4. A 44-year-old CKD 5 female, blood group A1 (Rh – ve) who received a kidney offer from her cousin who is blood group B (Rh – ve). The recipient anti-B IgG antibody titre is 1/256 his IgM 1/128. 020 mismatch. There are non-DSA antibodies (against HLA-A2 with MFI 10,000 and HLA-B8 with MFI 5500) due to pregnancy and blood transfusion.
- What is the relevance of IgM in ABOi transplantation?
- 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?
When is biopsy indicated in the ABOi transplantation?
A. Rise of s creatinine by 10% of the baseline
B. The appearance of proteinuria
C. The appearance of DSA is an absolute indication of biopsy
D. Positive urine PCR for BKV
E. CMV viraemia
Answer: B
Fluctuation of serum creatinine is considered within the normal range if it is in the range of 10 to 15% rise. Most of the DSA post-transplantation disappear without any immunological damage. Proteinuria is a clear indication for biopsy and also significant deterioration of the kidney function (>15% rise in creatinine). The rise of ABOi antibody titre to 2 dilutions or more is another indication of biopsy
Dear All
What about the Paired Exchange Scheme in the
index case? what is the success rate if you decided to go into Paired Exchange
Scheme?
It is one of the options for this patient, but the problem is this patient has antibodies against HLA-A2 which is a very common antigen in the population( 48% of the population have this antigen). So it will be difficult to find a compatible donor.
Excellent Huda, you are the only one who noticed this so far. Well done, very impressive. You put an effort to read before answering the question
thank you
Dear Huda ,
The antibodies against HLA A2 in this case is non-DSA , would it carry the weight as HLA-A2 DSA ?
in other words, Does both non-DSA & DSA affect the decision for PKD or only DSA is important ?
Of course, these DSA or non-DSA will limit the number of donors the recipient will be matched to
Hi Ben,
As Prof Halawa said, It is a matter of matching and you can review Dr. Ala lecture, he talked about the effect of common antigens.
Those that are sensitized like our patient ,
and/or are blood type O have match rates as low as 15%.
REFERNACES:
Thomas A. Pham et al .Kidney paired exchange and desensitization: Strategies to
transplant the difficult to match kidney patients with living donors. Transplantation
Reviews 31 (2017) 29–34.
Yes paired exchange scheme is possible , but this will basically depend on the PRA % which is not shown in this example. Recipient with PRA % > of 97.5% will have around 15% chance of getting into paired exchange donors pool
In the above case putting matters simply would go as:
ABOi recipient is A
donor is B
So antibodies to be closely followed are anti B isoagglutinins
HLA incompatibility is:
no DSA
non DSA A2 ,DSA B8
Non DSA are not without danger but not as DSA
so following non DSA titre is needed but definitely not as the anti B isoagglutinins.
To me, ABOi transplantation is not an option in the index case due to the high titre.
Also, you look always keen to use ATG as an induction agent here, It is not the right approach, think of Rituximab which is appropriate in ABOi transplant.
What about the paired exchange scheme in this case?
Do you think it would be successful?
Yes ABO-incompatible transplantation, in this case, is associated with a high risk of ABMR so it is not the ideal option in this case
But also KPD will be challenging in this case and the patient may not receive an acceptable offer and may wait for a long time to be transplanted due to the following :
The selection between basiliximab and ATG will be according to how we define transplantation risk irrespective of ABO compatibility, if we consider the presence of high PRA and the presence of high level of non-DSA as risk factors for ABMR so I will use ATG and actually the data in this issue is misleading
So … from my understanding that the right is not to consider third party antibodies by itself as a risk factor for transplantation if there are low HLA mismatches, no DSA and negative crossmatch and its significance relies mainly on before transplantation (to decide the right donor)
REFERENCES
1- Opelz G, Collaborative Transplant Study. Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies. Lancet 2005; 365:1570
2- MorathC,Döhler B, KälbleF, et al. Pre-transplant HLA Antibodies and Delayed Graft Function in the Current Era of Kidney Transplantation Front. Immunol., 26 August 2020.
3- Jun, K.1; Kim, M.1; Hwang, J.1; Park, S.1; Moon, I.1; Lee, M.1; Kim, S.2; Kim, J.1. Impact of Pre-Transplant PRA Level On Renal Graft Survival in Patients With Negative Cross-Match and No Donor Specific Antibody. Transplantation: July 15, 2014 – Volume 98 – Issue – p 463
4- Perasaari JP, Kyllonen LE, Salmela KT, Merenmies JM. Pre-transplant donor-specific antihuman leukocyte antigen antibodies are associated with high risk of delayed graft function after renal transplantation. Nephrol Dial Transplant. (2016) 31:672–8
I put these 2 HLA antigens in cPRA calculator and i found that cPRA is 58% (HLA A2 48%, HLA B8 17 %) which is acceptable, thus there is a good chance in KPD so the best option will be
the chance to find a compatible donor with negative cross match is 42% which is acceptable
Thank you, Sherif, for this excellent reply. You are the first one to mention the cPRA calculator. You excluded more than 50% of the population by having this non-DSA; therefore the chance is not that good
I think it will be successful as finding a comptable ABO donor is prefered to exposing the donor for the risk of desensitization protocol and the risk afterwards. Regarding the NDSAs, It want be precluding factor as its of debatable significance.
paired exchange depend on matching and PRA %
if HLA-A2 match so patient can receive
PK exchange with desensitizing for other mismatch
Although kidney paired donation (KPD) or paired exchanage scheme is one option for highly sensitized patients and ABO incompatible transplantation, the anti HLA A2 is a common antigen, and it is difficult to find compatible donor.
So desensitization may be preferred in such case to minimize waiting time and further sensitization.
1) What is the relevance of IgM in ABOi transplantation?
it is associated with type 2 antibody medicated rejection which gradual in onset.
2) Will you go ahead?
Nope.
3) If yes, what is your immunosuppression plan?
Desensitization with plasmapharesis and IV IG.
Induction ATG
Maintenance Tacrolimus base immunosuppressants.
4) If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
Yes
5) If no, what are your other options?
Paired kidney donation.
What is the relevance of IgM in ABOi transplantation?
It is not clear yet,IgG is most important
Will you go ahead?
No, we should did desensitization by plasmapheresis and rituxmab as this patient has ABOi and high MFI of non DSA which made her had high risk for transplant
If yes, what is your immunosuppression plan?
ATG induction with triple immunosuppressive medication include Tac, MMF and predinsilone
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
Yes we need frequent check to gard against any antibody mediated rejection
If no, what are your other options?
Deceased donation or paired exchange
What is the relevance of IgM in ABOi transplantation?
It’s unremarkable
It’s still unclear if IgM antibody associated with ABMR, Also It’s easily removed by plasma exchange
Will you go ahead?
Yes but should be under going to desensitisation protocol
If yes, what is your immunosuppression plan?
Double filtration plasma exchange with pulse therapy of steroid and intravenous immunoglobulin plus rituximab
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
Yea we need to monitoring DSA level and anti-B antibody titre
If no, what are your other options?
PKD (Paired kidney donation)
I don’t know actually but it may give another clue about incompatibility with IgG
It has high risk to loose the graft so I will not go ahead
Needs desensitization with PE, IVIG , rituximab and monitor the level of abs
Yes we need that
Paired excagnge program although it is not easy to find a suitable donor
What is the relevance of IgM in ABOi transplantation?
IgM and IgG Ab to non-self ABO antigens develop during the first few years of life. IgM staining can be seen in peritubular capillaries in cases of rejection post transplant.One-hour postperfusion biopsies have shown C4d in 57% of ABOi grafts, usually also with IgM (88%) and occasionally with IgG (40%)1 .
Will you go ahead?
Yes I wil proceed for transplantation despite of ABO incompatibility and non-DSA antibodies.
Graft survival rates for ABOi grafts are almost similar to ABO-compatible grafts, with 1-year Graft survival rate of 95% and 5-year graft survival rate of 91%1.
If yes, what is your immunosuppression plan?
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
The one to be monitored is the anti-B( against the donor Ag, )No need to monitor the anti-A antibody titer as there’s no or low expression of A-antigen on tissues of individuals with blood group A2. Adding to that no late rebound after removal of formed antibodies to ABO-antigens.
If no, what are your other options?
Options include:
(1) being placed on the deceased donor waiting list
(2) entering a paired living donor program
(3) undergoing a desensitization protocol and receiving the ABO-incompatible living donor kidney despite the presence of antidonor antibody.
Reference
Not clear, still needs more research
no
Desensitization: Plasma exchange, IVIG, Rituximab. Till titer less than 1/32.
Induction: ATG or almtuzumab
Maitenanace: Tac+steroids+MMF
YES, daily for first 2 weeks then twice weekly for another 2 weeks.
If no, what are your other options?
Paired kidney exchange
1. Regarding ABO incompatible transplantation, the main antibody titer accused and usually measured to assess the risk of hyper_acute rejection is IgG. However, IgM is easily removed through plasmapheresis and the available data till today suggest that it is of low significance.
2. This offer has 2 obstacles:
_ ABO incompatible with high Anti B titer 1/256.
_ HLA mismatch and presence of non DSA. Although non DSA are less significant in Acute rejection, they are still accused in poor graft function and mortality. DSA MFI titer of more than 2000 in HLA class I is of high risk of rejection.
So, for this case better not to proceed, is no other available option, desensitization protocol is a must.
_ desensitization with plasmapheresis, IVIG and rituximab till achieving anti B titer of 1/8 and negative FCXM to allow a window for transplantation.
3. The suggested immunosupressives here is induction with ATG then followed by tacrolimus based triple maintenance immunosupressives together with steroids and MMF
_ targeting higher tacrolimus therapeutic window of 8_10 mg/ml and high dose of MMF of 2 gm/day together with steroids.
Steroid free protocol should be avoided here.
_ CMV and PJP prophylaxis for at least 3 months in such patient after desensitization and strong immunosupressives.
_ close monitoring of DSA titer and anti B iso agglutinin ( as rebound can occur post transplant ) together with close follow up of the graft function and tacrolimus trough level are mandatory.
_ protocol biopsy for early detection of subclinical rejection and its treatment seems to improv long term graft outcome.
3. I will measure anti B isoagglutinin titer, daily in 1st week then weekly for a month then every month.
4 . Better options for this patient to avoid complications and minimize risk of desensitization protocols are:
_ KPD ( kidney paired donation) to getter better matched donor in LDKT( living donor kidney transplantation).
_ prioritization in KAS ( kidney allocation system ) in deceased donor transplantation.
_ acceptable mismatch ( after defining unacceptable antigens).
Although not of the caliber of IgG , they are considered relevant in this regard.
Not directly ahead
We should start a desensitisation protocol with Aphresis ( PLEX or DFPP or IA ) + Rituximab + IVIG aiming for an isoagglutinin titre of < 1/32 , induction with basiliximab & maintenance with Tac based triple Rx
Also DSA monitoring is also mandated regularly at 1 , 2, 4 8, weeks,3 months , 6 months 12 months
enroll in PKD or consider another living donor with a better match , or to wait for a deceased donor
Relevance of IgM in ABOi transplantation
IgM antibodies ave a role in diagnostic and therapeutic application for preventing AMR.
Going for transplant or not
Yes i will go for transplant, with desensitization protocol – plasmapheresis and rituximab prophylaxis in order to reduce antibody response.
Immunosuppression plan
ATG induction therapy, MMF, prednisone, tacrolimus.
Monitor
Monitor anti B antibody Titre and serum creatinine
Other options
References
The role of IgG is well established but IgM is still not clear and needs more studies. In clinical practice most of the centers ignore it
Regarding this high titer of IgG 1:256, most of the centers will reject the donor with no attempt to desensitize the recipient but in the case of accepting the donor the recipient should undergo heavy desensitization using plasma exchange, IVIG and rituximab till we reach the accepted anti b titer accepted as per center protocol which usually ranges from 1:8 to 1:32
According to mismatching 020 and suppose to have FCXM -ve and -ve DSA, so induction can be done by basiliximab plus 3 maintenance IS (tac + MMF +steroids)
Yes, we need to monitor anti-B titer daily for the 1st 2w then twice weekly for the 2nd 2w, there is no need to do it anymore.
Paired kidney exchange can be offered but according to the presence of anti-HLA antibodies against the common antigen (A2) and his PRA will be around 50% it will not be an easy task.
What is your consideration plan for the non DSA antibodies in this case?
The antibody titer is high for both IgM and IgG but IgM class is less significant than IgG in ABOi kidney transplantation.
This patient need desensitization : removal of circulating antibodies by double filteration plasmapheresis or immunoadsorption technique.
IVIG therapy
Rituximab for B cell depletion
TAC, MMF and prednisolone maintenance
Monitoring of the anibody titer is important for risk of rejction if rapidly increased
Other choice is to look for paired kidney exchange
What is the relevance of IgM in ABOi transplantation?
There are well-defined reports of the role of IgG in transplantation in ABOi patients, but the role of IgM is not well established.
Will you go ahead?
It would need an important desensitization process, with plasmapheresis, immunoglobulin, and rituximab. If the MFI values and titers decrease, I would proceed with the transplant and aftercare.
If yes, what is your immunosuppression plan?
Tacrolimus high doses, MMF, and prednisone
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
Yes, for bot
If no, what are your other options?
Kidney paired donation program and Unacceptable antigens
You need to monitor the anti B antibodies closely early post Tx as per center protocol.
The relevance of IgM in ABOi transplantation:
Many articles concluded that the presence of Ig G antibodies is strongly related to the occurrence of ABMR and DSA being of more antigen specificity and affinity while Ig M are known to be nonspecific and has no role in developing ABMR post renal Tx(but this is not thoroughly investigated whereas recent articles suggest that there are two categories of IgM classes ; class developed from B1cells which is nonspecific and class developed of B2 which is of high specificity and antigen affinity and can share in ABMR).
however this hasn’t been an obstacle for renal transplantation up till now and still urges to perform many studies.
Matsuda, Y.; Hiramitsu, T.; Li, X.-k.; Watanabe, T. Characteristics of Immunoglobulin M Type Antibodies of Different Origins from the Immunologic and Clinical Viewpoints and Their Application in Controlling Antibody-Mediated Allograft Rejection. Pathogens 2021, 10, 4. https://doi.org/10.3390/pathogens10010004
Will you go ahead?
It would wise not to proceed in this renal transplantation unless good desensitization should be performed,
If yes, what is your immunosuppression plan?
Desensitization mainly by:
Rituximab, from 5 to 7 plasmapheresis to achieve a negative flowcytometry crossmatch and IVIG according to the centre’s protocol.
However this patient may require repeated desensitization programme as A2ia a common domain in Caucasian, and Arab population.
Reaching an ABO titre less than 1l8, and calculated PRA should be of permissible level in order to proceed, plus triple immunosuppression (tacrolimus based) and induction by alemtuzumab or eculizumab or ATG would be mandatory for her case.
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
We have to monitor anti B antibodies as her cousin is blood group B ,DSA titres should be monitored according to transplant centre schedule 1,3 6 and 12 months post-transplant.
Also denovo DSA should be considered as this is a high risk patient.
Other option:
is to enroll to a paired kidney donation programme to achieve a more suitable donor or deceased kidney donation programme , meanwhile treatment of anemia should be targeted to abolish any need for blood transfusion and more sensitization and this viscous circle should be stopped.
Renal replacement therapy as dialysis option to be counselled with the patient and vascular access establishment as matching a more suitable donor in terms of anti A2 would be difficult.
Very good
REFERENCES
Well done
What is the relevance of IgM in ABOi transplantation?
The role of anti IgM in ABO I transplantation is not well established but still few studies conducted revealed IgM titers (1:64) to be associated with early acute rejection .However, IgG role well documented in ABOi transplantation and the cut off should be less than 1/ 8 to proceed for transplantation.
Will you go ahead?
No, as the patient is a high risk case having anti-B IgG antibody titer 1/256 and IgM 1/128.
If yes, what is your immunosuppression plan?
The patient can go for transplantation only with desensitization strategies :i.e., Rituximab 04 weeks before transplantation,5 sessions of plasmapheresis(1.5 plasma exchange ) with this level of titers followed by low dose IVIG to reach 1:8 before transplantation, Induction therapy with ATG and maintenance therapy with triple immunosuppressive regimen including Tacrolimus (keeping higher trough levels (10-12 ng/ml )- antimetabolite (MMF)), prednisolone along with CMV and PCP prophylaxis.
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
Monitoring anti-B antibody titer 2-3 times per week for the first month post transplant, weekly for months 2 to 3 post transplant, and then yearly thereafter.Recommendation is to keep antibody titer ≤ 1:16 during the first two weeks post transplant in ABOi transplant. DSA to be monitored 1, 3, 6, and 12 and then annually post transplant if there is graft dysfunction.
If no, what are your other options.
Wait for a suitable donor
Or PKD (though it will be difficult due to unacceptable antigen HLA A2)
REFERENCE:
1-Salvadori M, Tsalouchos A. Current protocols and outcomes of ABO-incompatible kidney transplantation. World J Transplant 2020 July 29; 10(7): 191-205
Well done
Although it has been seen that IgG is the primary risk factor in ABO incompatible kidney transplantation, IgM has also been shown to be relevant in ABO incompatible transplants.(1,2) IgM has been shown to be associated with type II AMR in ABO incompatible transplants which is characterized by less severe and insidious rejection.(3) IgG causes type I AMR in ABO incompatible transplants due to the direct stimulation of immune system by the graft causing explosive rise in antibodies in the early, critical period.(3)
This case pertains to combined ABO incompatibility and presence of third-party antibodies.
The anti-B antibody titres are 1:256 (IgG) and 1:128 (IgM) 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.
The HLA typing revealed 020 mismatch, which is good.
Presence of third-party antibodies: Although non-DSA, still anti HLA-A2 with MFI 10000 and anti HLA-B8 with MFI 5500 are present.
In presence of high anti-B antibody titres, this transplant should be avoided.
We also need to know about the crossmatch results.
No. I will not accept this donor.
I will not accept this donor.
If I have to accept this donor, and if the crossmatch is negative, then the patient will require desensitization with Plasmapheresis and IVIG and rituximab to achieve an anti-B 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.(4)
1) Induction therapy: Injection Basiliximab, in view of good HLA match (020 mismatch)
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.
CMV and pneumocystis prophylaxis should be given.
Post-transplant, patient requires close follow-up with clinical and laboratory evaluation.(4)
i) Complete blood count, urine examination and serum creatinine. Tacrolimus trough levels to be monitored.
ii) Anti-B 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) Antibody testing: Once in first three months, then annually or whenever there is any graft dysfunction, alteration in immunosuppression or suspicion of non-adherence.(5,6)
v) Protocol biopsy: Once in first three months.(5) If the biopsy shows features of AMR, it should be treated.
No. We do not need to monitor Anti-A antibody titres post-transplant.
The donor blood group is B, so we need to monitor anti-B 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-B antibody titres.
The other options available in this scenario include:
a) Change the donor to someone who is compatible (ABO and HLA)
b) Enrol in kidney paired exchange program to get a better match kidney, both regarding anti-HLA and anti-blood group antibodies. Although it would be difficult in view of presence of anti HLA-A2 antibodies with high MFI as HLA-A2 is very common. But desensitization of such patients could be better than desensitization for ABO incompatibility if the DSA-RIS is low.
c) Wait for a better matched offer through the deceased donor program
References:
1) Matsuda Y, Hiramitsu T, Li XK, Watanabe T. Characteristics of Immunoglobulin M Type Antibodies of Different Origins from the Immunologic and Clinical Viewpoints and Their Application in Controlling Antibody-Mediated Allograft Rejection. Pathogens. 2020 Dec 23;10(1):4. doi: 10.3390/pathogens10010004. PMID: 33374617; PMCID: PMC7822424.
2) Kim H, Choe W, Shin S, Kim YH, Han DJ, Park SK, Kwon SW, Ko DH. ABO-incompatible kidney transplantation can be successfully conducted by monitoring IgM isoagglutinin titers during desensitization. Transfusion. 2020 Mar;60(3):598-606. doi: 10.1111/trf.15672. Epub 2020 Jan 20. PMID: 31957888.
3) Takahashi K. Recent findings in ABO-incompatible kidney transplantation: classification and therapeutic strategy for acute antibody-mediated rejection due to ABO-blood-group-related antigens during the critical period preceding the establishment of accommodation. Clin Exp Nephrol. 2007 Jun;11(2):128-141. doi: 10.1007/s10157-007-0461-z. Epub 2007 Jun 28. PMID: 17593512.
4) 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
5) 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.
6) 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.
Thankyou Amit for emphasizing the measurement of anti B antibodies frequently and also the non DSA ones but not as frequently.
What is the relevance of IgM in ABOi transplantation?
Numerous studies have proven that anti-ABO IgG titers to be important and recommended titre value of less than 1:8 using in direct anti-globulin test. The data on anti-IgM antibodies are scarce, however some evidences showed that increased IgM titres more than 1:64 is shown to have early rejection and TMA. In contrary tom this, other studies shown no evidences of AR or TMA in the presence of anti-ABOi IgM antibodies.
IgM is large molecules and has small volume distribution, plasmapheresis could remove it with ease and rebound of titre is less of the concern, however few studies did prove that role of IgM in rejection.
Will you go ahead?
No, it’s a high risk transplantation with ABOi and presence of non-DSA ( third party DSA to HLA 1). I would suggest enrol in kidney exchange program.
Patient has not been started on dialysis and this is preemptive transplant, which is good for patient and graft survival, but High risk ABOi transplant with high MFI Non-DSA HLA type 1 (A2-10,000 and B8-5500) in the era of Kidney Paired donation program(KPDP) is something unwise to do. Third party DSA have been associated with worse graft outcome. Emerging data reassured that KPDP can safely and effectively facilitate transplantation for kidney transplant candidates in incompatible living donors. In UK there is steadily decrease in ABOi Kidney transplantation from peak of 99 procedures in 2012-2013 to 34 procedures in 2018-2019 attributed to National Living Kidney Sharing scheme incorporating every kidney transplantation centre in the country.
However, it is to be understand that Kidney paired exchange only successful in half of them who enrolled in the scheme. The failure of finding a successful match within a year of entry significantly reduces the probability of subsequent chances.
Another method can be employed to increase the chances in KPDP is desensitisation then enrol in kidney paired programs.
If yes, what is your immunosuppression plan?
Desensitisation
1-B cell immunomodulation
Rituximab as anti B cell has been shown to have comparable deat censored graft and patient survival to ABO-CRT in first year
2-Antibody removal
DFPP/IA- I would like to chose ideally, IA if possible with expense of cost to the health care.
SePE-new modality using smaller pore size membrane plasma separator but less efficient in removal of isoagglutinin titres.this method may not suitable for this patient.
3-Immunomodulator
IVIG- inhibit autoantibodies from binding to their specific Fc portion of receptors. However there is potential disadvantages of IVIG is that ABO antibodies are contained in the available preparations which can induce a temporary increase in titers.
Induction agent
rATG is the chose for induction together with methylpred due to presence of non DSA antibodies. Malheiro et al showed non ATG NDSA had adverse survival impact in non -ATG induced patients
Maintenance therapy with tacrolimus , MMF and prednisolone started 7-10 days prior to transplant.
If Yes, Do we need to monitor the anti-A antibody and the DSA post transplantation?
Yes , Anti A antibodies need to be monitored up to 2 weeks where till accommodation process happens then the Anti-A titres might not relevant to rejection.
Although its non-DSA antibodies, it is known to have poor graft outcome, so DSA monitoring is vital.
If NO, what are your other options?
No, it’s a high risk transplantation with ABOi and presence of non-DSA ( third party DSA to HLA 1). I would suggest enrol in kidney exchange program.
Patient has not been started on dialysis and this is preemptive transplant, which is good for patient and graft survival, but High risk ABOi transplant with high MFI Non-DSA HLA type 1 (A2-10,000 and B8-5500) in the era of Kidney Paired donation program(KPDP) is something unwise to do. Third party DSA have been associated with worse graft outcome. Emerging data reassured that KPDP can safely and effectively facilitate transplantation for kidney transplant candidates in incompatible living donors. In UK there is steadily decrease in ABOi Kidney transplantation from peak of 99 procedures in 2012-2013 to 34 procedures in 2018-2019 attributed to National Living Kidney Sharing scheme incorporating every kidney transplantation centre in the country.
However, it is to be understand that Kidney paired exchange only successful in half of them who enrolled in the scheme. The failure of finding a successful match within a year of entry significantly reduces the probability of subsequent chances.
Another method can be employed to increase the chances in KPDP is desensitisation then enrol in kidney paired programs.
References
1-Who Benefits From ABO-Incompatible Kidney Transplantation in the Contemporary Era? Adnan Sharif
2-Renal Transplantation Across HLA and ABO Antibody Barriers: Integrating Paired Donation into Desensitization ProtocolsRobert A. Montgomery
3–Latest insights on ABO-incompatible living-donor renal Transplantation Junji Uchida
Dear All
You should always think when you see DSA of the following:
1. Class I or Class II (they behave differently)
2. MFI level
3. Rare or common
What is the relevance of IgM in ABOi transplantation?
Isoagglutinin both IgG and IgM can hindered the ABOI kidney transplantation ,more with isoagglutinin IgG predictors of isoagglutinin rebound post transplantation and its associated risk of AMR includes the high initial isoagglutinin titer like in this index case ,low titer-reduction rate with desensitization ,short interval time between rituximab and first plasmapheresis session ( < 7 days ), and blood group O recipients .
Blood group A consist of A1, A2, majority of US blood group A express A1in 80%
the ABO blood subgroup A2 expresses lower levels of A antigen on the cell surface and is less immunogenic toward anti-A immunoglobulin present in blood type O or B recipients.
A1 and B blood group donors are considered “major,” and A2 donors “minor” So A2 kidneys can be safely transplanted into O or B recipients with low preoperative titers of isoagglutinin <1:16 was acceptable without desensitization .and shortening the waiting list for such specific blood groups (B, O)
While A1-incompatible kidney transplantation occurs only in living kidney transplantation and requires desensitization protocols using plasmapheresis, intravenous immunoglobulin (IVIG), rituximab.
some data show a high incidence of early acute rejection or thrombotic microangiopathy in A2 to O kidney transplants with high recipient anti-A IgM titers despite low IgG titers.
Steps to lower anti-IgM pre-transplant may reduce the risk of early allograft dysfunction in A2 to O or B kidney transplants. Attention should be paid to IgM titers in establishing individual center selection criteria for A2 to B kidney transplants under the new UNOS kidney allocation system (3).
Non-DSA in previously sensitized patient like this case should be carefully assessed
Non-HLA – DSA classified to alloantibodies or autoantibodies that can react with different polymorphic antigens not related to the donor and use different ways to cause endothelial injury, they are not express by lymphocytes so considered as diagnostic challenge as third parity but still can be associated with early AMR and graft loss in previously sensitized recipient like our case .
Will you go ahead?
No better avoid and try to find another donor by KPD or kidney allocation system for better compatible and matched donor
also we need to know about the FXCM if positive with MFI > 250 , CPRA % not mentioned , again we should declined this offer .
If yes, what is your immunosuppression plan?
can go for desensitization with plasmapheresis , rituximab and IVIG low dose ,the isoagglutinin titer should be < 1.16 at time of the transplantation with repeat negative FXCM.
Induction ATG 1.5mg /KG , PMP and additional dose of IVIG 0.5gm/kg
Maintenance triple therapy (tacrolimus trough target 8-12 first 3 months then 5-10 ng later , MMF , prednisolone )
Longer antiviral and antibacterial prophylaxis first 6 months
.
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
Yes, both need monitoring anti A antibody titer daily in the first weeks then in each visit and any increased of titer by two dilution and above from baseline its indication for graft biopsy or elective plasmapheresis also most important to monitor the DSA level day 4 nd 2,4 ,8 weeks then every 3 months till 12 months.
If no, what are your other options?
Better to be involved in PKD , the anti HLA-A2 as mentioned its non DSA third parity but still should be consider in this case due to historic sensitization and based on the CPRA% of the recipient.
References:
1-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
2- Alkhunaizi AM, de Mattos AM, Barry JM, Bennett WM, Norman DJ. Renal transplantation across the ABO barrier using A2 kidneys. Transplantation. 1999 May 27;67(10):1319-24.
3-Tierney J, Shaffer D. Transplantation of ABO A2 kidneys into O recipients: do IgM anti-A1 titers matter? Clin Transplant. 2015 Apr;29(4):379-82.
4-Azzi Y, Nair G, Loarte-Campos P, et al. A Safe Anti-A2 Titer for a Successful A2 Incompatible Kidney Transplantation: A Single-center Experience and Review of the Literature. Transplant Direct. 2021;7(2):e662. Published 2021 Jan 26.
Thankyou Saja
You need to measure anti B antibodies daily post operative,
And consider antiA2 antibodies bodies as non DSA ones which are also hazardous to the graft but not as frequent .
What is the relevance of IgM in ABOi transplantation?
The antibodies to blood group antigen are isohemagglutinins
and can be of either immunoglobulin M (IgM) or immunoglobulin G (IgG) type antibodies. However, in the context of transplantation, it is IgG that is functionally
significant.
Will you go ahead?
-No, because recipient and donor ABO incompatible with high anti-B IgG antibody titer are 1/256 and IgM 1/128.
If yes, what is your immunosuppression plan?
-The recipient needs desensitization by plasmapheresis and IVIg with rituximab to reduce Anti-B IgG˂1/8.
-Then induction with rATG and maintenance immunosuppression TAC, MMF, and Prednisolone.
-Protocol biopsy.
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
-Yes, monitor Anti B daily for the first 2week, and then according to the follow-up
-DSA monitoring: Day 4, week 2, 4, and 8; 6 months; 1 year; and annually
If not, what are your other options?
– Search for another living compatible donor
– deceased compatible donor.
– Kidney Paired Donation
– Antibodies against A and/or B blood group antigens either IgM or IgG can cause antibody-mediated graft damage with worse prognosis particularly related to preformed IgG antibodies.
Some studies reported that elevated IgM titers (1:64) is associated with early acute rejection/thrombotic microangiopathy while other studies did not correlate anti-ABO IgM antibodies with rejection .
-This case is considered a high risk transplant and considered highly sensitised due to HLA incompatibility and ABO incompitability
-If this transplant is to be done desensitisation need to be done with plasmapheresis , IVIG , and Rituximab.So that isoagglutinin titer at levels ≤ 1:16 during the first two weeks following ABO-I transplantation
Then induction can be done using r ATG and maintenance by Tac ,MMF ,prednisolone
-Isoagglutinin titer , DSA titer need to be monitored
-Paired kidney exchange program or a more compatible donor
Reference
-Lerman Mark .Communities Weekly Rewind: ABO incompatible kidney transplant; role and significance of IgM antibody titers.ASN2021
– 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 Nov 15;70(9):1331-5.
What is the relevance of IgM in ABOi transplantation?
Role of anti IgG titres is more important in renal transplant with desired level at 1:8. Limited data is available on the role of anti ABO IgM.
Will you go ahead?
No. As there is ABO incompatibility with IgG titres f 1/256 and IgM tires at 1/128.. This makes it a high risk transplantation
If yes, what is your immunosuppression plan?
Patient will require desensitization protocols with PLEX, IVIG and Rituximab. Maintenance with triple therapy -Tacrolimus, MMF and Steroids. Monitor Anti B IgG, DSA and then protocol biopsy
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
I will monitor daily isoaglutinin titre while the patient is in hospital. Twice per week for in month thereafter. After that weekly for next 3 months and then yearly
If no, what are your other options?
Stay on dialysis and wait for suitable compatible donor
Paired kidney donation or deceased donor programme.
What is the relevance of IgM in ABOi transplantation?
IgM can activate complement to a sufficient extent to induce complement-mediated clearance of the erythrocytes.
However, the targets of anti-blood group antibodies in ABO-i transplants are endothelial cells, not erythrocytes.
The role of IgM in transplantation is not as clear as for IgG.
There are donor-specific B-cell responses characterized
by secretion of donor specific IgM & sometimes donor-specific IgG during the first several months after transplantation.
ABO-i kidney transplants exhibit heightened risk of AMR during the first several weeks up to approximately 1 mo after transplantation. This risk reflects the ongoing production of antibodies specific for blood group antigens in the graft.
—————————————————
Will you go ahead?
No
The patient has high titer of A/B antibodies.
She is highly sensitized due to pregnancy & blood transfusion.
—————————————————
If yes, what is your immunosuppression plan?
1. Pretreatment with
– PP (or IA) aiming for an anti-A1 titer of ≤ 8 ( ≤ 16 for A2 donors) at
the day of transplantation.
– IVIG can be given after PP sessions.
– Rituximab
– Additional PP sessions are done if anti-A/B titers increase or there
is either suspicion of or biopsy confirmed rejection.
2. Induction by rATG.
3. Triple maintenance IS (tacrolimus, MMF, prednisolone)
4. Prophylaxis for CMV, PJP, & fungal infections
————————————————–
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
Anti-A antibody titers are monitored daily &, after discharge from the hospital, at outpatient clinic appointments.
————————————————-
If no, what are your other options?
Enrolement into PKD program
Search for a suitable ABO compatible donor
Reference
1. Mayara Garcia de Mattos Barbosa, Marilia Cascalho, Jeffrey L. Platt. Accommodation in ABO-incompatible organ transplants Xenotransplantation. 2018;25:e12418 https://doi.org/10.1111/xen.12418
2. Gunnela Nordén and Michael E. Breimer ABO-Incompatible Kidney Transplantation: Overview and New Strategies Trends in Transplantation 2007;1:61-8
# What is the relevance of IgM in ABOi transplantation?
Most studies show anti-ABO IgG titers to be the most important and recommend them being <1:8 using the indirect anti-globulin test (IAT) in an ABO incompatible kidney transplant. The data on anti-ABO IgM antibodies is limited, but there have been a few studies showing that elevated IgM titers (1:64) is associated with early acute rejection/thrombotic microangiopathy. Other studies have not shown the presence of anti-ABO IgM antibodies to be associated with rejection or outcome.
# Will you go ahead?
No , I willn't go ahead because he is highly risk patient with ABO-I high titre IgG 1/256 & IgM 1/128.
# If yes, what is your immunosuppression plan?
This patient needs desensitization by plasmapharesis,IVIG +/- Ritiximab
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?
No need to monitor antiA and DSA because there is no anti A and no DSA antibodies level.
Monitor anti B antibodies and routine
Fellowup of DSA is there is rising in creatinine
# If no, what are your other options
Other sutible donor
(deceased donor transplant)
paired exchange scheme
But in such case itis difficult, due to antibodies to HLA – A2 which is more common antigens in the population
American Journal of Transplantation 2015; XX: 1-10
Transplant Proc. 2015 Jul-Aug: 47(6):1720
Transplantation. 2015 Feb;99(2):400-4
◇What is the relevance of IgM in ABOi transplantation?
– Most of the studies in ABO incompatible kidney transplant showed that anti-ABO IgG titers is the most important & recommend them being <1:8 [1].
– The data on anti-ABO IgM antibodies is limited, but there have been a few studies showing that elevated IgM titers (1:64) is associated with early acute rejection and thrombotic microangiopathy.
– Other studies have not shown the presence of anti-ABO IgM antibodies to be associated with rejection or outcome. [1]
◇Will you go ahead?
-No, I will not go ahead
– I think this a difficult ABO incompatible transplants with high anti-B IgG antibody titre which is 1/256 although the HLA missmatch is good.
▪︎NOTE: The relation between the baseline antibody titer and the long-term outcome after ABO-I kidney transplantation is still unclear. Nevertheless, some studies reported a higher risk for AAMR with higher baseline antibody titers [2].
◇ If yes, what is your immunosuppression plan?
▪︎ In this case desensitization protocols [3] are used to allow ABO-I kidney transplants; these protocols include plasma exchange, B-cell depletion using rituximab, immunomodulation using IVIG, until reach an acceptable titer for IgG and IgM, and CDC cross match becomes negative
▪︎Induction with ATG and methyl prednisolone.
▪︎Maintainance therapy: Tacrolimus, MMF, and prednisolone
◇If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
▪︎We need to monitor anti B IgG antibodies (at 1, 3, 6, and 12 months of follow-up [4]).
▪︎Most centers recommend maintaining the isoagglutinin titer at levels ≤ 1:16 during the first two weeks following ABO-I transplantation[3].
▪︎ We need to follow DSA if there is any impairment in renal function or if there is any evidence of rejection.
◇If no, what are your other options?
– Search for another compatible donor but this is difficult in this case since this patient has DSA to HLA- A2 which is more common allele in the population
– Paired exchange donations
_____________________________
Ref:
[1]Mark Lerman. ABO incompatible kidney transplant; role and significance of IgM antibody titers
[2] Tobian AA, Shirey RS, et al. ABO antibody titer and risk of antibody-mediated rejection in ABO-incompatible renal transplantation. Am J Transplant. 2010;10:1247–1253.
[3] Mahmoud Mohamed, Tara Sweeney, […], and Karim M Soliman
ABO incompatibility in renal transplantation
World Journal of Transplantation
[4] Deepak Shankar Ray and Sharmila Thukral. "ABO-Incompatible Renal Transplantation with High Antibody Titer: A Case Report".
https://dx.doi.org/10.12659/AJCR.905633
IgM type isoglutinins are not that problem because they are cleared easily . after multiple plasmapheresis treatments and having a 1/8 or lower target of anti-B Ig G (other antibodies will decrease). we can check by single antigen bead may proceed if no other chance like paired donation.
Induction should be with ATG not basiliximab, triple regimen (TAC/MMF/steroid with optimisation of tough level of TAC
Monitoring anti HLA A level is good but may be unnecessary till there is a rise in creatinine level.
1-Most studies show anti-ABO IgG titers to be the most important and recommend them being <1:8 in an ABO incompatible kidney transplant. The data on anti-ABO IgM antibodies is limited, but there have been a few studies showing that elevated IgM titers (1:64) is associated with early acute rejection/thrombotic microangiopathy. Other studies have not shown the presence of anti-ABO IgM antibodies to be associated with rejection or outcome.
IgM is such a large molecule, which has a small volume of distribution, so it is easy to remove by plasmapheresis and associated with less rebound after transplantation
so even if the titre starts high, it is less likely to be a limiting factor in terms of transplantation
Any potential recipients of live donor ABO incompatible kidneys who have anti-ABO IgG or IgM titers above these thresholds should undergo desensitization protocols first.
Post-transplant anti-ABO titers must be closely followed for 2-3 weeks as these patients are at increased risk for AMR and potential early graft injury or loss. Additional desensitization may be necessary during this time.
2- No,I will not accept to preccd with this transplantion because it considered high risk for AMR
Due to HLA mismatch ,high titer of DSA((against HLA-A2 with MFI 10,000 and HLA-B8 with MFI 5500 due to pregnancy and blood transfusion.))
and ABO Incompatibility, so it is considered a double hit and high risk transplantation
3-If yes,
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
4-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.
5-other option
Waiting for another more compatible donor
Or preceded for PKD
Reference
1-Mark Lerman, MD, FASN. ABO incompatible kidney transplant; role and significance of IgM antibody titers. ASN Communities.
2-Up to date
Thank you
I agree with the monitoring plan, but at what level you would do a biopsy?
1- both IgM and IgG are involved in AMR occurrence
2-no, i will not go for transplantation, will proceed for PKD program if possible, so will search for an ABO compatible donor and also has no A2 antigen which is difficult because it is common antigen
3- we can do desensitization protocol first using plasmapharesis or immunoadsorption, ivig, and rituximab(medical splenectomy), until we get an acceptable titer for IgG and IgM, and cross match becomes negative, then give ATG induction , and maintained on Tac, MMF, and prednisolone
4- no need to monitor antiA and DSA because there is no antiA and no DSA antibodies, but we should monitor antiB antibodies and routine follow up of DSA
Thank you
Thanks for your answer
What about the paired exchange scheme in this case?
Do you think it would be successful?
What is the relevance of IgM in ABOi transplantation?
Data on anti-ABO IgM is so limited and mainly all centers protocol depend on anti-ABO IgG titer , some studies showed rejection association with anti-IgM titer >1/64 and the other denied.(1).
But overall high titer need desensitization and post – operative follow up.
Will you go ahead?
No. It is high risk as Hemagglutinins titer>256.
Better to look for ABO compatible donor by using PKD.
If yes, what is your immunosuppression plan?
There are many protocols for ABO I KTX which is mainly local center dependent e.g (Stockholm protocol, Johns Hopkins protocol,etc).
-will used PEX for antibodies removal 5-7 session one week before transplantation alternating with IVIg for immunomodulation.
-B cell depletion by using Rituximab 200 mg dose 1 week before.
-Basiliximab 20 mg two doses for day 0 and day 4 with pulse steroid.
-Maintained on triple tacrolimus based therapy which started 1-2 weeks before transplantation.
If yes, do we need to monitor the anti-A antibody titer and the DSA post-transplantation?
– No need for daily follow up of HLA or ABO antibody but according to clinical situation(2).
If no, what are your other options?
ABO compatible living transplantation by PKD it is still a source even though it still difficult because recipient has antibody against HLA -A2 which is common antigen .
References:
1-Weekly Rewind: ABO incompatible kidney transplant; role and significance of IgM antibody titers, By Mark Lerman posted 07-09-2018 14:07.
2- Guidelines for Antibody Incompatible Transplantation(Third Edition), British Transplantation Society Guidelines.
Thanks for your answer
What about the paired exchange scheme in this case?
Do you think it would be successful?
YES,
But as mentioned patient has higher immunological risk with HLA- A2 which is so common antigen and so decrease his chance to find a suitable donor specially this patient supposed to have high cPRA.
Thank you
Most research concentrate on IgG with a goal titer of 1:8 before transplantation, few studies revealed that IgM titer of >1:64 is significant and linked with ABMR.
So… goal IgG isoagglutinin titer is 1/8 and IgM is 1/64, and any patient with anti ABO over these levels should undergo desensitization.
Will you go through with this procedure, and if so, what are your plans for immunosuppression?
The presence of ABOi antibodies matches up with the presence of non-DSA antibodies in this instance.
It is possible to explore desensitization treatments since the titer of both IgG and IgM antibodies is close to the top limit of the permissible range. However, in this particular circumstance, the paired kidney exchange program needs to be thought about. I
f there was no other choice, however, I would go through with the desensitization procedure beginning one month prior to the operation. It is recommended that rituximab be administered, MMF should be begun one month in advance. Plasmapheresis+iv Ig will begin one week before. r-ATG (or Alumutozumab) induction and maintenance of immunosuppression based on triple therapy.
Isoagglutinin titers will be monitored on a daily basis until the patient is discharged from the hospital, then on a 2-3 times per week basis for the first month, then on a weekly basis until three months after the transplant, and finally on a yearly basis.
and I would prefer to do a protocol biopsy. keep tacrolimus on the higher limit.
KPD, or the alternative of waiting for an offer of a suitable dead donor via the allocation method.
well done.
it’s a deceased donor not a dead donor
Thanks for your answer
What about the paired exchange scheme in this case?
Do you think it would be successful?
It will be very difficult to find a suitable pair, as she has antibodies against HLA-A2, which is a common antigen. maybe with a different ethnic group.
The presence of pre-transplant IgM DSA did not predict rejection or graft failure.
Presence of IgM DSA post-transplant (de novo and resynthesize) was not associated
with rejection. However, post-transplant IgM was associated with graft failure.
Will you go ahead?
NO.
Recipient anti-B IgG antibody titre is 1/256 his IgM 1/128,
This high risk transplant .
Desensitization is needed as titer of antibodies is more than1/128 ,level accepted for
most transplant centers.
Either plasmapheresis, immunoadsorption, double filtration plasmapheresis, and
selective plasma exchange can be used ,to keep titer below 1/8 pretransplant.
IVIG
Rituximab .200 mg.
induction therapy :
ATG.
Maintenance Therapy: ,MMF AND Prednisolone.
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 .
Wait for suitable donor OR Deceased donor .
KPD.
.
Thanks for your answer
What about the paired exchange scheme in this case?
Do you think it would be successful?
IgM Ab role in ABOi Tx is controversial but a titer of 1:64 is probably associated with risk of acute rejection
With a titer of IgG 1:256 we cannot proceed without desensitization.
Rituximab and MMF to be given one month prior to scheduled transplant with concomitant initiation of antiviral and septran prophylaxis.
Two weeks prior we would require isoagglutinin titer and cross match and plan accordingly.
If titer is1/8 we can proceed otherwise we would require plasmaphresis . Each session would decrease titer by one dilution so we can admit patient accordingly.
We should give IVIg 10 post plasmapharesis
And 500 mg before Tx
Induction could be ATG with triple maintenance immunosupression.
we should 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.
Thanks for your answer
To me, ABOi transplantation is not an option in the index case due to the high titre.
What about the paired exchange scheme in this case?
Do you think it would be successful?
What is the relevance of IgM in ABOi transplantation?
Therole of IgG in kidney transplantation is well studies, however the impact of IgM is still unclear.One study reported that IgM deposition in PTCs was observed in approximately 30% of patients with ABOI-KTx within 3 months post-transplant. Anti-blood group IgM antibodies may be attributed to IgM deposition in PTCs, but the clinical relevance of IgM deposition in PTCs remains unclear in cases of ABOI-KTx.
Mark Lerman posted the role and significance of IgM antibody titers in ABO incompatible kidney transplant . Pre-op anti-ABO IgG titers <1:8 and anti IgM <1:64 (by IAT) would seem prudent. Any potential recipients of live donor ABO incompatible kidneys who have anti-ABO IgG or IgM titers above these thresholds should undergo desensitization protocols first.
Will you go ahead and if yes what is your immunosuppression plan?
This is a case of ABOi matching with the presence of non-DSA antibodies.The titer of both IgG and IgM are in the upper limit of acceptable range for desensitization protocols to be considered. However in this case, paired exchange kidney program should be considered. But if no other option, I would proceed with desensitization protocol starting 1 month before surgery.Rituximab should be given 1 month prior.MMF should be started also one month before.Plasmapheresis to be started 1 week before surgery( depending on local protocols).r-ATG induction and triple CNI-based immunosuppression maintenance, along with antiviral antibacterial prophylaxis.
If yes, do we need to monitor the anti-A antibody titre and the DSA post-transplantation?
In the context of ABO incompatible transplantation, patient should undergo monitoring of isoagglutinin titers daily till discharge from the hospital, then 2-3 times per week for the first month then weekly till 3 m post-ransplant then annually.
In case of antibody titer is ≥1:16 or 1:32, kidney biopsy should be considered if there is delay in kidney function or new kidney dysfunction. In this case plasmapheresis will be considered.
Screening of DSA and follow-up on non-DSA levels is also a must in this case because non-DSAs are also associated with inferior graft survival.
If no, what are your other options?
Alternatively patient should seek paired exchanges program, but the presence of anti- HLA A2 will consider the HLA A2 as unacceptable antigen so it would be difficult to have ABO compatible match with HLA compatibility.
Thanks for your answer
To me, ABOi transplantation is not an option in the index case due to the high titre.
I agree with you regarding 2 fold increase (not one fold) in the titre indicates biopsy. Well done.
What about the paired exchange scheme in this case?
Do you think it would be successful?
Alternatively patient should seek paired exchanges program, but the presence of anti- HLA A2 will consider the HLA A2 as unacceptable antigen so it would be difficult to have ABO compatible match with HLA compatibility because HLA A2 is a common antigen in population, as about 40% of the world is HLA A2 with between 35- 50% in every ethnicity in the USA.
In ABOi-T, antibodies against blood group antigens are isohemagglutinins of IgG & IgM, but in transplantation IgG is the most significant subtypes, because high level of IgG can predict the occurrence of AMR.
References:
Thanks for your answer
To me, ABOi transplantation is not an option in the index case due to the high titre.
What about the paired exchange scheme in this case?
Do you think it would be successful?
Significance of Ig M in ABO I transplant
The role of Ig G in ABO I transplantation is well established and most centres consider transplantation when Ig G levelm is less than 1/ 8 . But the data about importance of Ig M is limited and controverse . most studies considered Ig M levels higher than 1/ 64 risky and associated with increased incidence of DGF , AMR and poor graft survival.
Will you go ahead
No, This is ABO I transplantation with high risk as high level pretransplantation anti B Ig G and significant level of third party antibodies against both HLA class I and II which is associated with increased risk for DGF , AMR and poor graft survival , that necessates pretransplantation desensitization however , posttransplantation memory cell activation and rebound antibody formation still a high risk .
If yes,
Management plan
1- Prtranplantation desensitization ( PE, IVIG and rituximab)
2- IS protocol : induction with ATG , maintenance with triple IS ( steroid , MMF and Tac ) and keep trough level at high therapeutic level ( 10-12 ) during the first 3 month posttransplant
3- Protocol biopsy
4- Regular monitoring of DSA and anti B antibody levels
Other options
1- paired kidney donation
Thanks for your answer
To me, ABOi transplantation is not an option in the index case due to the high titre.
What about the paired exchange scheme in this case?
Do you think it would be successful?
Regarding ABO IgM antibodies, its of debatable relevance.the general consonsus is to have IgM titer below 1/64,As some reports showed higher risk of acute AMR with higher level of IgM .Similarly, IgG titer should be below1/8.
So my plan for this patient, I will advise to proceed ,
Desensetization hgas to be performed with aprotocol DFPP 5 sessions initially ,until IgM and IgG titers are below 1/64, and 1/8 respectively.IVIG prior to transplant.
Retuximab to be used in stead of splenectomy.2 doses.
Immunosuppresion protocol:
Basiliximab for induction 2 doses.on days 0 and day 4 .
Tacrolimus based immunosuppression protocol including MMF and prednisolon.
However in order to avoid the desensitization protocol with over immunosuppression. I would advise the patient to go for PKD programm prior to imbark on ABOi transplantation with Desensitization protocol.
Post transplant Monitoring of anti B titer has to be done closely over the first 2-3 weeks,
After which the patient is usually having an accomodation phenomina wherein the C4d is accumulated in the PTC with no active rejection.
As rebound of antibody titer is associated with rapid catastrophic AMR with microangiopathy of allograft a double rise of antibody dilution is a strong indication for a rebound and impending AMR, mandating the prompt initiation of PP ,ATG ,with potential use of Bortizomib and Eculizumab and splenectomy in exterely resistent AMR.
The non DSAs are usually associated with adverse long term outcome, therefore a close observation of DSAs titer and renal function is mandatory.
Kidney biopsy is contemplated if there is any abnormalities in allograft function.
Thanks for your answer
To me, ABOi transplantation is not an option in the index case due to the high titre.
What about the paired exchange scheme in this case?
Do you think it would be successful?
What is the relevance of IgM in ABOi transplantation?
Will you go ahead?
The decision to transplant this patient or not will depend on addressing the pros and cons of transplantation:
Pros :
1- Survival benefit of transplantation when compared to dialysis
2- Better outcome obtained from Living when compared to deceased donor kidney transplantation
3- Perfect HLA matching with 0 HLA DR mismatches which are associated with a good outcome. Graft survival 7 years after transplantation was found to be better in patients with 0 HLA-DR mismatches when compared to those with 1 and 2 DR mismatches. (80%, 76%, 73%, respectively).
4- Highly sensitized transplant recipients are extremely difficult to find a suitable donor with a negative cross-match, it was found that for patients with a cPRA of 100% only 1 from 300000 donors offer will be suitable for transplantation with a negative crossmatch. (2) this means this patient may have no further chance for transplantation
Cons
1-Impact of the transplanting highly sensitized recipient with the presence of significant non-DSA
2- Impact of ABO incompatibility
If yes, what is your immunosuppression plan?
1- Desensitization protocol
2-Induction better using r ATG as the patient is highly sensitized
3-Maintanace triple immunosuppressive regimen including
4- Antiviral prophylaxis according to CMV status
5- Monitoring
If no, what are your other options?
REFERANCES
1. Mark Lerman. Weekly Rewind: ABO incompatible kidney transplant; role and significance of IgM antibody titers. American Journal of Transplantation. 2015; 47(6):1720
2. Cecka JM, Cho L. Sensitization. In: Clinical Transplants 1988, Terasaki PI (Ed), UCLA Tissue Typing Laboratory, Los Angeles 1989. p.365
3.Keith DS, Vranic GM. Approach to the highly sensitized kidney transplant candidate. Clin J Am Soc Nephrol 2016; 11: 684.
4. US Transplant http://www.ustransplant.org (Accessed on February 10, 2010
5. Redfield RR, Scalea JR, Zens TJ, et al. The mode of sensitization and its influence on allograft outcomes in highly sensitized kidney transplant recipients. Nephrol Dial Transplant 2016; 31:1746.)
6. Opelz G, Collaborative Transplant Study. Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies. Lancet 2005; 365:1570
7. MorathC,Döhler B, KälbleF, et al. Pre-transplant HLA Antibodies and Delayed Graft Function in the Current Era of Kidney Transplantation Front. Immunol., 26 August 2020.
8. Jun, K.1; Kim, M.1; Hwang, J.1; Park, S.1; Moon, I.1; Lee, M.1; Kim, S.2; Kim, J.1. Impact of Pre-Transplant PRA Level On Renal Graft Survival in Patients With Negative Cross-Match and No Donor Specific Antibody. Transplantation: July 15, 2014 – Volume 98 – Issue – p 463
9.Perasaari JP, Kyllonen LE, Salmela KT, Merenmies JM. Pre-transplant donor-specific antihuman leukocyte antigen antibodies are associated with high risk of delayed graft function after renal transplantation. Nephrol Dial Transplant. (2016) 31:672–8
Excellent
If this patient was ABO compatible what is your management plan for the (third party) antibodies?
I will proceed with transplantation using ATG induction due to the presence of third-party antibodies, but the use of basiliximab is a reasonable option due to perfect HLA matching and absence of DSA with negative crossmatchh
Thanks for your answer
To me, ABOi transplantation is not an option in the index case due to the high titre. Also, you look always keen to use ATG as an induction agent here, It is not the right approach, think of Rituximab which is appropriate in ABOi transplant.
What about the paired exchange scheme in this case?
Do you think it would be successful?
Thank prof, few comments ;
The data on anti-ABO IgM antibodies is limited, but there have been a few studies showing that elevated IgM titers (1:64) are associated with rejection. Other studies have not shown the presence of anti-ABO IgM antibodies to be associated with rejection or outcome.
I think it is difficult to accept the current donor as there is a very high anti-B IgG level which may not be amenable for desensitization and the presence of high MFI anti-HLA antibodies. I would prefer to look for another more compatible donor.
Other information are required such as CXM result and cPRA.
Desensitization should be done to decrease the level of anti-B level to < 1:8 using DFPP, IVIG, Rituximab or Immunoadsorption and rituximab according to Guy’s Hospital protocol. CXM should be negative to reduce the risk of hyperacute rejection.
Induction with ATG, pulse MP for 3-5 days.
Tac based triple IS therapy as maintenance therapy.
Monitoring of Anti-B IgG ab level for at least 2 weeks post-transplant for risk of rebound.
Monitoring of DSA level.
Protocol biopsy.
Yes, for Anti-B IgG ab for risk of rebound post-transplantation and DSA level need to be followed.
PKD as the donor is a live donor, or we may list him for the deceased donor program.
References:
Remember these are non DSA antibodies (third party DSA so how does this influence your management?
Thank you
Evidence showed that non-DSA antibody levels slowly fall in the first-month post-transplantation and in some patients their levels initially rise at rejection episode with increased synthesis of DSA. Another study finds that the presence of non-DSA anti-HLA antibodies class I is a risk for the development of De novo DSA, ABMR, and graft loss.
References:
Thankyou very good.
So are you going to deal differently with them or just closely follow up DSA titres.
Follow up for:
+- protocol biopsy
pre – op anti-ABO IgG titers <1:8 and anti IgM <1:64 (by IAT) would seem prudent
Will you go ahead?
yes .since recipient has HLA A2 DSA and HLA A2 is present in around 40% of individuals in the population ,her getting another donor for which she does not carry DSA is less likely .
rituximab 200mg 15 days prior to transplant
tacrolimus 0.05mg/kg/day in divided doses and MPS 720 mg BD were started 7 days before transplant.
alternate day plasmapheresis F/B IvIg 100mg/kg/dose post plasmapheresis starting 7 days before transplant.
daily ABO IgG and IgM tigers to be checked and can proceed to transplant if IgG titer <1:8 and IgM titer <1:64 .
CDC and FCXM should be negative.
ABO titers to be monitored daily till discharge and plasmapheresis done in case of rising titers.
after 2 weeks post transplant DSA and ABO titers to be done only when serum creatine increases by more than 30% and CNI toxicity is ruled out with other obvious causes.
deceased donor
another live donor
Weekly Rewind: ABO incompatible kidney transplant; role and significance of IgM antibody titersBy Mark Lerman posted 07-09-2018 14:07 .