead?
An ABO subtype (A1 vs. A, non-A1) allows organs to be allocated to additional candidates.
A person who is primary blood type A normally could not donate their organ to a candidate who is blood type B.
If the person who is blood type A also has a non-A1 subtype(most commonly A2), then they could possibly donate a kidney to a person who is primary blood type B (or O), depending on other factors.
ABO-i-with low-dose rituximab were comparable with those of ABO-c- renal transplants(Itsutu Hamano et al. Japan).
ABO-i-KT with proper IS may be an option to help resolve the donor shortage.
Outcomes of ABO-I KTx were inferior to ABO-c KTx but tends to improve as more experience is gained.
Incidence of AMR was higher but infections and surgical complications were comparable.
================================================
If yes, what is your immunosuppression plan?
A preconditioning protocol including PP, IVIG, Rituximab, & ATG induction & a triple Tacrolimus-based IS regimen.
============================================
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
It is important to monitor the titers after transplant.
In a study done by Chung et al., 5 out of 8 patients with high baseline titer required post-transplant PP & IVIG due to a rebound of antibodies.
================================================
If no, what are your other options?
PKD
Combined PKD & desensitization.
Wait for a deceased donor offer.
Reference
1. Itsutu Hamano et al. Jul-Aug 2020;52(6):1700-1704.
doi: 10.1016/j.transproceed.2020.01.152.
2. Aniketh Brabhakar et al. Indian J Nephrol . Jul-Aug 2021;31(4):358-364.
doi: 10.4103/ijn.IJN_206_20. Epub 2021 Apr 2.
Will you go ahead Dr Mohamed regardless to the A subtype?
Will you go ahead?
No, patients with significant incompatibility both ABO (A1 donor which is the most antigenic and presents very high antibody values) plus HLA incompatibility (3 mismatches added to high DSA values per MFI greater than 10,000).
If yes, what is your immunosuppression plan?
I suggest do not transplantation
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
It is very important to monitor closely the antibody tiles
If no, what are your other options?
Paired kidney donation
Wait a more compatible deceased donor
This is HLAi and ABOi transplantation, the anti A ab titer is not so high and it is amenable to desensitization but there is a DSA with significant MFI, no information is given about CXM and HLA typing, I prefer finding a more compatible donor.
Desensitization with DFPP, IVIG, Rituximab to achieve anti A ab titer < 1:8, and negative CXM.
Induction: ATG 1.5 mg/kg, MP pulse.
Maintenance: Tac based triple IS therapy ( Tac, MMF, steroids).
Monitoring of DSA level
Monitoring of anti A ab in the early post-transplant period.
Protocol biopsy.
Yes, in the early period as there is a risk of antibody rebound.
Excellent
Thanks
Will you go ahead
I will not proceed in transplanting this patient because of ABO and HLA incompatibility (double hit) with significant MFI. Although the baseline of isoagglutunin titer is less than 1:256, the risk is high with DSA against class HLA-A which is associated with hyperacute rejection with immediate loss of the graft, and also with an increased risk of early and late AMR and TCMR.
If yes, what is your immunosuppression plan?
Desensitization therapy should be started as early as 1 month before surgery comprising of B cell depleting agent as anti- CD20 Rituximab( 200 mg or 375mg/m2 )(to be given 1 month before transplantation, Plasmapheresis to remove circulating antibodies (sessions depending on the titer and titer should be ≤1:32 for HLA and <1:8 for ABO) with IVIG 10 grams after each session or 500 mg/kg after the last session followed by induction and maintenance therapy compatible with his high immunological risk.
The target is to reach isoagglutinin antibody titer of (≤1:8 for ABO and <1:32 for HLA ) before transplantation.CDC and flow crossmatch should be negative before transplantation
INDUCTION: r-ATG.
Maintenance immunosuppression is Tacrolimus-based triple immunosuppression, along with MMF(started 1 month prior in a dose of 500 mg BD) and steroids.
Antiviral and anti-bacterial prophylaxis with acyclovir, and trimethoprim-sulfamethoxazole.
Tacrolimus trough level: 8-12ng/ml for first month then 5-10ng/ml thereafter
If yes, do we need to monitor the anti-A antibody titer and the DSA post-transplantation?
Close monitoring of isoagglutinin titers daily till discharge from the hospital, then 2-3 times per week for the first month then weekly till 3 months post-transplant then annually. Also monitoring of kidney function test, urine analysis, protein creatinine ratio.
If no, what are your other options?
Find a more compatible living donor (if available), or
The paired kidney donation program
REFERENCE:
1- E. Huang, and S. C. Jordan. Kidney transplantation in adults: HLA desensitization. © 2022 UpToDate.
Good
Will you go ahead?
This is a risky transplantation with ABO and HLA incompatibility especially in the context of anti-HLA-A antibodies with significant MFI. Although the baseline of isoagglutunin titer is less than 1:256, the risk is high with DSA against class HLA-A which is associated with early AMR. One can say that desensitization protocol in ABO incompatible transplant with cutoff of 1:128 is reasonable and the desensitization could also be a treatment of preexisting DSA, this is true. But desensitization protocol will not manage memory cells against HLA-A36, so the overall risk is high.
The crossmatch is expected to be positive between A and B blood groups, so crossmatch is reasonable to be done after desensitization if the decision is to proceed.
If yes, what is your immunosuppression plan?
Based on his baseline isoagglutinine titer and if the patient is willing to proceed with transplantation, the patient should undergo desensitization therapy as early as 1 month before surgery followed by induction and maintenance therapy compatible with his high risk.
Desensitization therapy include:
B cell depleting agent as anti CD 20 Rituximab to be given 1 month before transplantation. different doses has been considered in different protocols (100/200/375mg as total or dose per m2), with subsequent measuring or antibody titers in 2 weeks before starting plasmapheresis and IVIG.
MMF is also started 1 month before, with dose of 500mg Cellcept BID.
Plasmapheresis is indicated to remove circulating isoagglutinins with daily measuring of titers to confirm efficacy. Some centers have more experience with immunoadsorption but more expensive technique.
IVIG is given on daily basis to replace the removed antibodies during plasmapheresis and for deep immunosuppression having immunomodulatory effects.
Induction therapy ishould be r-ATG given his high risk,
Maintenance immunosuppression is Tacrolimus based triple immunosuppression, along with MMF( which is started 1 month prior) and steroids.
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
We should monitor the anti-A antibodies on daily basis during hospitalization, 3 times per week for the first month, then weekly for 3 months and then annually. If Any signs of renal function deterioration appear, we should measure the titer and do kidney biopsy. DSA should also be measured in the early post-transplant period first 3 months after transplantation along with protocol biopsy.
If no, what are your other options?
Paired exchange program is the best for this patient to obtain living related offer with low immunological risk.
No
I will consider this offer to carry high immunological risk (ABO incompatibility in addition to a highly significant DSA profile)
While thinking of the possibility of desensitization we should keep in mind that this recipient is young, and he will be exposed to the long-term complications of the desensitization protocol followed by a potent immune suppression. Additionally, this complicated offer may lead to the development of another multiple DSA, resulting in high cPRA, making subsequent transplantation challenging.
I will advise the patient to:
– seek a more compatible living donor (if available), or
– proceed with a paired kidney donation program (if available) or
– He will be listed for a more compatible deceased kidney allograft.
Will you go ahead?
The decision to transplant this patient or not will depend on addressing the risk factors related to this transplantation:
1- Impact of the presence of DSA which are extremely significant in this case due to
3- Impact of ABO incompatibility
So … I will not proceed in transplanting this patient due to very high risk of hyper acute rejection with immediate loss of the graft, moreover, combined ABO and HLA incompatible transplantation (double hit) is associated with much increase in the risk of early and late ABMR and TCMR
I will proceed if no expected available alternative after explaining risk of ABMR and graft loss associated with this transplant provided that FCM MCS < 250
If yes, what is your immunosuppression plan? Do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
1-Desensitization should be started 1 month before a transplant operation which involves
The target is to reach isoagglutinin antibody titer of ≤1:8 together with a negative cross match before transplantation.
2-Induction using ATG
3-Maintanace triple immunosuppressive regimen including
4- Antiviral prophylaxis according to CMV status
5- Monitoring
If no, what are your other options?
Will you go ahead?
i will not go ahead with high titre with anti B antibodies and this high DSA level , very risky transplantion.
If yes, what is your immunosuppression plan?
if yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
Recommendation from BTS is ,
If no, what are your other options?
the other option is finding donor with ABO comatibilty or going for PKD programm.
Thank you
Despite ABO desensitisation being durable (the cut off is 1/128), there is a significant DSA.
There is a “double hits” here
1. ABOi
2. HLAi
None of the scenarios gave details about the crossmatch. Do we need to know the crossmatch?
if not mentioned its is neagtive as i thought.
None of the scenarios gave details about the crossmatch. Do we need to know the crossmatch?
Yes
the essential step in living kidney donation is to have a negative crossmatch before proceeding to kidney transplantation.
A successful desensitization protocol should result in a negative CDC and flow cytometry crossmatch (a positive flow cytometry crossmatch with MCS ≤250 may be acceptable by some centres) as illustrated in the attached figure (1).
References:
1) E. Huang, and S. C. Jordan. Kidney transplantation in adults: HLA desensitization. © 2022 UpToDate. (Accessed on 25 April 2022).
absolutely,
as I mentioned in my answer , we need to have flow cytometry cross match and CDC cross match
Positive CDC, No transplant. PKD.
Negative CDC and positive FCX then depend on the MCS and RIS.
MCS more than 250 , No desensitization offered.PKD or KAS
MCS less than 250 , and RIS of more than 17 , similarly no desensitization will be offered .consider another life donor or PKD
MCS less than 250 and RIS less than 17 , and ABOi will offer desensitization program.
i will not go ahead except after doing desensitization and reach titer to less than 1/8
immunosuppression plan :
1- desensitization Rituximab 2 weeks prior to operation, plasmapharesis 4 sessions prior to transplant operation with IVIG post plasmapharesis
2- start Tac, MMF, and prednisolone 2-7 days prior to operation
yes we should do monitoring of anti-A antibody, and DSA closely post transplant as we can extend plasmapharesis session and ivig
if no will search for another ABO compatible donor or join PKD program
Thank you Riham
ALWAYS THINK OF THE PAIRED EXCHANGE PROGRAMME.
Despite ABO desensitisation being durable (the cut off is 1/128), there is a significant DSA.
There is a “double hits” here
1. ABOi
2. HLAi
None of the scenarios gave details about the crossmatch. Do we need to know the crossmatch?
no need to know about cross match
no.Will offer kidney paired exchange or deceased donor option as risk of AMR is high with the present recipient donor combo in view of ABOi with DSA MFI 10000.
Rituximab 100-200 mg / m2 15 days prior to transplant
Plasmapheresis 1 week pre transplant to be started on alternate day one plasma volume exchange f/b IvIg 100mg/kg after each plasmapheresis session .
There should be at least one week gap between Rituximab and plasmapheresis.
3-4 sessions of plasmapheresis will be required for a timer of 1/128.
Pre tx day titer < 1:8 and CDC negative with DSA < 1500 then to go ahead with transplant .
Induction – ATG
Tacrolimus, MMF, and prednisolone.
Isoagglutinin titre daily for the first 15 days post transplant till discharge and then DSA when clinically indicated when AMR is suspected .
Paired kidney exchange
Deceased donor
Another living donor .