4. A 41-year-old CKD 5 male, blood group A1 (Rh +ve) who received a kidney offer from his cousin who is blood group B (Rh +ve). The recipient anti-B IgG antibody titre is 1/512. 110 mismatch.
- Will you go ahead?
- If yes, what is your immunosuppression plan?
- If yes, do we need to monitor the anti-A antibody titre post-transplantation?
- If no, what are your other options?
Thank you, All. I went through your replies. Most of you are missing an important fact. Please answer the following questions (both have the same meaning):
1. Do we need to have a cut off for desensitisation? why?
2. Why not desensitise every patient who has a titre above 1/16 or above 1/8?
YesIt is necessary to detect the isoagglutinin titer to decide for desnesitisation ,The best technique is flux cytometry.
On the other hand the antibody basal titer before desensitization and the post-transplantation titer have a low predictive value for AMR
Reference
Salvadori M et al. Current protocols and outcomes of ABO-incompatible kidney transplantation. World J Transplant 2020 July 29; 10(7): 191-205
Reference
Chung B.H et al Impact of the Baseline Anti-A/B Antibody Titer on the Clinical
Outcome in ABO-Incompatible Kidney Transplantation Nephron Clin Pract
2013;124:79–88 DOI: 10.1159/000355855
_ actually, pre-transplant iso agglutinin titer plays a crucial role in determining risk of post transplant rebound of iso agglutinin and consequent AMR.
_ Iso agglutinin IgG is more important and more involved than IgM. Hence, cut of level of pre-transplant iso agglutinin can play a role in accepting ABO i transplant.
No consensus, but titer more than 1/256 was set as cut of point to eligibility for desensitization in many centers.
_ The rationale behind this is to allow accepted protocols of desensitization to reach target level of isoagglutinin ( which differs between centers between 1/4 to 1/16) , based on available expertise and facilities.
_ More than 1/265 will need aggressive desensitization with overwhelming infection and sepsis complications that threaten recipient lives in addition to inevitable rebound and AMR with graft loss.
_ So cut of point is wise to weigh risk of over Immunosuppression and desensitization protocol ( infections and mailgnancy) with benefit of transplantation and increased donor pool and availability to increase transplantability opportunity.
_ still,ABO i transplantation has better prognosis and QOL and less cost than maintenance HD.
Please add another question to the above two that can guide to the answer:
Do we need a TAILORED IS according to the baseline titre ?
Why in some results the mortality rate is higher P<0.0001 in year 1,3,5 then equal after that to ABOc cases?
This is probably due to IS side effects as infection,coagulation problems, Polyoma virus.
So TAILORED IS would be a good compromise depending on baseline titre:
<8. 8. 16-64. >264
Please riffed to JOURNAL CLUB
Current protocols and outcomes of ABOi TX. For plan of TAILORED IS according to baseline titres.
The aim of desensitization protocoles is the reduction and maintenance of A/B Antibody (isoagglutinins) titer during the transplantation and first 2 weeks after transplantation,below a threshold that is considered to be safe (e.g.,1:32 in tube technique) and not to portend a heightened risk of hyperacute rejection .Thereafter ,even when anti A/B antibodies rebound at high levels,they will not harm kidney transplant, a phenomenon that is called accomodation.
In general the risk of hyperacute rejection is directly related to level of anti donor organ antibodies.
Cutoff is definitely indicated as the level of antibodies above which, absolute risk of hyperacute rejection prevails,(that is 1/32).
Reference:
Daniel C Brennan.Kidney transplantation in adult:ABO incompatibility. Mar.2022 .www.uptodate.com
Do we need to have a cut off for desensitisation? why?
YES. initial ABO isoagglutinin titer of ≤1:128. At some transplant centers, an initial titer of
≤1:256 may be acceptable.
Transplantation is performed when the isoagglutinin antibody titer is ≤1:8
The initial titer of the anti-A or -B isoagglutinin antibody, rather than the antigen
targeted (A1, A2, or B), was initially reported to correlate with the risk of ABMR .
low Antibody titer , transplant can be performed without any desensitization.
2. Why not every desensitised patient who has a titer above 1/16 or above 1/8?
Transplant can be performed without any desensitization if baseline titers are <1:32.
Ref:
B.V.Shah et al. Baseline Anti-blood Group Antibody Titers and their Response to
Desensitization and Kidney Transplantation. Indian J Of Nephrology.017 May-Jun; 27(3):
195–198.
Yes it’s mandatory to detect antibodies titer to give desensitisation protocol
Because it’s expensive and high risk of infection
1. Do we need to have a cut off for desensitisation? why?
2. Why not desensitise every patient who has a titre above 1/16 or above 1/8?
The process of desensitization has its own set of complications including increased infections, coagulation abnormalities, higher costs and prolonged hospital stay etc.
So, a cut-off for taking up ABO incompatible transplants (usually <1:128) as well as taking up for desensitization is important to minimize the side effects and maximizing the benefits.
Tailoring the desensitization protocol according to the antibody titres, as used by Barnette et al (desensitization according to isoagglutinin titres. <8: none, 8: rituximab, 16-64: rituximab with plasmapheresis, >64: rituximab with immunoadsorption) has shown results comparable to ABO compatible transplants.(1)
Reference:
1) Barnett AN, Manook M, Nagendran M, Kenchayikoppad S, Vaughan R, Dorling A, Hadjianastassiou VG, Mamode N. Tailored desensitization strategies in ABO blood group antibody incompatible renal transplantation. Transpl Int. 2014 Feb;27(2):187-96. doi: 10.1111/tri.12234. Epub 2013 Dec 28. PMID: 24188566.
No clear cutoff for desensitization it ranges between 1/4 to 1/32, most commonly a cutoff of 1/8 is used
A clear cutoff is important to define because it prevent unnecessary desensitization if the initial titer is 1/8 for example and allow even for reduction of the number of the sessions required for plasmapharesis thus reducing the cost
On the other hand a high titer defined as titer more than 1/ 256 is associated with high risk of ABMR and loss of the graft even with desensitization
So titer of 1/8 or less proceed in transplantation without desensitization, titer of > 1/256 exclude the donor , while titer inbetween proceed in transplantation after desensitization.
Desensitization process itself carries risks putting patients at risk of infection and bad survival on long term
1- Yes,we need cut off for desensitization
initial titer of the anti-A or -B isoagglutinin antibody, rather than the antigen targeted (A1, A2, or B), was initially reported to correlate with the risk of ABMR in such cases
The incidence of acute ABMR after ABOI has been reported in the range of 10 to 30 percent.
The patient must have an initial ABO isoagglutinin titer of ≤1:128. At some transplant centers, an initial titer of ≤1:256 may be acceptable.
the total isoagglutinin antibody titer is generally reduced to at least 1:32 (and often to ≤1:8) before proceeding to transplantation as higher titers are associated with acute ABMR posttransplant
Most centers also use plasmapheresis or immunoadsorption to maintain an isoagglutinin titer ≤1:16 during the critical two-week period following ABOI transplantation. If fresh frozen plasma (FFP) replacement is required as a result of plasmapheresis treatment, donor blood type or AB donor FFP should be given to avoid the administration of anti-allograft isoagglutinin antibodies.
2- If the titer below 1:32 (and often to ≤1:8)
No need for desensitization because there is very low risk of rejection with this low titer
as higher titers are associated with acute ABMR posttransplant
Reference
1- up to date
1 – Yes, a cut off is necessary to carry out studies that bring evidence regarding the outcomes that we usually evaluate. The cost X effectiveness is another factor involved.
2 – Because this can increase costs without impacting results.
Do we need to have a cut off for desensitisation? why?
Yes, as the desensitization process has its own complications such as the increased risk of bleeding, thrombocytopenia, hypocalcemia, infection…..
so we need to detect who is in need of this process.
Why not desensitise every patient who has a titre above 1/16 or above 1/8?
According to Barnett et al, a tailored desensitization strategy obtains good results with personalized therapy and lower costs. The different strategies were adopted according to the initial anti-ABO antibody titer, with a titer of 8, only RTX was used; with a titer between 16 and 64, plasmapheresis was added to RTX therapy; and with a titer > 64, IA and RTX were used.
The results were comparable to ABOc transplants(No difference in allograft and patient survival rates at 1 and 3 years or in the ABMR rates).
· Q1: Yes, because Tailored immunosuppression according to isoagglutinin titer before TX is a good practice to reduce unnecessary aggressive immunosuppression.
· Q2: When recipient has high titer of isoagglutinin, then needs aggressive desensitization and immunosuppression which exposes patient at risk of infections such as sepsis or BK virus that increases mortality.
yes, although, up to date no standard cut-off
due to, each centre using their familiar technique in the assay of antibody titer.
Kobayashi et al., in Japanese centres, found isoagglutinin titer 1:8 -1:32 for IgM and 1:16 – 1:256 for IgG.
the desensitization protocols are based on different titer levels, so can not be generalized
the only high titer is associated with a high rebound rate after transplantation and ultimately a high risk of ABMR.
desensitization therapy is costly and associated with adverse events.
1.Do we need to have a cut off for desensitisation? why?
Yes, we need to have a cut off. Anti-ABO IgG should be less than 1:16 or a maximum of 1:32.
2.Why not desensitise every patient who has a titre above 1/16 or above 1/8?
We need to weigh things and make a balance between the benefit of desensitization and the risk of infection related to desensitization treatment beside the cost of treatment and the economic burden.
Reference
Shah Titers and their Response to Desensitization and Kidney Transplantation. Indian Journal of Nephrology. 2017 May-Jun;27(3):195-198. DOI: 10.4103/0971-4065.202402. PMID: 28553039; PMCID: PMC5434685.BV, Rajput P, Virani ZA, Warghade S. Baseline Anti-blood Group Antibody
Sure we need for isoagglutinin detection for desensitisation
1)Will you go ahead?
Nope.
2)If yes, what is your immunosuppression plan?
Desensitization : Cycle of plasmapheresis and IVIG
Induction : ATG
Maintenance : Tacrolimus MMF Prednisolone.
3)If yes, do we need to monitor the anti-A antibody titre post-transplantation?
Yes.
4)If no, what are your other options?
Paired kidney exchange program.
Yes ; after reaching target titer less than (1/8 – 1/32 ).
Desensitization protocol: could be Rituximab 375 mg/m2 month before KTx + PE 3-7 sessions or IAs or DFPP ±IVIG 500 mg IVIG/kg better week before RTX.
Mainatince therapy : Steroids + MMF + Tac regimen.
Yes , monitor Anti-A ABs in the first 2 weeks due to rebound ABs.
other options? PKD.
Will you go ahead?
I wouldn’t go ahead with these barriers: ABOi with high anti-B IgG and 2 HLA mismatches.
If yes, what is your immunosuppression plan?
If I have to proceed for TX with this donor then I will consider the followings:
· desensitization treatment before transplant(DFPP + IVIG + RTX).
· Induction with ATG.
· Intense IS regimen; TAC, MMF, Prednisolone.
If yes, do we need to monitor the anti-A antibody titre post-transplantation?
We need to monitor the anti-B IgG titer( the donor’s blood group) rather than the antibody titer for the recipient’s blood group
If no, what are your other options?
Options include:
· Paired kidney donation.
· Altruism
· Waiting list for deceased donation.
* Will you go ahead?
No, I will not go ahead because it is ABO incompatibility with high isoagglutinin titre 1/512, so high risk of rejection.
The cut-off baseline titer for ABO- I KT has been suggested in only one study, the researchers proposed that KT was not recommended when the baseline titer was ≥1:512, because of the high rate of failure to reach the target anti-A/B antibody titer. However, they did not examine the clinical impact of the baseline titer after transplantation (1).
* If yes, what is your immunosuppression plan?
most centres performing ABOi renal transplantation have a protocol that if the antibody titre after desensitization on the planned day of surgery exceeds a certain value (such as 8), then the transplant will be delayed; if the antibody titre on referral to the ABOi programme is already at or below that value, desensitization will be administered.There are different approach and some do not use any desensitization if the antibody titre is 4 or lower. Furthermore, they use tiered approach for antibody titres of 8 or more, so that they minimize desensitization based on initial anti-ABO blood group antibody titres. This approach to ABOi renal transplantation leads to similar outcomes to ABOc transplantation (2).
Desensitization with Plasma exchange, IVIG, Rituximab , induction with Basiliximab or ATG
Maintenanceance triple I.S (Tac, MMF, Steroid)
* If yes, do we need to monitor the anti-A antibody titre post-transplantation?
Yes, It is important to detect the antibody level post transplant in the first month, because he may need others PP and to detect AR
* If no, what are your other options?
Paired exchange kidney donation program or DD program for better matching
References
1) Impact of the Baseline Anti-A/B Antibody Titer on the Clinical Outcome in ABO-Incompatible Kidney Transplantation
Byung Ha Chung, Jeong Uk Lim, Yaeni Kim, Ji-Il Kim, In Sung Moon, Bum Soon Choi , Cheol Whee Park, Yong-Soo Kim, Chul Woo Yanga, Transplant Research Center, Division of Nephrology, Department of Internal Medicine, and Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul , Korea, Nephron Clin Pract 2013;124:79–88
(2) Edited By: Thierry Berney Impact factor (2021):3.842 Journal Citation Reports (Clarivate, 2022): 47/212 (Surgery)10/25 (Transplantation) Online ISSN:1432-2277
with the current situation , i would not proceed with the Tx as high risk of rejection secondary to high anti B IgG level.
i may consider desensitization first with plasma pharesis sessions + Induction using basilixmab and maintenance using Tacrolimus, MMF and steroids.
yes to early detect if a rebound increase in titer occurs.
Wait for better matched donor Or paired Kidney transplantation
.
Will you go ahead?
No, high risk of cute rejection because of ABO i
If yes, what is your immunosuppression plan?
Needs desensitization at least one month before hand till titer below 1:8
Plasma exchange, IVIG, Rituximab
Induction: ATG
Maintenance: tacrolimus/MMF/steroids
If yes, do we need to monitor the anti-A antibody titre post-transplantation?
He needs monitoring of Anti-B antibody titer not anti- A, because his blood group is A and donor is B
If no, what are your other options?
Paired kidney exchange scheme, wait for another donor (deceased or living)
Thank you, All. I went through your replies. Most of you are missing an important fact. Please answer the following questions (both have the same meaning):
1. Do we need to have a cut off for desensitization? why?
Yes, below 1:8
2. Why not desensitize every patient who has a titre above 1/16 or above 1/8?
1- Will you go ahead
No
This is a high risk transplant recipient as
a- ABO incompitable donor with high level of anti B Ab as accepted level of pretransplant Anti A/B isoagglutunin in most centres is less than ¼ as higher level of AB correlates with higher risk of acute vascular rejection and AMR .
2- If yes, what’s the immunosuppression protocol?
e- Pretransplantation reduction of Abs level through either PE , DFPE or immuneadsorption.
f- B cell depletion with Rituximab .
g- Induction with r ATG followed by maintenance with triple IS ( Tac , MMF and steroid)
h- Regular monitoring of Anti B isoaggulitin Ab titre postoperative.
3- Do we need to monitor Ab postoperative?
Yes as rebound increase in Ab level is associated with AMR.
4- Other options
c- Paired kidney donation
d- Remain on waiting list for more suitable donor either living or deceased .
This is a donor-recipient pair ABO incompatibility (donor B, recipient A1) with high IgG anti-B antibody titres of 1:512.
A high baseline antibody titre has been shown to be associated with increased incidence of AMR.
pre-transplant iso agglutinin titer plays a crucial role in determining risk of post transplant rebound of iso agglutinin and consequent AMR. Iso agglutinin IgG is more important and more involved than IgM. Hence, cut of level of pre-transplant iso agglutinin can play a role in accepting ABO I transplant.
No consensus, but titer more than 1/256 was set as cut of point to eligibility for desensitization in many centers.
The rationale behind this is to allow accepted protocols of desensitization to reach target level of isoagglutinin ( which differs between centers between 1/4 to 1/16) , based on available expertise and facilities. More than 1/265 will need aggressive desensitization with overwhelming infection and sepsis complications that threaten recipient lives in addition to inevitable rebound and AMR with graft loss.
High baseline antibody with low titre reduction rate is a predictor of antibody rebound, leading to increased risk of AMR.
But recent studies have shown that high baseline antibody titres, despite increased risk of rebound, do not have a bearing on graft outcomes, if adequate desensitization is done.
In light of this evidence, a recipient with 1:512 antibody titres can be taken up for transplant, if CDC crossmatch and DSA is negative.
But my first choice would be either to change the donor with someone ABO compatible, or enrolling the patient in a kidney paired donation program.
The patient will require: Desensitization using
A) Injection Rituximab: 200 mg IV, 4 weeks prior to the tentative transplant date.
B) Immunosuppression: MMF 500 mg twice a day, Tacrolimus 0.1 mg/kg/day to be started 2 weeks prior to the tentative date of transplant.
C) Immunoadsorption: Using Anti-B column to reduce anti-B antibody titres to ≤1:8 prior to transplant
At the time of transplant:
A) 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). ATG has been shown to have less rejection episodes than IL-2 receptor antibody induction.(5)
B) 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.
C) CMV and pneumocystis prophylaxis should be given.
D) Anti-B antibody titres monitoring: daily for first 2 weeks, then twice a week for next 2 weeks.
No.
The recipient blood group is A (Rh +ve), while the donor blood group is B (Rh +ve). So we need to monitor anti-B antibody titres post-transplant.
First choice is to get a blood group compatible donor. If there is no other donor and the patient is not taken up for ABO incompatible transplant, he can be enrolled in a kidney paired donation transplant program. The chances of getting an early match are high in view of the B-A donor-recipient pair. The patient can also be enrolled in a deceased donor program.
References:
1) Lee KW, Park JB, Oh DK, Na BG, Choi JY, Cho WT, Lee SH, Park HJ, Cho D, Huh WS, Kim SJ. Short-Term Outcomes of ABO-Incompatible Living Donor Kidney Transplantation With Uniform Protocol: Significance of Baseline Anti-ABO Titer. Transplant Proc. 2016 Apr;48(3):820-6. doi: 10.1016/j.transproceed.2016.01.027. PMID: 27234744.
2) Won D, Choe W, Kim HJ, Kwon SW, Han DJ, Park SK. Significance of isoagglutinin titer in ABO-incompatible kidney transplantation. J Clin Apher. 2014 Oct;29(5):243-50. doi: 10.1002/jca.21312. Epub 2013 Dec 24. PMID: 24375675.
3) Baek CH, Kim H, Yang WS, Han DJ, Park SK. Clinical significance of isoagglutinin titre with the current desensitization protocol in ABO-incompatible kidney transplantation. Nephrology (Carlton). 2019 Jun;24(6):654-660. doi: 10.1111/nep.13412. Epub 2019 Apr 15. PMID: 29877001.
4) Rivera CF, Rodriguez MC, Hermida TF, Jarrin DA, Muñiz AL, Saavedra CA, García AG, Hernandez ÁA. Isoagglutinin Titers in ABO-Incompatible Kidney Transplant. Transplant Proc. 2021 Nov;53(9):2675-2677. doi: 10.1016/j.transproceed.2021.07.059. Epub 2021 Oct 2. PMID: 34610865.
5) Mohamed M, Sweeney T, Alkhader D, Nassar M, Alqassieh A, Lakhdar S, Nso N, Fülöp T, Daoud A, Soliman KM. ABO incompatibility in renal transplantation. World J Transplant. 2021 Sep 18;11(9):388-399. doi: 10.5500/wjt.v11.i9.388. PMID: 34631470; PMCID: PMC8465511.
Will you go ahead?
The transplant is an ABO incompatible renal transplant with recipient being A positive and donor Blood group B positive… The recipient anti B IgG antibody is 1:512. This is a high level baseline titre of the recipient.. Studies have shown that higher baseline antibody titre are associated with higher risk of AMR in the future despite the method of desensitization used…So this has to be explained to the patient and then proceed for antibody removal technique…We need to also check the CDC, DSA and FCXM before transplant…
If yes what’s the immunosuppression plan?
There are a number of different protocols used for antibody removal in ABO icompatible renal transplants….Patient needs to be started on triple immunosuppression that is Tacrolimus (trough level 10-12 ng/ml), mycophenolate mofetil 1000 mg, prednisolone 0.5mg/kg 2 weeks before transplant. Patient needs a minimum dose of Inj Rituximab 2 doses 375mg/m2 1 week apart. I would use immunoadsorption technique if affordable. Else go for DFPP to reduce the titre to a pre transplant level of 1:8. .I would use Inj basiliximab 20mg if there is no history of positive DSA or FCXM on day 0 and day 4 of transplant….I would also use standard triple immunousuppression protocol wit prophylaxsis for CMV and PCP…I would monitor the anti B titre every alternate day after transplant for the first week and then twice a week in the second week….
We need not monitor anti A titre after renal transplant as the donor is B blood group…We need to monitor ant B titre
If no..the other options are to find another donor with blood group compatibility r to go for Paired kidney exchange or get listed in deceased donor renal transplant program
Will you go ahead?
Yes after protocol for reduction of A/B antibodies titer with target titer less than 1/32 (preferred less than 1/8 )
If yes, what is your immunosuppression plan?
Desensitization protocol:
include Rituximab 375 mg/m2 1 month before KT + plamaphareis or IAs or DFPP ±IVIG (500 mg IVIG/kg on the day before transplantation)
Mainatince therapy : Steroids + MMF + Tacrolimus
If yes, do we need to monitor the anti-A antibody titer post-transplantation?
it is important to monitor Anti A antibodies in the first 2 weeks due to the high risk for the rebound of antibodies
and can be done any time if associated with allograft dysfunction
If not, what are your other options?
PKD
waiting for a compatible deceased donor
Current protocols and outcomes of ABO-incompatible kidney
transplantation
Maurizio Salvadori, Aris Tsalouchos
No, as the anti-B antibody titre is high.
If yes, what is your immunosuppression plan?
Desensitization by Plasmapheresis till the anti-B antibody titre is between 1:8 and 1:32 then IVIG and Mabthera.
Induction IS with ATG
Triple maintenance immunosuppression ;Tac based .
If yes, do we need to monitor the anti-A antibody titre post-transplantation?
yes, anti-B antibody titre should be monitored early – first 2 weeks .
If no, what are your other options?
Kidney paired donation and an acceptable deceased donor.
will you go ahead?
yes, high-risk transplantation
what is your immunosuppression plan?
desensitization with selective IA if available or DFPP, +rituximab + IVIG
induction with ATG
maintenance therapy Tac+MMF (started 2 wks pretransplant) + steroids
If yes, do we need to monitor the anti-A antibody titre post-transplantation?
post-transplant monitor of anti-B antibody(critically during the first 2 weeks posttransplant), looking for its rebound and possibly use of plasmapheresis at that time
as it carries a high risk of AMR
If no, what are your other options?
PKD or waiting for a more suitable deceased donor or continue on dialysis
Will you go ahead?
Yes , it is considered high risk transplant and can be done after desensitization protocol after according to Ab titer
If yes, what is your immunosuppression plan?
Desensitization protocol:
B cell depletion by Rituximab 375 mg/m2 1 month before operation
Removal of antibodies by either plamaphareis or IAs
Immunemodulation by IVIG (500 mg IVIG/kg on the day before transplantation)
Mainatince therapy : Steroids + MMF + Tacrolimus
If yes, do we need to monitor the anti-A antibody titer post-transplantation?
it is important to monitor Anti A antibodies in the first 2 weeks due to the high risk for the rebound of antibodies
If not, what are your other options?
PKD
· Q1: Yes, but needs desensitization before TX. With rituximab and DFPP or immunoabsoption (IA). To reach a low-titer (< 1/8) of isoagglutinin before TX. To reach a negative XM. In addition, giving IVIG before TX or after each session of IA.
· Q2: Induction therapy with ATG, 1 – 1.5 mg/kg/dose for 4-6 doses and maintenance immunosuppression therapy with triple therapy (Tacrolimus, MMF and steroids) at least 2 days before TX. Tac level 8-12 mg/ml in the first month is needed.
· Q3: Monitoring of anti-B Ab titers post-TX is necessary to detect rebound. First, daily until 2 week stay in hospital. Then, two-three times a week for 4 weeks and then weekly for 3 month post-TX. Protocol biopsy after 3 months is recommended.
Q4: Other options are: KPD and waiting for a compatible deceased donor
Will you go ahead?
No as it’s ABOi transplant with very high isoagglutinin titer , and liability of hyperacute rejection is very high
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
Post transplant isoagglutinin titer monitoring should be done plus optional biopsy
Best option would be to be part of paired exchange program if available in his country
or deceased donor program or waiting list for living donor and continuation on RRT
Yes, I would get the organ. In this case, receptor desensitization to ABOi would be required.
Pre-transplant I would do double-filtration PP + intravenous immunoglobulins (IVIG) as measures for desensitization associated with Rituximab. As an immunosuppression measure for induction, I would use ATg and, for maintenance, I would use CNi + MMF + steroids and a protocol for measuring the titer of anti-B IgG antibody for 4 weeks, with biopsy if necessary.
I will prefer not to proceed with transplantation. I wşll prefer kidney pairing. the titer of 1/512 is very high. desensitization may be successful but the other problem is the degree of mismatch (not provided). supposing we proceeded after desensitization with plasmapheresis, IVIF, Rituximab and no DSA with an acceptable mismatch. I prefer ATG induction (according to mismatch, maybe basiliximab). close monitoring of ant-B titers post-transplantation.
keep monitoring any Ab rebound and manage acccordingly with aphresis
Will you go ahead?
*No as recipient and donor are ABO incompatible and recipient anti-B IgG antibody titer is 1/512and high preoperative anti-A/B IgG titers are accompanied with poor long-term allograft survival.
If yes, what is your immunosuppression plan?
*Desensitization with PE followed by IVIG.
*Induction including r ATG and maintenance immunosuppression with Tac, MMF, and prednisolone.
* Prophylaxis for infections with PJP & CMV .
* Posttransplant follow up for anti-B antibodies, Tac level, CBC, RFT, urine analysis and protocol biopsy.
If yes, do we need to monitor the anti-A antibody titer post-transplantation?
Yes, to predict rebound of Anti-B titer which increase risk of AMR.
If not, what are your other options?
* Kidney Paired Donation ,or another suitable donor.
1.Yes we may go with tranplantation but after explaining these to patient ( A) very high titre will need many sessions of plasmapheresis before transplant to reach acceptable level of titre,which will increase cost of tranplant .Also high-titer group have more frequent antibody rebound post transplant ,which may need additional plasmapheresis (B) During the postoperative period and out-clinic follow-up, ABMR rate is more in higher titre group.Infection and complication like bleeding can be more frequent compared to low titre group due to Rituximab,IVIG and more plasmapheresis use . Though It is found that graft function is indepedent of intial titre , So we can go with transplant,provided resources for higher cost of transplant are available. . 2. I will use rituximab low dose 200 mg about 4 weeks before kidney transplant ,will start triple immunosuppression about 10 to 14 days before transplant , will give IVIG 0.5 g/kg , 1 day before transplant.I will prefer to Give ATG induction ,followed by triple immunosuppression to continue. . 3.We need to monitor anti B antibody and not Anti A antibody .We need to monitor anti B antibody for 2 weeks. . 4.Kidney pair donation and Deceased kidney transplantation are the options.
1-Will you go ahead?
ABO incompatible (recipient is blood group A1and the donor is blood group B ) with recipient anti-B IgG antibody titre is 1/512 , which is above the cut of point of not to desensitize ABO incompatible transplant( less than1/32) . HLA mismatches are 110 , no DSA and no reported cross match result .
Transplant can be performed with desensitization.
2-If yes, what is your immunosuppression plan?
a-Desensitization using plasmapheresis with IVIG and rituximab .
b-Induction with ATG .
c-maintenance triple TAC.
d-Prophylaxsis against opportunistic infection.
monitor anti-A antibody titre especially during the first 2 weeks post transplantation because the risk of rebound is high during this period .
3-If yes, do we need to monitor the anti-A antibody titre post-transplantation?
Yes . Antibody titres need to be monitored especially in first two weeks, thereafter the process of accommodation will start.
4-If no, what are your other options?
-Kidney paired donation.
-Combined desensitization and PKT
Reference;
Annelies E. et al. ABO-Incompatible Kidney Transplant Outcomes. CJASN August 2018, 13 (8) 1234-1243.
this patient need aggressive desensitization treatment because the level of anti B antibody is high and above 1:256 at risk of AMR.
i will use RIT, IA and IVIG before transplant and maintenace with tacrolimus triple therapy.
antibody titer need to monitored with protocol biopsy.
yes, we can go ahead after desensitization by plasmapheresis, or immunoadsorption best if available, and IVIG till antibody titer is acceptable to be below 1 l 8.
prior to Tx desensitization by :(2 weeks before tx plasmapheresis or immunoadsorption with concomitant use of IVIG ), induction would be by ATG and triple immunosuppressive regimen in the form of tacrolimus , MMF and corticosteroids ). rituximab can be used initially 1 month prior to Tx.
yes , and aggressive management would be mandatory if titers exceed 1l8 with suspected rejection episode may be presented by rise of serum creatinine initially.
kidney paired donation program and deceased donor lines to be considered in order to find more matched suitable donor.
Will you go ahead?
If yes, what is your immunosuppression plan?
If yes, do we need to monitor the anti-A antibody titre post-transplantation?
If no, what are your other options?
Will you go ahead?
Here there is ABO incompatibility between donor and recipient. The recipient has high titres of anti-B IgG antibodies- 1/512, HLA match is good . So there is high risk of AMR. This is associated with poor graft outcome . So I will not go ahead with transplantation.
If yes, what is your immunosuppression plan?
Whilst considering transplant in ABOi , desensitisation protocol need to be followed. This will involve Plasmaphresis with IVIG.and Rituximab
Induction with ATG and maintenance with triple therapy- Tacrolimus, MMF and prednisolone.
If yes, do we need to monitor the anti-A antibody titre post-transplantation?
Yes . Antibody titres need to be monitored especially in first two weeks, thereafter the process of accommodation will start.
If no, what are your other options?
Kidney paired donation
Enrol in deceased donor programme
Find a suitable compatible donor and continue on dialysis
Reference.Annelies E. et al. ABO-Incompatible Kidney Transplant Outcomes. CJASN August 2018, 13 (8) 1234-1243
1. It’s possible to do ABOI kidney transplant but high risk of AMR and patient need high dose of desensitisation therapy
2. Desensitisation protocol
a. Remove of anti B IgG antibodies by plasma exchange
b. High dose of IV IG post plasma exchange
c. Rituximab monoclonal antibody against CD20 B cell
d. Inhibition of complement activation by ecluizmab
Triple immunosuppressive agents
Serial monitoring of anti B IgG antibodies before and post transplant
Serial graft biopsy at 3m and 12m
Patients need monitoring to anti B IgG antibodies
Another option PKD program from living donor
Will you go ahead?
-No, both recipient and donor are ABO incompatible with the recipient anti-B IgG antibody titer is 1/512, high preoperative anti-A/B IgG titers are associated
with poor long-term allograft survival in ABOi-KT, so the recipient needs desensitization to reduce Anti-B IgG , acceptable titer of anti-A/B antibody at the time of transplant has varied between 1:4 and 1:32 in line with the protocol of individual centers.
If yes, what is your immunosuppression plan?
-Desensitisation of the recipient with plasma exchange followed by IVIg.
-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-B antibodies
-Tac level, CBC, RFT, urine analysis
-Protocol biopsies.
If yes, do we need to monitor the anti-A antibody titer post-transplantation?
Yes, to detect rebound of Anti-B titer which increase risk of AMR, but how long the monitoring should be continued remains unclear.
If not, what are your other options?
– Search for another living compatible donor
– deceased compatible donor.
– Kidney Paired Donation
Desensitization
Rituximab single dose 375 mg /m₂ 4 weeks before transplantation
Immunoadsorption Using Anti-B column to reduce anti-B antibody titres to ≤1:8 prior to transplant 2-3 times till the titer reaches the target 1/8.
The different strategies were adopted according to the initial anti-ABO antibody titer. With a titer of 8, only RTX was used; with a titer between 16 and 64, plasmapheresis was added to RTX therapy; and with a titer > 64, IA and RTX were used
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
Ref:
1. Current protocols and outcomes of ABO-incompatible kidney transplantation
Maurizio Salvadori and Aris Tsalouchos
Author information Article notes Copyright and License information Disclaimer
1. This offer provides a kidney with very high level of anti B isoagglutinin.
_ actually, pre-transplant iso agglutinin titer plays a crucial role in determining risk of post transplant rebound of iso agglutinin and consequent AMR. Iso agglutinin IgG is more important and more involved than IgM. Hence, cut of level of pre-transplant iso agglutinin can play a role in accepting ABO I transplant.
No consensus, but titer more than 1/256 was set as cut of point to eligibility for desensitization in many centers.
The rationale behind this is to allow accepted protocols of desensitization to reach target level of isoagglutinin ( which differs between centers between 1/4 to 1/16) , based on available expertise and facilities. More than 1/265 will need aggressive desensitization with overwhelming infection and sepsis complications that threaten recipient lives in addition to inevitable rebound and AMR with graft loss.
_ based on all above mentioned, it is better not to proceed to transplantation, as it will exhaust resources and expose patient to high risk of rejection
_ it is better to wait for ABO compatible transplant by engaging him in PKD or deceased donor via KAS.
_ if the patient has long waiting time, may proceed to this offer after discussion with the patient about high risk and need for aggressive desensitization and possible consequences. However, it may be better QOL and less costly than maintenance HD.
_ the missing point here also is state of DSA and cross match, which can add additional immunological risk that can preclude transplantation or add additional load or risk of acute rejection. Although he has 2 mismatch , he can still has postive cross match which will be risky if present together with such high isoagglutinin titer .
2. In such case, I will need aggressive desensitization by either 3_7 sessions of PEX or ID starting one month prior to transplantation. In addition, rituximab can be used till reach target isoagglutinin of 1/4 to 1/16.
_ In addition, starting solumedrol and MMF prior to transplant by one week , use of basiliximab induction followed by maintenance therapy with tacrolimus based triple Immunosuppression together with MMF and steroids may help to decrease rebound of isoagglutinin titer and decrease risk of AMR.
3. Sure , close monitoring post transplant is essential by:
_ isoagglutinin titer daily in 1 st week then twice weekly , as 1st month is most critical period for hyperacute rejection in ABO i transplantation, thereafter accomodations can occur with decreased risk of rejection.
_ protocol biopsy at 3 months is needed.
Excellent
No, as the anti-B antibody titer is high.
High titers are associated with poor long-term graft survival and are predictors of AMR
They need intense immunosuppression to decrease the titer and permit transplantation.
Desensitization:
Plasmapheresis till reach anti-B antibody titer between 1:8 and 1:32, IVIG and rituximab.
Induction with ATG
maintenance immunosuppression with Tacrolimus, MMF and steroids
yes, anti-B antibody titer should be monitored to detect rebound in antibody production early
Kidney paired donation
waiting for ABO compatible deceased donor transplant
Shimmura H, Tanabe K, Ishikawa N, Tokumoto T, Takahashi K, Toma H. Role of anti-A/B antibody titers in results of ABO-incompatible kidney transplantation. Transplantation 2000; 70: 1331-1335.
Muramatsu M, Gonzalez HD, Cacciola R, Aikawa A, Yaqoob MM, Puliatti C. ABO incompatible renal transplants: Good or bad? World J Transplant 2014; 4(1): 18-29
Very good
Will you go ahead and do it?
ABO incompatibility between a donor and a recipient (donor B, recipient A1) with high IgG anti-B antibody titres of 1:512 has been identified in this case.
Increased incidence of AMR has been linked to a high baseline antibody titre, which has been demonstrated in several studies. A recipient with 1:512 antibody titres can be considered for transplantation if the CDC crossmatch is negative before transplantation.
If you answered yes, what is your immunosuppressive strategy?
There is no common desensitization protocol; instead, it differs from centre to centre. Ex, protocol:
One week before transplantation, plasmapheresis was performed(4-5 sessions, followed by IVIG after each session in order to keep the isoagglutinin titre below 1:16 or immunoadsorption(A1)
prior to the transplanting
Rituximab 375 mg/m 2 weeks before transplantation is recommended.
basiliximab and pulse steroid for induction
Triple immunosuppression medication with Tacrolimus (trough level 10-12), MMF and prednisolone were administered.
what are your alternative options?
PKD Donation or wait for a cadaveric with better compatibility.
–Rivera CF, Rodriguez MC, Hermida TF, Jarrin DA, Muñiz AL, Saavedra CA, García AG, Hernandez ÁA. Isoagglutinin Titers in ABO-Incompatible Kidney Transplant. Transplant Proc. 2021 Nov;53(9):2675-2677.
–Gan CC, Jalalonmuhali M, Nordin NZ, Abdul Wahab MZ, Yahya R, Ng KP, Tan SY, Lim SK. ABO-Incompatible Living-Donor Kidney Transplantation
Very good
Thankyou for mentioning cross match.
Induction therapy with basiliximab (Simulect) 20 mg given intravenously perioperatively and on day 4, and peri-operative methylprednisolone 500 mg intravenously
Maintenance therapy tacrolimus, administered pre-operatively at a dose of 0.075 mg/kg followed by 0.075 mg/kg twice daily. Target tacrolimus trough concentrations 10–15 ng/mL day 0–30, 8–12 ng/mL from day 31–90 and 5–8 ng/mL from day 91.
MMF 1000 mg twice daily for days 0–30 with reduction to 500 mg twice daily from days 31–90.
prednisolone with a reducing regimen to 5 mg once daily by day 43.
· Yes Ab titer need to be monitored posttrasnplanation
first week daily.
second week twice per week.
weekly for 4 week
· Other options could be paired kidney exchange program,
Waiting for a more compatible deceased donor
Waiting for a more suitable living donor
Reference
Phanish MK, Hull RP, Andrews PA, Popoola J, Kingdon EJ, MacPhee IAM; South West Thames Renal Transplantation Network. Immunological risk stratification and tailored minimisation of immunosuppression in renal transplant recipients. BMC Nephrol. 2020 Mar 11;21(1):92.
Apart from the cutoff value would your desensitization plan differ according to the baseline titre?
Yes ,with Pretransplant desensitization. with rituximab 200mg.
Four weeks:
prior to the scheduled transplant surgery date, immunosuppression by administering
oral EC-MPS 360 mg twice daily (mycophenolate mofetil [MMF] 500 mg twice daily).
Two weeks prior to the scheduled transplant surgery date, we obtain an isoagglutinin
titer and a final crossmatch.
we plan for pretransplant plasmapheresis to achieve a goal isoagglutinin titer of ≤1:8 by
the time of transplant surgery.
achieve a goal isoagglutinin titer of ≤1:8(depend on the center).
We give IVIG 10 grams after each plasmapheresis session.
Induction therapy : rATG.
Maintenance immunosuppression:
CNI(TAC) ,MMF and prednisolone. Target higher whole-blood TAC.
8 to 12 ng/mL for the first month after transplantation
5 to 10 ng/mL for subsequent months.
Posttransplant monitoring of 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,
Yearly thereafter.
Wait suitable donors.
PKD.
DDA.
Very good
This is a donor-recipient pair ABO incompatibility (donor B, recipient A1) with high IgG anti-B antibody titres of 1:512.
A high baseline antibody titre has been shown to be associated with increased incidence of AMR.(1)
High baseline antibody with low titre reduction rate is a predictor of antibody rebound, leading to increased risk of AMR.(2,3)
But recent studies have shown that high baseline antibody titres, despite increased risk of rebound, do not have a bearing on graft outcomes, if adequate desensitization is done.(4,5)
In light of this evidence, a recipient with 1:512 antibody titres can be taken up for transplant, if CDC crossmatch and DSA is negative.
But my first choice would be either to change the donor with someone ABO compatible, or enrolling the patient in a kidney paired donation program.
The patient will require: Desensitization using
A) Injection Rituximab: 200 mg IV, 4 weeks prior to the tentative transplant date.
B) Immunosuppression: MMF 500 mg twice a day, Tacrolimus 0.1 mg/kg/day to be started 2 weeks prior to the tentative date of transplant.
C) Immunoadsorption: Using Anti-B column to reduce anti-B antibody titres to ≤1:8 prior to transplant
At the time of transplant:
A) 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). ATG has been shown to have less rejection episodes than IL-2 receptor antibody induction.(5)
B) 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.
C) CMV and pneumocystis prophylaxis should be given.
D) Anti-B antibody titres monitoring: daily for first 2 weeks, then twice a week for next 2 weeks.
No.
The recipient blood group is A (Rh +ve), while the donor blood group is B (Rh +ve). So we need to monitor anti-B antibody titres post-transplant.
First choice is to get a blood group compatible donor. If there is no other donor and the patient is not taken up for ABO incompatible transplant, he can be enrolled in a kidney paired donation transplant program. The chances of getting an early match are high in view of the B-A donor-recipient pair. The patient can also be enrolled in a deceased donor program.
References:
1) Lee KW, Park JB, Oh DK, Na BG, Choi JY, Cho WT, Lee SH, Park HJ, Cho D, Huh WS, Kim SJ. Short-Term Outcomes of ABO-Incompatible Living Donor Kidney Transplantation With Uniform Protocol: Significance of Baseline Anti-ABO Titer. Transplant Proc. 2016 Apr;48(3):820-6. doi: 10.1016/j.transproceed.2016.01.027. PMID: 27234744.
2) Won D, Choe W, Kim HJ, Kwon SW, Han DJ, Park SK. Significance of isoagglutinin titer in ABO-incompatible kidney transplantation. J Clin Apher. 2014 Oct;29(5):243-50. doi: 10.1002/jca.21312. Epub 2013 Dec 24. PMID: 24375675.
3) Baek CH, Kim H, Yang WS, Han DJ, Park SK. Clinical significance of isoagglutinin titre with the current desensitization protocol in ABO-incompatible kidney transplantation. Nephrology (Carlton). 2019 Jun;24(6):654-660. doi: 10.1111/nep.13412. Epub 2019 Apr 15. PMID: 29877001.
4) Rivera CF, Rodriguez MC, Hermida TF, Jarrin DA, Muñiz AL, Saavedra CA, García AG, Hernandez ÁA. Isoagglutinin Titers in ABO-Incompatible Kidney Transplant. Transplant Proc. 2021 Nov;53(9):2675-2677. doi: 10.1016/j.transproceed.2021.07.059. Epub 2021 Oct 2. PMID: 34610865.
5) Mohamed M, Sweeney T, Alkhader D, Nassar M, Alqassieh A, Lakhdar S, Nso N, Fülöp T, Daoud A, Soliman KM. ABO incompatibility in renal transplantation. World J Transplant. 2021 Sep 18;11(9):388-399. doi: 10.5500/wjt.v11.i9.388. PMID: 34631470; PMCID: PMC8465511.
Excellent wise as usual Amit.
will you go ahead?
regarding higher anti -ABO titre and it effect on graft out come controversial
more data needed regarding PRA ,MFI titre in this case.
If there is no alternative I will go ahead though patient will expose to intensive
immunosuopion therapy and its side effects.
check cross match (CDC&FCXM).
keep isoagglutinin titre to less than 1:32
if ,yes what is your immunosuppression plan?
there is no universal desensitization protocol,it varies between centers this one of protocol:
1- plasma pharsis one week before transplantation followed by IVIG after each session to keep isoagglutinin titre below 1:1antion.
.6 or below 1:32.before transplantation
2-Rituiximab 375 mg /m2 3 week before Transplantation
3-induction basiliximab 500mg and 250 mg
4- immunosupression therapy
Tacrolimus trough level 10-12 in first two month.
MMF 1 gm po BID
prophylaxies for CMV and pneumocystic jeroveci
if ,yes do we need to monitor the anti-A antibody titre transplantation ?
yes we need to monitor antibodies titre post renal transplantation
first week dialy or every other day.
second week twice per week.
weekly for 4 weeks
additional check if clinical indicated (after 6 weeks) since accommodation occur 3 to 6 month.
if no .what are other option ?
1-ABOc and HLA compitable .
2-paired kidney donation.
3-Deceased donor program.
References1. Magee CC. Transplantation across previously incompatible immunological barriers. Transpl Int. 2006;19:87–97. [PubMed] [Google Scholar]
2. Tobian AA, Shirey RS, Montgomery RA, Ness PM, King KE. The critical role of plasmapheresis in ABO-incompatible renal transplantation. Transfusion. 2008;48:2453–60. [PubMed] [Google Scholar]
3. Sonnenday CJ, Warren DS, Cooper M, Samaniego M, Haas M, King KE, et al. Plasmapheresis, CMV hyperimmune globulin, and anti-CD20 allow ABO-incompatible renal transplantation without splenectomy. Am J Transplant. 2004;4:1315–22. [PubMed] [Google Scholar]
Very good you considering HLA and cross match
This patient has high baseline isoagglutinin titers > 500, which is consider as independent risk factor for AMR and lower graft survival in ABOI KTX (1).
Anti-ABO IgG response was more important than the IgM response in AMR after ABOi KT [2]
he had two mismatches but no details about the PRA % and the CDCX or FXCM, as the high panel-reactive antibody (PRA) values were considered additional risk and significantly associated with the development of chronic antibody-mediated rejection (CAMR) and transplant glomerulopathy (TGP).
Will you go ahead?
If CDCXM or FXCM negative ,no DSA ,and patient don’t have alternative ABOc donor or no access to KPD program then yes we still can accept this donor after full discussion with patient about the need of desensitization before transplantation with proper counselling about the risk of desensitization including surgical complication , infection coagulopathy and also the risk of rejection due AB rebound after transplantation and the risk of intense immunosuppression if agree then will go ahead with desensitization to target the isoagglutinin titer to < 1.32 at day of transplantation .
If yes, what is your immunosuppression plan?
No specific desensitization protocol each center has their own protocols for examples the Japanese protocol and Swedish protocol targeting anti-A/B isoagglutinin titer of 16 or 32 on the day of transplant by using combination of therapeutic plasma exchange 3-5 sessions with IVIG 0.1gm/KG after each session of plex with rituximab dose range 200mg/m2 ( low dose) or standard 375mg/M2 3weeks prior to the surgery , followed by induction with basiliximab , PMP 500mg ,250mg , IVIG0.5gm , followed by triple maintenance IS with tacrolimus 0.15mg/KG with target higher trough level 10-12 first two months then 7-9ng after , MMF 500mg BID first two weeks then gradually increased to full dose 1gm BID , prednisolone 20mg then tapper to 5 mg in two months , each center have their specific protocol based on the available resources ,expertise and cost .
All patients should keep on CMV prophylaxis and PJP prophylaxes for 6 months with close monitoring with CMV PCR, BKV pcr every month first 6 months.
If yes, do we need to monitor the anti-A antibody titer post-transplantation?
Post-transplant very frequent monitoring for antibodies titer (ABs -rebound) daily in first two weeks then weekly for another two weeks, then every 3 months till 12 months, usually after the first 4weeks they will be graft accommodation with less risk of AMR. Graft biopsy once indicated or protocol biopsy depend on center policy and patient acceptance.
If no, what are your other options?
Kidney pair exchange program, or DD program for better ABO c and HLA Compatible transplant
References:
1-Koo TY, Yang J. Current progress in ABO-incompatible kidney transplantation. Kidney Res Clin Pract. 2015 Sep;34(3):170-9. doi: 10.1016/j.krcp.2015.08.005. Epub 2015 Aug 20. PMID: 26484043; PMCID: PMC4608875.
2-Toki D, Ishida H, Setoguchi K, Shimizu T, Omoto K, Shirakawa H, Iida S, Horita S, Furusawa M, Ishizuka T, Yamaguchi Y, Tanabe K. Acute antibody-mediated rejection in living ABO-incompatible kidney transplantation: long-term impact and risk factors. Am J Transplant. 2009 Mar;9(3):567-77. doi: 10.1111/j.1600-6143.2008.02538. x. PMID: 19260836.
3-Gan CC, Jalalonmuhali M, Nordin NZ, Abdul Wahab MZ, Yahya R, Ng KP, Tan SY, Lim SK. ABO-Incompatible Living-Donor Kidney Transplantation in a Developing Country: A Multicenter Experience in Malaysia. Transplant Proc. 2021 Apr;53(3):856-864. doi: 10.1016/j.transproceed.2020.10.038. Epub 2021 Jan 22. PMID: 33487455
Excellent
Will you go ahead?
First of all I will look for ABOc related donor and or I will involve him in PKD if it is possible for graft and patient survival with lower exposure to immunosuppression drugs and specially that modality is extremely expensive (1).
If it is the only option and with high waiting time on list I will proceed after discuss with the patients about highly immunological situation.
If yes, what is your immunosuppression plan?
Desensitization with PEX or nonselective IA 2 weeks before transplantation .(titer should be less than <1/16).
Rituximab two doses on day 0 and day 4 which give good out come rather than one dose (2).
With one session PEX one day before transplantation(3).
With tacrolimus based therapy (steroid / MMF/ tacrolimus) 2wks before transplantation.
If yes, do we need to monitor the anti-A antibody titer post-transplantation?
We will follow isoagglutinin antibody titers every other day in the first week post-transplant period then two to three times per week for the first month post-transplant, weekly for months 2nd and 3rd post-transplant, and then yearly after that if rising we may need another session of PEX or non-selective IA.
If no, what are your other options?
Paired Exchange Kidney program which I think it’s the best option for this situation looking for ABOc.
Compatible deceased donor kidney.
References:
1-Ray DS, Thukral S. Outcome of ABO-Incompatible Living Donor Renal Transplantations: A Single-Center Experience From Eastern India. Transplant Proc. 2016 Oct;48(8):2622-2628. doi: 10.1016/j.transproceed.2016.06.048. PMID: 27788792.
2-Hamasaki Y, Aikawa A, Itabashi Y, Muramatsu M,et al. Efficacy of 2 Doses of Rituximab on B-Cell and Antidonor Antibody and Outcomes of ABO-Incompatible Living-Donor Pediatric Kidney Transplant. Exp Clin Transplant. 2019 Jan;17(Suppl 1):105-109. doi: 10.6002/ect.MESOT2018.O43. PMID: 30777532.
3-Morath Christian, Zeier Martin, Döhler Bernd, et al,ABO-IncompatibleKidneyTransplantation,Frontiers,ImmunologyVOLUME=8,2017URL=https://www.frontiersin.org/article/10.3389/fimmu.2017.00234.
Yes, agree, well done
1.yes I will go ahead with transplant, eventhough anti-B titre is very high, but high titre is not a contraindication to transplant,which differs according to the center.
2.my transplant protocol will be-
A.inj rituximab 200mg start (as titre is more
than 1/128,inj rtx 100mg for titre <1/128) at
Day (-14).
B.Tacrolimus (0.15mg/kg) and mmf 1g/d start
at Day(-14).
C.I will go with immuneadsorption of anti-B
as the titre is more than 1/128 which will
require more than 4 sessions ,where even
Though immuneadsorption is expensive but
bit of cost-effective.
D.pretx titre should be <1/16.
E.ATG induction 3mg/kg in two divide doses.
F.triple immunesuppression maintainnance.
G.maintainance steroid 30mg/day initially.
3.yes anti-B titre should be monitored
Daily in 1st week
Thrice in 2nd week
Twice in 3rd week
Then once in a week
If renal dysfunction occurs with normal titre
Then to repeat DSA also
4.kidney paired donation.
Reference:
Chung B., Lim J., Kim Y., Kim J., Moon I., et al. Impact of the Baseline Anti-A/B Antibody Titer on the Clinical Outcome in ABO-Incompatible Kidney Transplantation. Nephron Clinical Practice, 2013;124: 79-88.
Will you go ahead?
Emerging evidences showed that high baseline titer did not show any differences in graft outcome and patient outcome in use of MMF-and Tacrolimus based immunosuppressive regimens. If there is more compatible donor, i would go for more ABO compatible but there is none, i will proceed with current transplant
If yes, what is your immunosuppression plan
Chung et al 2011 reported that if the target isoagglutinin titer was maintained below 1: 32 in the early post-transplant period, the graft survival was good.
as for protocol;
I would start Rituximab 100mg -375mg/M2 28-21 days before transplant
initiate MMF 2g /day and Tacrolimus0.1mg/kg/day at D10-14
Patient will admit a week or 2 before transplant for DFPP/IA/IVIG
If yes, do we need to monitor the anti-A antibody titer post-transplantation?
If no, what are your other options?
anti A titers or anti A/B titres tends to wax and wane, i would repeat the titre 3-6 months later
if still not possible, paired kidney donor or Deceased donor kidney
references
Chung B, H, Lim J, U, Kim Y, Kim J, -I, Moon I, S, Choi B, S, Park C, W, Kim Y, -S, Yang C, W: Impact of the Baseline Anti-A/B Antibody Titer on the Clinical Outcome in ABO-Incompatible Kidney Transplantation. Nephron Clin Pract 2013;124:79-88. doi: 10.1159/000355855
C.C. Gan, M. Jalalonmuhali, N.Z. Nordin, M.Z. Abdul Wahab, R. Yahya, K.P. Ng, S.Y. Tan, S.K. Lim,
ABO-Incompatible Living-Donor Kidney Transplantation in a Developing Country: A Multicenter Experience in Malaysia,
Transplantation Proceedings,
Volume 53, Issue 3,
2021,
Well done
What is the evidence for DFPP?
Serum IgG and IgM levels were significantly reduced after DFPP. Approximately 70% of IgM and 60% of IgG were removed by one DFPP treatment.
The anti-ABO IgM antibody levels were reduced from 4.44 to 1.0, which was significant, and the pretransplant level was sufficiently low to perform successful ABO-ILKT.
The anti-ABO IgG levels were reduced from 8.0 at preDFPP to 4.4 at the time of transplantation. The pretransplant anti-ABO antibody titer was good enough for us to successfully perform ABO-ILKT.
The graft survival rate was 97%
DFPP was designed to selectively remove the immunoglobulin fraction from serum and, as a result, to minimize the volume of substitution fluid of 8% albumin solution required.
Obviously, using this technique, albumin is not removed from the serum. Consequently, the need for albumin replacement is reduced. In this procedure, we usually use 0.5– 1.0 L of 8% albumin solution as the replacement fluid. This is equivalent to the 2.5–5.0 L of albumin solution or fresh plasma used in regular plasma exchange. Theoretically, albumin cannot be removed during DFPP because the molecular weight (Mw) of albumin is only 66,000 and much lower than that of both IgG (Mw 146,000) and IgM (Mw 970,000). Our data clearly show the effectiveness of removal of both IgG and IgM with minimization of albumin removal from the serum.
Double-Filtration Plasmapheresis Kazunari Tanabe
4. A 41-year-old CKD 5 male, blood group A1 (Rh +ve) who received a kidney offer from his cousin who is blood group B (Rh +ve). The recipient anti-B IgG antibody titre is 1/512. 110 mismatch.
Will you go ahead?
A high baseline ABO antibody titer is no longer a contraindication for successful renal transplant in ABO-i pairs.
But most programs exclude patients with high titers & consider other options like PKD.
Whether baseline antibody titer affects the graft outcome is debatable:
– Some centers reported high rates of AMR & early graft loss in those with high baseline titers. This was attributed to a rebound of post-transplant anti-ABO antibodies.
– The strongest predictor of graft outcome was considered to be baseline antibody titer.
– Successful ABO-i KTs with high antibody titers are reported. The highest titer without splenectomy was =>1: 2048, using 2 doses of Rituximab, 200 mg/body on days –14 & –7 & 2 doses of basiliximab 20 on day 0 & day 4. Antibody removal was done by PP & triple IS (Tac (0.2 mg/kg) & MMF (1000 mg) & steroids)).
– Graft & patient survival outcomes were excellent.
In Japan, 3 patients with titers >1: 512 underwent successful ABO-i KT after pre-transplant 2 doses of Rituximab at 150 mg/m2, 6–8 sessions of PP, Basiliximab induction, & Tac-based triple IS. Splenectomy was done on the day of transplant.
Chung et al. compared outcomes of high & low baseline antibody titer groups (>1: 256 & <1: 126). The target pre-transplant titer was kept at below 1: 32. It was concluded that if the titer was maintained < 1: 32 in the early post-transplant period, the graft survival was good. Graft & patient survival were similar both groups. There was no episode of AMR in any group.
The preconditioning protocols were more intense in patients with high baseline titer. At some centers, splenectomy or a combination of Rituximab with splenectomy was used for patients with high baseline titers.
In the study done by Chung et al., splenectomy was not done, but recipients with baseline antibody titers >1: 1024 were given Rituximab in the dose of 375 mg/m2 twice or Rituximab was administered once & Bortezomib twice before transplant.
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If yes, what is your immunosuppression plan?
A simple preconditioning protocol including PP, IVIG, Rituximab, & ATG induction & a triple Tacrolimus-based IS regimen.
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If yes, do we need to monitor the anti-A antibody titre 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.
Due to the prolonged effect of Rituximab, B cells remain suppressed for many months, preventing AMR & permiting transplant across the blood group barrier in recipients with high titer.
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If no, what are your other options?
PKD
Combined PKD & desensitization.
Wait for a deceased donor kidney.
References
© Am J Case Rep, ABO-Incompatible Renal Transplantation with High Antibody Titer: A Case Report 2017; 18: 1073-1076
DOI: 10.12659/AJCR.905633
Thank you.
Why is it from Japan?
Will you go ahead?
Group B antigen expression is lower than A1, but still higher than A2. As the patient has a low mismatch for HLA, I would consider a desensitization protocol for a drop in anti-B IgG antibody levels (less than 1/32) for transplantation.
I suggest plasma exchange (at least 20% drop expected) associated with rituximab and IVIG
If yes, what is your immunosuppression plan?
rATG for induction, and elevated doses of tacrolimus, MMF, and prednisone
If yes, do we need to monitor the anti-A antibody titre post-transplantation?
Yes, it is a high-risk patient and needs to be monitored with DSA, antiagglutinnin, and protocol biopsies
If no, what are your other options?
Kidney paired exchange
Wait for a more compatible deceased donnor
▪︎Will you go ahead?
There is a very high titre of anti B IgG which is great risk for hyperacute rejection it is not contraindicated but I will reconmmed more compatible donor.
▪︎If yes, what is your immunosuppression plan?
desensitization with plasmapheresis, IVIG, Rituximab to achieve low and acceptable antibody titer below if the isoagglutinin titer was maintained below 1: 32 in the early post-transplant period, the graft survival was good.
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,
triple maintenance immunosuppression with Tac trough level maintained at 8–10 ng/ml for the first few weeks after transplantation. , MMF, and steroids.
The anti-B antibody titers were measured every day for the first 2 weeks after transplantation. The frequency was reduced to 3 times a week in the next 2 weeks, weekly for next 2 months, and fortnightly for 3 months, then monthly for 6 months.
▪︎If yes, do we need to monitor the anti-A antibody titre post-transplantation?
Yes,monitoring is highly recommended to detect rebound increase of antibodies ,protocol biopsies to detect early or subclinical rejection
▪︎If no, what are your other options?
Paired Kidney Donation to find more compatible donor
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?
No as it’s ABOi transplant with very high isoagglutinin titer of 1/512
If yes, what is your immunosuppression plan?
If forced to proceed I think we need to give
Rituximab at least one week before
Immunoadsorption followed by IVIG to bring down the isoagglutinin titer to around 1/8.
Induction with basiliximab and tripple immunosupression protocol would be needed that includes Tacrolimus, Mycophenolate and prednisolone
Vigilant post transplant isoagglutinin titer monitoring would be needed initially daily then twice weekly and the weekly for three months.
Best option would be to be part of paired exchange program
Or deceased donor program with allocation system
No, this is a very high anti-ABO ab titer, I don’t think it is amenable for desensitization.
First desensitization with DFPP, IVIG, Rituximab to achieve antibody titer of less than 1:8, induction with ATG, some centers use basiliximab, triple maintenance IS consist of tac, MMF, and steroids. monitoring of IgG levels in the early post-transplant period.
Yes, a rebound could happen and this will increase the risk of rejection.
There is ABO incompatibility with high, anti- B antibody titer of 1/512. HLA antigen profile is showing class I antigen 2 mismatchs. But no class II antigen mismatch.
2 options are there:
Due to high risk of acute AMR ,PKD is an option ,to get a compatable ABO donor.
The other option is to undergo a desensitization protocol pre transplantation to minimize the B antibody titer from 1/512 to the acceptable level 1/8 to 1/32.The protocol , I would consider North European protocol in this context ,which include Immune Adsorption IA and high dose IVIG 2 gms/kg, avoiding Rituximab ,due to higher risk of infection and malignancy related to oversuppresion in one hand and due to a comparable result In the other hand.Target antibody titer is 1/4 pre-transplant.
Post transplant IA procedure is not routinly considered, but depend on level of Antibody titer which will be assessed daily over the post transplant first 2 weeks, after which the risk of rejection is much less due to the phenomenal poorly understood Accomodation process, in which allograf tolerance is established.
Immunosuppressive protocol should include induction with Basiliximab and maintenance ,Tacrolimus dependent ,include MMF and prednisone.
Reference:
Tai yeon koo and jaeseok yank.current progress in ABOi kidney transplant.kidney Res clin pract. Sept 2015.
Regarding DSAs I will recommend CDC and FCX, and plan according to the result to stratify risk of rejection,
Case Scenario IV
A 41-year-old CKD 5 male, blood group A1 (Rh +ve) who received a kidney offer from his cousin who is blood group B (Rh +ve). The recipient anti-B IgG antibody titre is 1/512. 110 mismatch.
Will you go ahead?
No, his isoagglutinin Ab titer is very high >= 1:256. So, the patient is at high risk of ABMR.
If no, what are your other options?
Paired exchange kidney program
Kidney allocation system.
Will you go ahead?
I will not transplant this patient as the patient is ABO incompatible with the very high isoagglutinin titer i.e., >1:256 (1/512)which is not feasible and acceptable for desensitization due to high risk of ABMR.
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 ≤1:8)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.
Target is to reach isoagglutinin antibody titer of ≤1:8 before transplantation
INDUCTION: r-ATG, some centers recommend Basiliximab.
Maintenance immunosuppression is Tacrolimus based triple immunosuppression, along with MMF(started 1 month prior in a dose of 500 mg BD) and steroids.
Ntiviral 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 titre post-transplantation?
Close monitoring of isoagglutinin titers daily till discharge form 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?
Paired Exchange Kidney program
Deceased donor program through kidney allocation system
REFERENCE:
1- Tobian AA, Shirey RS, Montgomery RA, et al. ABO antibody titer and risk of antibody-mediated rejection in ABO-incompatible renal transplantation. Am J Transplant. 2010 May;10(5):1247-53.
No
I will consider this offer to carry a high immunological risk.
We can argue that different desensitization protocols may allow transplantation across the ABO barrier. However, 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 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?
Although, the protocols among different centers and different countries vary as Japan, Europe and USA, the common issue is that the pretransplant isoagglutinin titers (baseline) should be no more than 1:256 in order to proceed with desensitization thrapy and have at the end acceptable pretransplant titer,which is not the case in this clinical scenario. So having at baseline antibody titer of 1:512 exclude the patient from surgery. The patient must be also willing to undergo ABOI transplantation and all the therapies associated with ABOI transplantation.
If yes, what is your immunosuppression plan?
If the transplant center policy accepts his baseline isoagglutinine titer and 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 anf for deep immunosuppression having immunomodulatory effects.
Induction therapy is center bases so basiliximab or r-ATG are given but with this risk, and with the potent T cell depleting function of r-ATG, I would proceed with antithymoglobulin, because T cells play a great role in activation o B cells and subsequent maturation into plasma cells and antibody production.
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 post-transplantation?
To extrapolate from ABOi transplantation and pretransplant titers of 1:256 and subsequent reduction to below 1:8 which is acceptable by most centers, we should monitor the anti-A antibodies on daily basis during hospitalization, 3 times per week for the first month and the weekly for 3 month. If Any signs of renal function deterioration appear, we should measure the titer and do kidney biopsy.
If no, what are your other options?
Alternative options are Paired Exchange Kidney program and deceased donor kidney through allocartion program