3. A 32-year-old male, with a history of previous 2 failed transplants, both failed due to chronic antibody mediated rejection (cAMR). He had cerebral PTLD, which was treated successfully by reduction of immunosuppression, radiotherapy and chemotherapy. He has now received a cadaveric kidney offer with 222 mismatch. FCXM was negative. The donor is 69-year-old with serum creatinine of 63 µmol/L.
- Will you accept this offer?
- What induction immunosuppression can be used?
- Would your management differ if the mismatch was 000 and FXCM showed weak positive B cell with negative autocrossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500)?
- Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells?
I may change tacrolimus with sirolimus but later after kidney transplantation
-I will not accept the offer :Pt has high immunological risk (base on previous 2nd transplants ,6 missmatches ,the other issue is that pt has history of PTLD so we will not be able to use ATG .
– Induction chemotherapy should be Basiliximab +steroids as ATG will increase the risk of PTLD
– If no missmatches+weak positive FXCM (B cells )+negative auto cross match +DSA (DP3 with MFI:2500) >It will require desensitization with IVIG ,plasmapheresis and rituximab , then induction with Basiliximab and methyleprednisone ,maintainance with CNI ,MMF and prednisone but better to be avoided and go for Paired donor exchange due to DSA and positive cross match
– If the donor was his brother so it is bettter with no DSA and negative cross match ,I will go with Basiliximab +methyleprednisone and maintenance Tacrolimus +MMf and prednisone and and needs protocol biopsy and screening for PTLD recurrence
correction Q4 in case the donor is brother with negative DSA/FCXM , one would try Basiliximab as induction agent. DSA monitoring + protocol biopsies are needed
1- Will you accept this offer?
1- sensitization from previous grafts,
2- past history of Cerebral PTLD.
3- cadaveric graft with 100% mismatch.
2- What induction immunosuppression can be used?
3- Would your management differ if the mismatch was 000 and FXCM showed weak positive B cell with negative autocrossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500)?
4- Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells?
I may reject offer as the recipient is high immunologic risk with high sensitization (previous transplantation) , history of PTLD; better with more matched kidney offer
Induction: Basiliximab with maintenance including Tac ,MMF &steroids.
Patient has high risk for PTLD and positive HLA DP3 MFI 2500, Will be
in need for desensitization using Rituximab ,IVIG plus Plasmapheresis.
Induction: Basiliximab
maintenance including : Triple immunosuppressive drugs due to previous failed 2 transplantation.
Reference
1. Caillard S., Cellot E., Dantal J., Thaunat O., et al. A French Cohort Study of Kidney Retransplantation after Post-Transplant Lymphoproliferative Disorders. CJASN.2017,Oct, Vol.12.
2- up to date 2021
No I would not accept it , the patient is highly sensitized due to 2 previous transplants , both were rejected due to AMR, on the other hand graft is from Deceased donor old age with 6 mis matches ,all increase chance for graft rejection , and if the patient underwent aggressive IS protocols either induction , desensitization and mentainence , this would carry hazardous effect on the patient who had aprevious Hx of PTLD.
Basiliximab , keeping in consideration the adverse events associated with ATG as a potent depleting immune suppressant in this patient with a previous Hx of PTLD
Desenstisation could be of value : IVIg, PE, Rituximab
No. still Basiliximab induction is advisable followed by mentainence: steroids, sirolimus, MMF
Yes , I can skip Basliximab as induction, with mentainence steroids, sirolimus, MMF
I may decline this donor as the recipient is high risk for transplantation due to his high sensitization (repeated transplantation) , history of PTLD. he would be better with more matched kidney.
Induction: Basiliximab
Weak positive b cell may be secondary to rituximab therapy for PTLD. however, HLA-DP carries a risk for poor graft survival.
Induction: Basiliximab
maintenance therapyt: Triple immunosupressive drugs due to previous failed 2 transplantation.
Q1: The patient is a young man and this is his third transplantation and there is history of cAMR and PTLD but the offered cadaveric donor is old and completely mismatch which increases the risk of performed DSA and necessitates a potent immunosuppression but due to history of PTLD, potent immunosuppression increases the risk of relapse.
Q2: This is the third TX but there is increased risk of EBV reaction and if DSA is negative, basiliximab is a suitable induction.
Q3: Positive B cell crossmatch may be related to rituximab used to treat PTLD.
EBNA1 protein is presented to T helpers associated with HLA-DP3: This subject helps targeting tumors that contain this Ag, which is good for treatment of PTLD but HLA-DP3 DSA, even though rare, are associated with decrease rate of graft survival and need increased immunosuppression that is not favored in this patient.
Q4: Yes, induction with monclonal Ab (basiliximab) and then triple immunosuppression with using mTOR inhibitors after wound healing instead of cellcept.
Will you accept this offer?
This patient has high immunological risk due to previous 2 failed renal transplant and history of treated PTLD with this 6 mismatch offer , I will not accept this donor.
What induction immunosuppression can be used?
Due to the risk of infection and reactivation of EBV when use aggressive is ,so basiliximab induction is fair in this scinarew.
Would your management differ if the mismatch was 000 and FXCM showed weak positive B cell with negative autocrossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500)?
Positive B cell related to the previous Rituximab treatment, presence of HLA DP associated with high risk of rejection
With the presence of DSA mean that this offer is carring a high immunological risk.
Refuse this offer
Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells?
Induction with basiliximab and triple IS
With close monitoring for PTLD.
Will you accept this offer?
The patient is young, he deserve a better life with kidney transplantation rather than continuing dialysis. But this patient carry few risk rejection and infection.
First, patient had 2 prior transplantations, which make him high immunological risk, more so, both failed due to cAMR. I would like to know the induction therapy used, the maintenance therapy and CNI though levels and adherence to meds.
Second, patient had PTLD which was successfully treated by reduction of immunosuppression, radiotherapy and chemotherapy. If the patient need to undergo another transplantation, he might need aggressive induction therapy, which may pose risk of reactivation of EBV. Measurement of EBV EBV-DNA might give an idea of viral load and risk of reactivation of disease.
Third, 2-2-2 mismatches make the situation even more complicated.
In view of higher risk of rejection / infection (more harm) than benefit, I would not proceed with transplantation. Would advice for more compatible donor or paired kidney transplantation.
What induction immunosuppression can be used?
Due to the risk of infection patient, I would like to start Basiliximab induction therapy. My decision is baed on study by Nassim Kamar showed that highly sensitized kidney-transplant patients without pDSAs, both ATLG and basiliximab can be used efficiently and safely.
Would your management differ if the mismatch was 000 and FXCM showed weak positive B cell with negative autocrossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500)?
Weak positive B cell FXCM can be related to rituximab that was used in the treatment of PTLD.
Liesbeth Daniëls et al 2021 showed Isolated HLA-DP DSA are rare yet constitute a significant risk for AMR. So, this patient still considered high immunological risk for rejection.
Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells?
I would induce with Basiliximab, as patient has high immunological risk- 2 prior transplantations and start triple immunosuppression maintenance but would monitor closely for PTLD or other infections.
References:
Highly sensitized patient , with an offer with complete mismatch, and ECD is a very high risk ,
If we considered his negative cross match, he will still be high risk patient that requires desensitization and induction therapy which will be risky in this particular patient with History of PTLD
This offer better to be avoided .
The patient s best induction therapy would be basiliximab which is not suitable for high risk patients
2nd offer :
000 mismatch
Weak positive B cell flow cytometry
DSAs include DP3 with MFI 2500
This would be a better option , since DP DSAs have lower significance on graft survival ,
I would proceed with this offer using basiliximab as induction , tacrolimus, MMF and steroids
3rd offer
Brother
-ve DSAs , -ve FCXM
He failed transplantation twice , he s still considered sensitized patient, so I would also proceed with basiliximab as induction , tacrolimus, MMF and steroids .
●Will you accept this offer?
It is a high risk 222 means 6 mismatches.
Recipient had previous tx means highly sensitized.
Old age of doner and decreased e.gfr so it marginal kidney doner .
Patient with cns ptld .
Reference https://pubmed.ncbi.nlm.nih.gov/24126003/.
●What induction immunosuppression can be used?
.. Basiliximab
Maintenance
Mmf /tac/steroids.
●Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells?
It is considered weak positive test should be repeated as it may be due to drug induced as the patient may be given retiuximab before .
●
Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells?
It has better prognosis induction only with Basiliximab Maintenance on
Triple tacrolimus/ mmf /prednisone.
Reference
Hand book of transplantation
Will you accept this offer?
CNS PTLD is serious complication occurs mostly after 1y post-transplant associated with 25% patient survival in which patient receive induction by rATG then high doses of immunosuppression with cause flaring of EBV b cells or chronic inhibition of tcell.
the recipient is 32y old with history of CNS PTLD and you offer him graft with 222 mismatch and extended criteria donor exposing him to DGF and poor graft survival also to be transplanted he will be high risk patient need ATG induction which not be accepted in such case
so no I will not accept this offer in such young patient.
· What induction immunosuppression can be used?
immunological stautus regarding EBV in both donor and recipient . if recipient is EBV negative and donor positive I will reject this donor for sure if both positive I will go for rtx with basiliximab induction and tac/mmf/steroids day -2 with followup EBV PCR monthly and preemptive treatment if copies more than 1000 with rutiximab also with protocol biopsy and DSA
· Would your management differ if the mismatch was 000 and FXCM showed weak positive B cell with negative autocrossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500)?
weak positive crossmatch in b cell may caused by antibodies against class 2 (like DP3) or by rutiximab so repeating test using pronase to exclude rutiximab effect if still positive this patient will need desensitization and postpone transplantation as positive DSA against DP3 and strong enough to cause positive FXCM associated with poor graft survival
· Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells?
sure,I will go for renal transplantation directly with basiliximab induction plus tac/mmf/steroids then EBV PCR monthly and DSA monitoring.
Reference
-uptodate
Will you accept this offer?
High immunologic risk transplant offer: Young recipient with previous 2 Tx failed because of cAMR, h/o PTLD, MM 222, Old age of ECD donor.
He will need heavy induction IS, and intensified maintenance IS that might increase the risk of recurrence of PTLD.
I would rather prefer to wait for better matched donor, if this offer is accepted, the chance of poor graft and patient survival will be high.
It is recommended to wait for a period of one year from control of PTLD before re-transplant to reduce the risk of recurrence. The prognosis of a patient with PTLD is poor with overall survival of 25-35%
What induction immunosuppression can be used?
It is a high immunologic risk offer with high risk of recurrence of PTLD.
Options of induction IS include: Basiliximab, Almetuzumab or low dose ATG not more than 3 doses of 1.5mg /kg.
I will opt for Basiliximab as induction IS.
It is recommended to proceed for Re-transplant 2 years after complete remission of cerebral PTLD.
Maintenance immunosuppression: CNI/ MMF/ steroids. Switch from CNI to mTOR inhibitors can be done after 3 to 6 months.
Would your management differ if the mismatch was 000 and FXCM showed weak positive B cell with negative autocrossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500)?
Immunotherapy for PTLD includes Rituximab.
Rituximab can induce B-cell weak positive FXCM.
FXCM results should be confirmed by Pronase,which might be one of the following options:
a/ FXCM is negative after pronase: this means it was +ve because of Rituximab, then induction can be done using Basiliximab, maintenance with CNI+MMF+Steroids, m-TORi can replace CNI after 6 months.
b/ FXCM is positive: needs desensitization with PLEX+ IVIG, then induction with Basiliximab. Maintenance as above.
HLA-DP antibodies don’t affect the first transplant however have poor outcome (Acute rejection and cAMR) on re-transplant, in our case it will be the 3rdtransplant.
Follow-up for EBV and DSA level.
Protocol biopsy because this patient has a history of 2 failed transplant
Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells?
It is expected to be a better mismatch, at least MM 111, Negative DSA and negative FXCM will make this a better donation offer and allow for less immunosuppression which decreases the risk of PTLD recurrence.
He still needs induction IS with Basiliximab, 2 previous Tx keeps the patient in high immunologic risk group.
Follow up:EBV and DSA level.protocol biopsy because of ABMR could be subclinical and needs immediate treatment.
References:
1- Caillard S., Cellot E., Dantal J., Thaunat O., et al. A French Cohort Study of Kidney Retransplantation after Post-Transplant Lymphoproliferative Disorders. CJASN.2017,Oct, Vol.12.
2- Soliman K., Ali H., Fulop T., Osman A., Halawa A. Causal Relationship between Anti-Thymocyte Globulin Induction Therapy and Development of Monomorphic PTLD in Renal Transplant Recipients. Am J Transplant. 2020; 20 (suppl 3).
3- Marie Y., Key T., Halawa A. Renal transplantation against a positive crossmatch due to HLA-DP donor-specific antibodies without prior antibody removal – Case report.Transplantation Reports 6 (2021) 100076.
4. KDIGO Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation: transplantation April 2020 ■Volume 104 ■Number 4S.
5. Eszter Lazar-Molnar, Denise Hurst, Ann Pole, Julio C. Delgado,Residual serum rituximab induces false positive flow cytometric B cell crossmatch more than 6months post-infusion, Human Immunology,Volume 76, Supplement,2015,Page 128,ISSN 0198-8859,
6. Yazin Marie, Tim Key, Ahmed Halawa, Renal transplantation against a positive crossmatch due to HLA-DP donor-specific antibodies without prior antibody removal – Case report,Transplantation Reports, Volume 6, Issue 3,2021,100076,ISSN 2451-9596,
7. Alexandre Hertig, Andreas Zuckermann,Rabbit antithymocyte globulin induction and risk of post-transplant lymphoproliferative disease in adult and pediatric solid organ transplantation: An update,Transplant Immunology,Volume 32, Issue 3,2015,Pages 179-187,ISSN 0966-3274,
Will you accept this offer?What induction immunosuppression can be used?
The patient is sensitized by 2 previous transplants
There is 6 mismatches with the donor and he is deceased donor which will require more aggressive IS which increase the risk for recurrence of PTLD.
history of PTLD that requires reduction of immunosuppression.
So I prefer to find another donor
No data available about the time after recovery from the PTLD which was was recommended not to be less than 1 year and up to 90 months according to french registry.
And EBV status must be checked at the time of retransplantationas it is an important predictor of recurrence after retransplantation.
If i have to accept this doner .
patient undergoing retransplantation after PTLD receive an induction agent with :
– IL-2R antagonists are the favoured induction agents (30–40%) in most cases .
– antilymphocyte globulins have been used in cases of retransplantation after PTLD, it is noteworthy that in the data analysis by Johnson et al., none of the patients who received a T cell depleting agent in the first transplantation were rechallenged by a T cell depleting agent during retransplantation .
-Rituximab has been used in retransplantations after PTLD both as a desensitisation protocol in high risk sensitised cases and as a prophylaxis for proliferation of EBV in cases with high viral counts .
If mismatch was 000 it would be better option and FXCM showed weak positive B cell with negative autocrossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500) we still need induction eith rituximab.
With brother donor and no DSAs and Negative FCXM i won’t give induction therapy and keep him on triple immunosuppression protocol with follow-up of DSA
Reference
Pallavi Prasad, Dinesh Khullar, et al .Retransplantation after post transplant lymphoproliferative disorder: overcoming the obstacles!CEN Case Rep. 2020 Aug; 9(3): 200–203.
Will you accept this offer?
deceased donor and 69 years old so it’s considered as extended criteria
The recipient have history of 2 failed kidney transplant,
222 mismatch,PTLD
All these factors make our patient at high risk group and need aggressive induction regem
Which also can make problem in patient with PTLD
So it’s better to wait for more comparable donor
What induction immunosuppression can be used?
Induction
can be done by basiliximab
Maintenance IS
Tacrolimus, MMF, Prednisolone
Monitoring for EBV serostatus and DSA titer
Would your management differ if the mismatch was 000 and FXCM showed weak positive B cell with negative auto crossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500)?
Weak positive B cells can be IVIG the received rituximab as treatment of PTLD
But if the patient didn’t receive ritiximab and the XM positive with high titer of DSA so we need desensitization before transplantation
Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells
Donor with negative DSA and negative FXCM for both B and T cells
So no need for desensitization but still need DSA monitor because of previous 2 transplantation and failed due to chronic AMR
Induction
can be done by basiliximab
Maintenance IS
Tacrolimus, MMF, Prednisolone
Reference
1. Caillard S., Cellot E., Dantal J., Thaunat O., et al. A French Cohort Study of Kidney Retransplantation after Post-Transplant Lymphoproliferative Disorders. CJASN.2017,Oct, Vol.12.
2- up to date 2021
3- Stuart J. Knechtle, MD, FACS. Kidney
Transplantation Principles and Practice
EIGHTH EDITION
I will not accept this offer for some important reasons:
The donor is ECD and his/her organ is appropriate for recipients with high EPTS.
A kidney transplant from ECD is associated with a higher risk of DGF and therefore need more aggressive induction and maintenance therapy that is not appropriate in this patient with a history of PTLD.
on the other hand, recipient and donor are 6 HLA-mismatches that correlate with poor transplant outcome. Thus, induction therapy with depleting-antibodies (rATG, Alemtuzumab), that are related to higher incidence of PTLD, in addition to more aggressive maintenance immunosuppressive therapy are needed.
Presence weak positive B crossmatch in combination with negative auto crossmatch implicates the presence of alloantibodies. HLA-DP3 DSA with MFI>1000 identified by Luminex-SAB is an important finding. Because HLA-DP antibodies are related to reduced allograft survival among recipients of a second or more transplants. The frequency of HLA-DP antibody increases in patients who were previously transplanted. If the donor has unaccepted antigen, kidney transplantation is contraindicated.
I would accept kidney transplantation if the donor was his brother with negative DSA and negative FCXM and would use non-depleting induction therapy such as basiliximab, followed by maintenance therapy with tacrolimus, MMF and prednisolone.
With history of PTLD ,ATG increase risk of recurrence . We can use basiliximab as induction therapy .
this case is a very highly sensitized case. I will only accept if this is the only recipient non otherwise. It is wisdom to try to find better-matched recipient. although the donor has 63mmol/L kr (0.73 mg/dl) the eGFR is acceptable as marginal donor. but since this case has previous transplants with previous failure history and need to minimize immunosuppression due to PTLD. we need to check EBV situation of donor (if possible). If we are obliged to do this transplant we have to use high-dose rATG pulse steroidand preferably giving Rituximab both for B cell depletion and probable antibodies.
In case of 000 mismatch, I will still give the same treatment (here may I become more comfortable with transplant)
In case of donor being living (his brother) with negative DSA and negative FXCM, I will check for single antigen and consider high risk due to previous sensitization but I will give only rATG plus standard triple immunosuppression with close monitoring both for PTLD and rejection. I am not sure about Rituximab as a preventive measure due t previous (PTLD)
1-I will not accept this offer
-patient highly sensitized due to previous 2 failed transplant
-high mismatch mean aggressive immunosuppressant (induction & maintenance) that not compatible with previous PTLD
-age of donor 69 years old (deseased )mean high incidence of fibrosis (not accepted for recipient age and requirement)
2-we need use of ATG but it not accepted due to previous PTLD & pulse steroid
3-yes
as we can use retuximab previous transplant as desensitization then use IL2 antagonist induction (maintenance with mTOR as it has anti proliferative effect plus MMF)
4- yes
induction with basileximab or may use pulse steroid only -maintenace with (MMF-mTOR)
-Highly sensitized patient and 222 mismatches, His past history of PTLD that necessitates reduction of immunosuppression in the course of its management. The donated kidney is not matching in age and the comorbidities so will not accept the offer except it’s the only available one .
-In case that transplantation is accepted:
I will consider desensitization protocol( PLEX,IVIG AND IL-2I, Rituximab for induction )
In maintenance Immunosuppression : TAC,MMF and Prednisolone.
-The mismatch was 000 and FXCM showed weak positive B cell with negative auto-crossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500)
B cell positivity may be due to previous use of Rituximab for in his previous transplantation, or may be due to low levels of antibodies management will be the same as he is sensitized by his previous transplantation.
-If the donor was his brother with negative DSA and negative FXCM for both B and T cells?
Induction by non-depleting drugs
Will you accept this offer?
The problem with this offer is the requirement of high level of immunosuppression as the donor is deceased, increased age donor, there is a high degree of mismatching and this is the third transplant, So I would prefer a more compatible donor for this recipient with history of PTLD.
What induction immunosuppression can be used?
Given a negative XM and if there is no DSA, Basiliximab can be given and maintenance IS with Tac, MMF, and steroids then after 6 months we can change Tac to mTOR inhibitors or use low dose Tac+ mTOR inhibitors.
some studies added Rituximab to Basiliximab at induction.
The patient should be free of the PTLD for at least one year.
Monitoring of EBV status.
Would your management differ if the mismatch was 000 and FXCM showed weak positive B cell with negative auto crossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500)?
Weak positive B cell XM may be due to Rituximab, so XM result require confirmation by using pronase. if the result was negative after pronase then induction with basiliximab and maintenance therapy with Tac, MMF, steroids for 3-6 months then to either replace tac with mTORi or use low dose Tac and mTORi.
If the XM still positive then desensitization with PE and IVIG then induction with basiliximab and same maintenance therapy as above. with monitoring of DSA level and protocol biopsy.
Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells?
In this case, there is no need for desensitization, and being his brother, i expect better HLA matching, so low level of immunosuppression can be used.
References:
-PTLD affects patient and graft survival. Risk factors for PTLD extremes of age, tacrolimus use, use of T cell depleting antibodies, net maintenance immunosuppression, EBV seronegative, or EBV seromismatch.PTLD treatment is the reduction of immunosuppression which may be associated with a high risk of rejection. Other strategies include the use of chemotherapy including rituximab, EBV-specific cytotoxic T lymphocytes, antiviral agent, surgical resection, and radiation.
Will you accept this offer?
No, I will not accept this offer.
This patient is a high-risk patient because :
1. Had a history of previous 2 transplants failure.
2. History of PTLD
3. Donor with 222 mismatches:
4. Extended criteria donor.
What induction immunosuppression can be used?
Basiliximab as an induction agent and Rituximab as prophylaxis to prevent reactivation of EBV.
Would your management differ if the mismatch was 000 and FXCM showed weak positive B cell with negative autocrossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500)?
Weak positive B cell FXCM can be related to rituximab that was used in the treatment of PTLD, so management would be :
Induction by basiliximab, Maintenance IS Tacrolimus, MMF, Prednisolone and keep them in low target level.
Follow-up for EBV serostatus and DSA level.
Protocol biopsy because this patient has a history of 2 failed transplant
If Luminex identifies DSA (HLA DP3 with MFI 2500):
The role of matching HLA-DP on graft survival from deceased donors does not affect the first transplant but has a significant effect(acute rejection and chronic antibody-mediated rejection) on retransplants.
Desensitisation of the patient (plasmapheresis, IVIG, rituximab).Induction by alemtuzmab
– Maintenance IS Tacrolimus, MMF, Prednisolone and keep them in low target level.
Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells?
NO. Induction by basiliximab.Rituximab prophylaxis for EBV.
Manintenance IS Tacrolimus, MMF, Prednisolone and keep them in low target level.
Follow-up for EBV status and DSA.
References
1.Pallavi Prasad, Dinesh Khullar,Nimish Gupta,Rahul Grover,Gagandeep Chhabra, Kunal Raj Gandhi, Sagar Gupta,and Sahil Bagai .Retransplantation after post transplant lymphoproliferative disorder: overcoming the obstacles. CEN Case Rep. 2020 Aug; 9(3): 200–203.
2.YazinMariea1TimKeyb2AhmedHalawaac3. Renal transplantation against a positive crossmatch due to HLA-DP donor-specific antibodies without prior antibody removal – Case report .Transplantation Reports Volume 6, Issue 3, September 2021, 100076
Will you accept this offer?
He is very highly sensitized recipient based on previously failed two transplantation due to AMR , 6 mismatches , CPRA LEVEL ( no information), ECD with risk of DGF and rejection, morbidity and mortality with death risk based on previous history of PTLD , so in his case he need aggressive Immunosuppressive therapy for both induction and maintenance triple therapy but as a clinician we need to balance the risk and benefit and address this patient medical background as he is young recipients with previous history of cerebral PTLD , still malignancy is the second leading cause of death post transplantation and PTLD is the second common malignancy after the skin cancers (nonmelanoma skin cancer , SSC , BCC Kaposi sarcoma ) we need to know the duration of remission , how aggressive the PTLD by histology , localized ? mentioned its cerebral PTLD ( rare recurrence) French case series of 54 cases of PTLD recurrence was rare only in one case , despite the use ATG as induction IS in this series;(1).
Recent ANZDATA registry reported that overall kidney transplant recipients’ survival were poor with 5 years survival rate of < 50%- and 10-years survival < 20% from the time of the cancer diagnosis (3).Recipients with previous history of cancer also have an increased risk of developing de novo malignancy after transplantation, the risk of cancer recurrence post-transplant is higher in the first 5years post transplantation, I would decline this donor and offer for paired donation program and also need desensitization with plasmapheresis, rituximab and IVIG before the 3rd transplantation.
What induction immunosuppression can be used?
If difficult to allocate another donor, and the cerebral PTLD in complete remission for more than 2 years as per recient KDIGO guidline , the patients should go for desensitization with plasma pheresis, IVIG and rituximab, screen the EBV serology status of the patient and donor should be negative and need close monitoring, consider antiviral prophylaxis.
Rituximab as induction IS not in routine use but there is one randomized double placebo control trial using single dose rituximab as Induction IS with primary outcome of AR in 6 months,according to this study there is no difference in the rate of AR in both groups however after 3 years FU the mortality rate was higher in rituximab group due to infection and CVD death with no difference in Dn DSA development (2).
This case need proper counselling, multisepciality meeting including oncology service and transplantteam addressing all above mentioned risks including risk of death as he need potent induction with ATG and it will be big gun ,use of alternative induction therapy like alemtuzumab or basiliximab will put him at risk of early rejection likely ABMR in addition to the possible recurrence PTLD with possible transforming to aggressive type of lymphoma or development of second primary cancer , especially in the first 5 years post transplantation
desensitaztion will be challanging with ECD , time factor will limit proper desenstazation , may be rituximab with IVIG still can be given ,with induction should be either almetuzimab induction or low dose ATG not more than 3 doses of 1.5mg /kg followed by Maintenance IS for first 3-6 months with tacrolimus based MMF steroid then may consider conversion to M TOR inhibitor with CNI minimization and steroid, close monitoring with EBV serology and DSAs monitoring, protocol biopsy
Would your management differ if the mismatch was 000 and FXCM showed weak positive B cell with negative auto crossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500)?
Weak positive B cells can be explained by previous therapy with rituximab , still possiblity of anti HLA Class 11 DSA like HLADP3 , and should be taken seriously as this is the third transplant can put him at risk of AMR he is highly sensitized recipient and will go for desensitization followed by induction with basiliximab then triple maintenance immunotherapy with tacrolimus ,MMF ,steroid with considering the early conversion to everolimus with Cni minimization plus steroid , close monitor with DSAs assay and EBV serology , proteinuria , protocal biopsy.
Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells?
Still patient high risk group based on previous two transplantation with ABMR so he is at risk for performed anti-HLA , DSA , Dn DSA development need to assess his PRA with lumenix SAB assay and decide accordingly also his brother should be EBV negative, and will use basiliximab as induction IS followed by triple maintenance IS and consider early conversion to everolimus with Cni minimization , steroid with frequent DSA s monitoring and EBV serology , proteinuria , protocal biopsy .
References:
1- A French Cohort Study of Kidney Re-transplantation after Post-Transplant Lymphoproliferative Disorders,Sophie Caillard, Etienne Cellot, Jacques Dantal, Olivier Thaunat, Franc¸ois Provot, Be´ne´dicte Janbon, Matthias Buchler,Dany Anglicheau, Pierre Merville, Philippe Lang, Luc Frimat, Charlotte Colosio, Eric Alamartine, Nassim Kamar,Anne Elisabeth Heng, Antoine Durrbach, Vale´rie Moal, Joseph Rivalan, Isabelle Etienne, Marie Noelle Peraldi,Anne Moreau, and Bruno Moulin, for the French PTLD Regis.
2- Up to date medicine , accessed 2021,Transplantation 2012, Aug,94(3),21.2:Tyclone G,EK berg H,Tufreson G, Mjorusst.
3-KDIGO Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation: transplantation April 2020 ■ Volume 104 ■ Number 4S.
1- No , I will not accept this donor with this high degree of mismatch , we will need strong induction therapy and post transplantation heavy immune suppression that is not suitable for this recipient regarding his past history of PTLD which is one of the severest post transplantation complications that require minimizing immunesuppresion for its treatment. It is better to wait for more suitable donor with better HLA matching
2- Retransplantation after treatment of PTLD is difficult , requiring balance between the need for heavy immunesuppresion ( as retransplant is a high risk patient and previus history of chronic rejection ) and the need to minimize the immunesuppresion to prevent recurrence of PTLD .
For this patient , induction with monoclonal Ab as basiliximab may be reasonable as monoclonal Ab are beneficial for treatment of PTLD specially with his negative crossmatch
Karras A and his collegue investigated retransplantation after PTLD and their recommendations were:
a- Kidney retransplantation can safe in patients with previous monoclonal B-cell PTLD, especially if the lymphoma was limited to the kidney allograft.
b- Treatment with B cells monoclonal Ab , MMF and Tac can be safe in these patients .
c- Check EBV status of the patient : the patient should be positive for anti-EBNA IgG before consideraring retransplantation .
3- B + FCXM in this patient may be caused by previous treatment with rituximab for PTLD , so to confirm the result we need to do pronase test .
4- if the donor was his brother with negative DSA and negative FXCM for both B and T cells :
I will use the same management
Induction with Basiliximab
Maintenance with MMF, Tac and low dose steroid
So after pronase test and proof that it is not Retximab what is you decision.
What about DP3
Will you accept this offer? No. this patient has a history of AMR of his 2 previous kidney transplantation which will make him highly sensitized despite the low level of MFI. The mismatch is 6. With this donor (deceased and 6 mismatch) and his history ,he needs induction and aggressive immunosuppressant medication or he will develop rejection again . This will put him at high risk for PTLD recurrence.
What induction immunosuppression can be used?
In this case , induction is preferred with IL-2 receptor antibody induction 1.
I need to do PRA and Luminex-SAB looking for any DSA. if these are present I need to do desensitization .
Would your management differ if the mismatch was 000 and FXCM showed weak positive B cell with negative autocrossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500)?
the weak positive b cell positive FCM could be due to his previous treatment with rituximab. We need to do pronase treatment to rule out this possibilty2
Regarding the DP3 , it needs induction as it is associated with adverse outcome in second transplant. The choices are depleting antibody or Alemtuzumab induction .3 However , Alemtuzumab is a bad choice since it is associated with aggressive PTLD 4 .so we can proceed with lowest dose rATG5
Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells? Despite the fact he is still high immunological risk, I need to consider his previous history of PTLD. So I will use basiliximab as induction. But I will keep looking for any subclinical AMR by protocol biopsy
1-Cherikh WS, Kauffman HM, McBride MA, Maghirang J, Swinnen LJ, Hanto DW. Association of the type of induction immunosuppression with posttransplant lymphoproliferative disorder, graft survival, and patient survival after primary kidney transplantation. Transplantation. 2003 Nov 15;76(9):1289-93. doi: 10.1097/01.TP.0000100826.58738.2B. PMID: 14627905.
2- Eszter Lazar-Molnar, Denise Hurst, Ann Pole, Julio C. Delgado,Residual serum rituximab induces false positive flow cytometric B cell crossmatch more than 6months post-infusion, Human Immunology,Volume 76, Supplement,2015,Page 128,ISSN 0198-8859,
3-Yazin Marie, Tim Key, Ahmed Halawa, Renal transplantation against a positive crossmatch due to HLA-DP donor-specific antibodies without prior antibody removal – Case report,Transplantation Reports, Volume 6, Issue 3,2021,100076,ISSN 2451-9596,
4- Muzaffar M, Taj A, Ratnam S. Aggressive posttransplant lymphoproliferative disease in a renal transplant patient treated with alemtuzumab. Am J Ther. 2010 Nov-Dec;17(6):e230-3. doi: 10.1097/MJT.0b013e3181c08042. PMID: 19918163.
5-Alexandre Hertig, Andreas Zuckermann,Rabbit antithymocyte globulin induction and risk of post-transplant lymphoproliferative disease in adult and pediatric solid organ transplantation: An update,Transplant Immunology,Volume 32, Issue 3,2015,Pages 179-187,ISSN 0966-3274,
Nice reply and your references are good. Donor age 69 years, does that make any effect on acceptance of this offer?
thank you sir
donor age more than 50 or 60 is associated with poor graft survival and death with functioning graft in deceased organs.
Baid-Agrawal, S., Frei, U. Living donor renal transplantation: recent developments and perspectives. Nat Rev Nephrol 3, 31–41 (2007). https://doi.org/10.1038/ncpneph0383
1&2- cerebral PTLD or PTLD in general is rare complications post-transplantation, overimmunosuppression EBV infection are two risk factors for its development, its treatment based on reduction of immunosuppression and chemotherapy like rituximab, he is high risk patient has previous 2 transplant with history of chronic AMR of course will need strong induction like ATG which may be risk factor for recurrence but it is rare, so, if i have no other option of donor, will accept him but with close monitoring of DSA, EBV IgM should be negative , also close follow up of EBV antibodies IgM and IgG is mandatory. induction should be ATG , we should weigh the risk of overimmunosuppression versus risk of rejection.
Pallavi Prasad,1 Dinesh Khullar,Nimish Gupta,1 Rahul Grover,1 Gagandeep Chhabra,1 Kunal Raj Gandhi,1 Sagar Gupta,1,3 and Sahil Bagai1. Retransplantation after post transplant lymphoproliferative disorder: overcoming the obstacles!. CEN Case Rep. 2020 Aug; 9(3): 200–203.
3-Would your management differ if the mismatch was 000 and FXCM showed weak positive B cell with negative autocrossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500)?
FXCM with weak positive B cell may be due to treatment by rituximab, so we can repeate it using pronase treatment, as regard DSA is below cutoff 3000, so we use basiliximab as induction , with tacrolimus, MMF and steroid as conventional therapy, with follow up of DSA.
4- Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells?
no, will not differ, will be the same like above answer.
Please justify your answer that your management would be same for cadaveric donor age 69 and living donor (young brother).
high immunological risk as young patient with previous 2 kidney transplant failed due to antibody mediated rejection, 6 mismatches and deceased donor with extended criteria will need intensified immunosuppression but with prior history of PTLD, it is suggested that T cell depleting agents should be avoided in induction as it increase the risk of lymphoma and intense immunosuppression may lead to recurrence of PTLD
EBV seronegative recipient shouldn’t receive kidney from EBV seropositive donor as may increase risk of recurrence of PTLD
so will not accept this offer as will lead to poor graft and patient survival
Thymoglobulin should be avoided as increase the risk of recurrence of PTLD
Basiliximab can be used to avoid risk of recurrence although it is high immunological risk transplant
weak positive B cell FCXM and negative autocrossmatch may be due to Rituximab used in treatment of PTLD so FCXM with pronase should be repeated
if negative so induction with basiliximab
if positive so desensitization with plasmapheresis and IVIG
post transplant monitor of DSA
Induction with Basiliximab as the patient has 2 previous failed transplants due to chronic antibody mediated rejection
post transplant monitor of DSA
Retransplant after PTLD can be generally considered safe
It is recommended to wait for a period of one year from control of PTLD before retransplant to decreased the risk of recurrence.
regarding EBV status, It is recommended that patients should have EBV seroconversion before retransplant (should test positive for EBV nuclear antigen IgG)
It is suggested that EBV viral load should be low or undetectable at time of retransplantation
Opelz G, Naujokat C, Daniel V, Terness P, Do¨hler B: Disassociation between risk of graft loss and risk of non-Hodgkin lymphoma with induction agents in renal transplant recipients. Transplantation 81: 1227–1233, 2006
Apithy MJ, Desoutter J, Gicquel A, Guiheneuf E, Westeel PF, Lesage A, Piot V, Choukroun G, Guillaume N. Pronase treatment improves flow cytometry crossmatching results. Hla. 2017 Sep;90(3):157-64.
Caillard S, Cellot E, Dantal J, Thaunat O, Provot F, Janbon B, Buchler M, Anglicheau D, Merville P, Lang P, Frimat L. A French cohort study of kidney retransplantation after post-transplant lymphoproliferative disorders. Clinical Journal of the American Society of Nephrology. 2017 Oct 6;12(10):1663-70.
Parker A, Bowles K, Bradley JA, et al. Management of posttransplant lymphoproliferative disorder in adult solid organ transplant recipients – BCSH and BTS Guidelines. BrJ Haematol. 2010;149(5):693-705.
Riddler SA, Breinig MC, McKnight JL: Increased levels of circulating Epstein-Barr virus (EBV)-infected lymphocytes and decreased EBV nuclear antigen antibody responses are associated with the development of posttransplant lymphoproliferative disease in solid-organ transplant recipients. Blood 84: 972–984, 1994
Leeaphorn N, Thongprayoon C, Chewcharat A, Hansrivijit P, Jadlowiec CC, Cummings LS, Katari S, Mao SA, Mao MA, Cheungpasitporn W. Outcomes of kidney retransplantation in recipients with prior posttransplant lymphoproliferative disorders: An analysis of the 2000–2019 UNOS/OPTN database. American Journal of Transplantation. 2021 Feb;21(2):846-53.
Well done Heba
Need to comment on DP3.
Will you accept this offer?
The patient in the mentioned scenario has a history of 2 failed renal transplants with chronic ABMR, History of PTLD most probably as a result of overimmunosuppression. He received an offer of cadaveric transplant with 6 HLA mismatch and donor aged 69-year-old (Expanded criteria donor). So, the transplant offer has two risk factors making him at high immunological risk for acute and chronic rejection that needs strong induction with polyclonal lymphocyte depletion agent as ATG. With history of PTLD predisposing him to recurrence with strong immunosuppression, that why I think I will not accept this offer.
What induction immunosuppression can be used?
Lymphocyte depletion agent as ATG of 3 doses 3 mg/kg intraoperatively followed by 1.5 mg/kg on postoperative days 1 and 2 or Alemtuzumab (campath).
Would your management differ if the mismatch was 000 and FXCM showed weak positive B cell with negative auto crossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500)?
In this case we can induced with interleukin (IL) 2 receptor blocking antibodies in combination with conventional immunosuppressive agents. Basiliximab 20 mg intraoperatively and 20 mg on postoperative day 4. There is still debate about the clinical significance of a positive B-cell only FCXM (B+FCXM).
Regarding Luminex-SAB identified DSA (HLA DP3 with MFI 2500):
The influence of donor-directed antibodies against the products of HLA class I and II genes in renal transplantation are well described for class I (HLA-A, B and C), but still not clear for class II notably HLA DP. The clinical effects of donor-specific antibodies (DSA) directed against HLA-DP are still controversial.
secondly the DSA level is below the cut off value of MFI of 3000.
Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells?
No, it will be the same as previous scenario of induction with interleukin (IL) 2 receptor blocking antibodies in combination with conventional immunosuppressive agents.
References:
F. Kissmeyer-Nielsen, S. Olsen, V.P. Petersen, O. Fjeldborg
Hyperacute rejection of kidney allografts, associated with pre-existing humoral antibodies against donor cells. Lancet, 2 (7465) (1966 Sep 24), pp. 662-665
agree to most but justify your answer for management for cadaveric donor 69 years versus young brother as living donor
Old age donor is considered from a high immunological risk group, so induction with ATG is needed as per KDIGO guidelines.
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9 Suppl 3:S1.
This patient is a high risk patient in view of:
1) Prior 2 transplants with chronic AMR
2) History of cerebral PTLD
3) Donor with 222 mismatch
4) Extended criteria donor
The patient will require intensive induction and immunosuppression (due to high risk), leading to increased risk of PTLD recurrence.
So, it would be better to reject this offer and look for some other donor.
This patient will be having his 3rd kidney transplant with past history of chronic AMR leading to 2 graft loss and presently having 222 mismatch with the prospective donor.
Hence Induction will be needed in the patient. But due to PTLD, it will not be prudent to use ATG. (1)
Hence induction with Basiliximab should be given.
Maintenance immunosuppression in form of Tacrolimus/ MMF/ steroids. (2)
Changeover from Tacrolimus to mTOR inhibitors can be done after 3 to 6 months.
Prior to transplant, it is imperative to wait for at least 1 year post PTLD remission, with EBV IgG positive and EBV DNA negative in the recipient. EBV positive donor should be avoided. (3)
Post transplant follow-up should include DSA level monitoring, EBV viral load and protocol biopsy.
This weak positive B cell FXCM could be due to rituximab. If FXCM is positive even after pronase treatment, then it signifies positivity due to the DSA.
1) In case of False positive FXCM (due to rituximab):
Induction with Basiliximab should be given.
Maintenance immunosuppression in form of Tacrolimus/ MMF/ steroids.
Post transplant follow-up should include DSA level monitoring, EBV viral load and protocol biopsy.
2) In case of Positive FXCM due to Anti DP3 antibody:
Desensitization with Plasmapheresis and IVIG
followed by induction with Basiliximab and maintenance immunosuppression in form of Tacrolimus/ MMF/ steroids.
Post transplant follow-up should include DSA level monitoring, EBV viral load and protocol biopsy.
FXCM is negative, hence no need of desensitization.
Rest protocol remains same.
Prior to transplant, it is imperative to wait for at least 1 year post PTLD remission, with EBV IgG positive and EBV DNA negative in the recipient. EBV positive donor should be avoided.
Induction with Basiliximab should be given.
Maintenance immunosuppression in form of Tacrolimus/ MMF/ steroids.
Post transplant follow-up should include DSA level monitoring, EBV viral load and protocol biopsy.
References:
1) Ali H, Soliman K, Daoud A, et al. Relationship between rabbit anti-thymocyte globulin and development of PTLD and its aggressive form in renal transplant population. Ren Fail 2020;42:489-494.2) Caillard S, Cellot E, Dantal J, et al. A French cohort study of kidney retransplantation after post-transplant lymphoproliferative disorders. Clin J Am Soc Nephrol 2017;12:1663-1670.
3) Parker A, Bowles K, Bradley JA, et al. Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients – BCSH and BTS guidelines. Br. J Haematol 2010;149:693-705.
good. What are views on donor age and type in this case? ( old cadaveric donor versus young living donor)
The graft survival depends on the donor source, being superior in case of living donor than a deceased donor. Similarly, the lower the age of the donor, the better survival is.
Will you accept this offer?
the donor is not the best option for this patient(ECD and 6 antigen mismatch) with a previous history of cAMR and PTLD.
What induction immunosuppression can be used?
basiliximab will be used as induction, Anti-thymocyte globulin (ATG), calcineurin inhibitors, anti-CD3 (OKT3), tacrolimus, and cyclosporine have been individual agents implicated as potential risk factors for PTLD(1).
Would your management differ if the mismatch was 000 and FXCM showed weak positive B cell with negative auto crossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500)?
first the patient may be treated with Rituximab from the previous attack of PTLD.and this may be the cause of postive B-cell(false positive) this need to be excluded by repeating the cross match after abolishing the CD20 from the B-cell.
IF the false positive FXCM exculded, with the retransplant ,the DSA against HLA DP has a significance on the incidence of the rejection post transplanation, so better to induce him with ATG( low dose<=3mg\kg). follow up DSA level and possible protocol biopsy.
Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells?
induction with basiliximab, and maintenance on tacrolimus,cellcept and prednisilone for the first 3 month .then shift to sirolimus instead of tacrolimus after 3 month or keep tacrolimus on the lower range.
Will you accept this offer?
The pt is young , so better to proceed for transplant inspite he is high risk due to previous 2 transplant and has another problem PTLD
For the donor 222 mismatch , deceased and also old age All these factors make our patient at high risk group and need aggressive induction protocol , Which also can make problem in patient with PTLD
this donor not a good option and better to wait till another matched donor
What induction immunosuppression can be used?
Induction
basiliximab
Maintenance IS :Tacrolimus, MMF, Prednisolone with close Monitoring for EBV serology and DSA titer
Would your management differ if the mismatch was 000 and FXCM showed weak positive B cell with negative auto crossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500)?
weak positive crossmatch in b cell may be due to antibodies against class 2 (like DP3) or by rituximab , so repeating test to exclude rituximab effect if still positive this patient will need desensitization
Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells
it is good donor , I will accept and no need for desensitization but the problem still need DSA monitor because of previous 2 transplantation and failed due to chronic AMR
Induction
basiliximab
Maintenance IS :Tacrolimus, MMF, Prednisolone
Will you accept this offer?
No I will not as this recipient is highly sensitized due to the previous 2 RTx failure and PTLD,and because of this 6 mismatch ECD .
What induction immunosuppression can be used?
ATG for induction and triple is (CNIs,MMF and steroid) then after 6mo consider mTOR inhibitors
Would your management differ if the mismatch was 000 and FXCM showed weak positive B cell with negative autocrossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500)?
Yes I will chose to desensitized the patient by plasmapheresis ,IVIG , and Retuximab
Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells?
After confirming the EBV status of the donor
I will be more cosiuos regarding immunosuppressant agent putting PTLD in our mind , so choice basiximab for induction and triple is for maintenance and consider shifting to mTOR inhibitors after 6 months
With EBV prophylaxis and monitoring DSA and protocol biopsy
-This offer is not good enough for him
as he had cerebral PTLD before which responded to lowering immunosuppression, radio and chemotherpay
And had 2 rejections before with CAMR
So he is considered highly sensitised and high risk patient therefore better not to receive again high immunosuppression doses which will be applied in this offered transplant having 222 mismatch
– The risk factors for PTLD development include EBV serological status at transplantation time , type of transplant, and the type and intensity of immunosuppressive medication also other contributing factors are emerging such as human leukocyte antigen system and of non-EBV viruses.
The largest registry analysis to assess rATG found no risk of PTLD after kidney transplantation, data on the effective dose of rATG are inconclusive, but in patients receiving antiviral prophylaxis it does not appear to be hazardous meanwhile it is reasonable to employ the lowest dose of rATG compatible with effective induction, particularly in EBV-seronegative recipients and high-risk groups(2)
So r ATG can be used as induction as he is considered highly sensitised
Despite lack of hard evidence, most transplant physicians agree to reduce calcineurin inhibitor dose (at least 50%), discontinue antimetabolites, and continue steroids although steroid use after PTLD diagnosis is associated with an increased relapse rate, whereas the use of antimetabolites is not.(1)
-The management wont differ as there is identified DSA (HLA DP3 with MFI 2500)
– Yes since the DSA and FXCM are inegative and the donor is his brother so less immunogenicity is expected so induction can be done by IL2 R inhibitor as the immunosuppression dose will be reduced and this will lower the risk
While maintenance can be done with MMF ,CNI and steroids with close monitoring and biopsy will be needed.
On the other hand CNI agents can increase the risk for PTLD specially with tacrolimus more than cyclosporine,MMF has a neutral effect on PLTD riskand mTOR inhibitors is risk-neutral or tend to reduce risk by inhibiting growth signals in PTLD-associated EBV+ B-cell lymphomas.Treatment of rejection with high-dose steroids can increase PTLD risk (2)
Reference
1-Dierickx etal. Management of post-transplant lymphoproliferative disorders. HemaSphere: June 2019 – Volume 3 – Issue S2 – p 74-77
2-Heritg A etal. Rabbit antithymocyte globulin induction and risk of post-transplant lymphoproliferative disease in adult and pediatric solid organ transplantation: An update. Transplant Immunology2015 ,Volume 32, Issue 3, June 2015, Pages 179-187
PTLD carries adverse implications for both patient and graft survival post kidney
transplantation.
Risk factors for PTLD include :
Extremes of age (both pediatric and older recipients > 60 years old).
Use of T cell depleting antibodies (for induction or rejection).
Tacrolimus use.
Net maintenance immunosuppression.
EBV seronegativity or EBV seromismatch (transplantation of organs from an EBV +
donor into an EBV-recipient.)
Will you accept this offer?
This patient is high risk patient being transplanted twice and had history of PTLD, donor
with 6mismach will be a risk for him even with negative crossmatch FCXM. CAUSE OF
NEED FOR DESNSTIZATION and aggressive immunosuppression, which put him in risk
of PTLD recurrence. So prefer not to accept this donor.
What induction immunosuppression can be used?
IL-2R antagonists are the favored induction agents (30–40%) in most cases of PTLD.
Would your management differ if the mismatch was 000 and FXCM showed weak
positive B cell with negative autocrossmatch and Luminex-SAB identified DSA
(HLA DP3 with MFI 2500)?
In this case patient with high risk for PTLD and positive HLA DP3 MFI 2500, Will be
considered for desensitization using Rituximab ,IVIG plus Plasmapheresis.
Would your management differ if the donor was his brother with negative DSA and
negative FXCM for both B and T cells?
Basiliximab as induction, maintenance therapy Calcineurin inhibitor, mycophenolate
sodium and prednisolone.
Advisable to keep low target levels of maintenance agents in these patients.
Mycophenolate sodium is the only agent seen to have a significant protective effect
against PTLD and its use is common in most series.
mTOR inhibitors deserve a special mention in cases of PTLD.
Although these agents have antiproliferative effects and have been used in combination
with chemotherapy for treatment of PTLD, there is not enough evidence to recommend
their use to prevent PTLD.
References :
1-Pallavi Prasad,Dinesh Khullar et al.Retransplantation after post-transplant
lymphoproliferative disorder: overcoming the obstacles!. CEN Case Rep. 2020 Aug; 9(3):
200–203.
Will you accept this offer?
Post transplant lymphoproliferative disorder (PTLD) carries adverse implications for both patient and graft survival post kidney transplantation [.Risk factors for PTLD include extremes of age (both paediatric and older recipients > 60 years old), use of T cell depleting antibodies (for induction or rejection), tacrolimus use, net maintenance immune suppression and EBV seronegativity or EBV seromismatch (transplantation of organs from an EBV + donor into an EBV-recipient) .
This patient risks, should be assessed from two point
1- Immunological risk ; he carries a high immunological risk ,from his previous 2 failed transplant due to cAMR ,his current old deceased donor with 6 mismatched HLA (expanded criteria donor ) ,despite his negative FCMX
2- Also he is high risk for tumor recurrence ,if aggressive immunosuppressant is planned to use
According to the above justification ,it is better to avoid acceptance of this donor to minimize overall risks.
What induction immunosuppression can be used?
Rituximab has been used in re transplantations after PTLD both as a desensitization protocol in high risk sensitized cases and as a prophylaxis for proliferation of EBV in cases with high viral counts .
IL-2R antagonists are the favored induction agents (30–40%) in most cases .
Would your management differ if the mismatch was 000 and FXCM showed weak positive B cell with negative autocrossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500)?
Yes
I go ahead for transplantation because patients waiting for a deceased allograft with HLA-DP DSA and a positive FCXM can be transplanted successfully with depleting antibody or Alemtuzumab induction without prior antibody removal followed by standard immunosuppression.
Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells?
Yes
Donor should be screened for EBV.
I go ahead for transplantation ,with induction (Rituximab ) and Maintenance immune suppression in re transplantation post PTLD is generally the standard combination of calcineurin inhibitor, mycophenolate sodium and prednisolone . Mycophenolate sodium is the only agent seen to have a significant protective effect against PTLD and its use is common in most series . mTOR inhibitors deserve a special mention in cases of PTLD.
Reference ;
Anil Kumar MS, Khan SM, Jaglan S et al. Successful trans-
plantation of kidneys from deceased donors with acute renal
failure: three year results. Transplantation 2006; 82: 1640-5
Remuzzi G, Cravedi P, Perna A et al. Long-term outcome
of renal transplantation from older donors. N Engl J Med 2006;
354: 343-52.
Caillard S, Cellot E, Dantal J, et al. A French cohort study of kidney retransplantation after post-transplant lymphoproliferative disorders. Clin J Am Soc Nephrol. 2017;12:1663–1670. doi: 10.2215/CJN.03790417.
Reddy N, Rezvani K, Barrett J, et al. Strategies to prevent EBV reactivation and posttransplant lymphoproliferative disorders (PTLD) after allogeneic stem cell transplantation in high-risk patients. Biol Blood Marrow Transplant. 2011;17(5):591–597. doi: 10.1016/j.bbmt.2010.08.007.
Renal transplantation against a positive crossmatch due to HLA-DP
donor-specific antibodies without prior antibody removal – Case report
Yazin Marie a,1,*, Tim Key b,2, Ahmed Halawa a,
This patient had failed transplant due to chronic AMR and had previous PTLD which had been cured . we can proceed with transplantation after 1 year of remission of PTLD with best result if the patient became EBV IgG positive and EBV viral load undetectable or low .
The most important risk factor for PTLD is the net state of immunosuppression .
The offered kidney is from extended criteria donor (donor age > 60 years ) and had 6 antigen mismatches which carries high risk of acute rejection and need aggressive induction and potent immunosuppression which will increase the risk of recurrence of PTLD. So it will be better to wait for better offer with better match and standard criteria donor.
This patient had 6 mismatches and previously sensitized ( previous cAMR) , cPRA is not provided in the scenario , puts him in the category of high immunological risk. So if we proceeded with transplantation we need induction with ATG and maintenance with triple drugs ( CNI, MMF, PRD) . We should consider conversion to mTOR inhibitors after 6 months if no contraindications.
The positive B cell crossmatch could be due to previous rituximab treatment but the negative auto crossmatch excludes this possibility . so this positive crossmatch is due to the anti DP DSA which the patient had ( despite low level). So it will be better to avoid this donor offer and if we accept the donor offer , we need to do desensitization before transplantation .
If the donor was his brother ( at least 3 HLA match ) and negative flow crossmatch , with low cPRA , this will puts the transplantation at low immunological risk category ( from all scenarios given , this will be the best offer) and we can do induction with Basiliximab and maintain him on low dose immunosuppression (CNI, MMF, PRD) with considering switch to mTOR at 6 months post transplantation if no contraindication. Viral prophylaxes with Ganciclovir for 1 year is preferred.
Reference:
(1) Sophie Caillard, Etienne Cellot, Jacques Dantal, Olivier Thaunat, Franc¸ois Provot, Be´ne´dicte Janbon, Matthias Buchler, Dany Anglicheau, Pierre Merville, Philippe Lang, Luc Frimat, Charlotte Colosio, Eric Alamartine, Nassim Kamar, Anne Elisabeth Heng, Antoine Durrbach, Vale´rie Moal, Joseph Rivalan, Isabelle Etienne, Marie Noelle Peraldi, Anne Moreau, and Bruno Moulin.
A French Cohort Study of Kidney Retransplantation after Post-Transplant Lymphoproliferative Disorders Clin J Am Soc Nephrol 12: 1663–1670, 2017. doi: https://doi.org/10.2215/CJN.03790417
Retuximab is not an auto antibody so still can give a positive result
1- yes I will accept this offer but after PRA test and possible desensitization and screening for EBV as he had history of PTLD(this high risk patient)
2-The patient is high risk so the induction would be with ATG
3-No the mangment will be the same as he has DSA even with this good match
4-May be if the PRA test was negative and there is good match we can decrease the immune suppression
PLTD risk is high in SOT especially in cardiac & lung transplant when the risk increased 50-120% comparing to general population while in liver & renal transplant the risk around 1-5%. There are several risk factors for developing PTLD:
PTLD with EBV-ve recipient occur later than PTLD with EBV +ve recipient( 62 mon vs 11.5 mon). CNS disease constitute 10-15% of all PTLD & usually associated with decrease survival.
Second transplant after cure from PTLD is possible with waiting time in adult at least 1 year & in pediatric at least 2-3 years with remission of EBV viremia & seroconversion from positive to negative in previous EBV -ve recipients. French registry show that patient with cured PTLD & re transplantation who use ATG for induction, the recurrence of PTLD was low.
Due to elderly donor with high HLA mismatch & sensitized recipient, it is better to find another donor.
As this patient is highly sensitized he need desensitization with plasmapharesis +IVIG with rituximab & induction with ATG.
If the HLA mismatch was 000 the induction will be with anti-Il-2 blocker. If the donor was his brother without DSA, & because he loss his graft twice due to AMR so the induction will be with ATG.
References:
Reconsider ATG with PTLD are there safer alternatives?
PTLD is well recognized complication of SOT and the most common post-transplant malignancies. In most cases PTLD is associated with EBV infection of B cells either from primary EBV or consequence or reactivation post-transplantation. PTLD usually occur in the first year post-transplantation when the patient received potent immunosuppression and therapeutic levels of immunosuppression drugs are higher. The higher the immunosuppression used, the greater the risk of PTLD. It may present as localized or disseminated. The initial management of PTLD is reduction or withdrawal of immunosuppression which allows the natural immunity to recover and gain control over lymphoproliferation and may reverse the lymphoproliferation. But decreasing immunosuppression in the setting of kidney transplantatuion carries also high risk of allograft rejection.
To minimize the risk of developing PTLD, according to the 2012 consensus on PTLD from Seville workshop group, recommended that the EBV status of both donor anr recipient should be addressed and whenever possible, EBV negative recipients should receive grafts from EBV negative donor. The next suggestion is minimization of immunosuppression. The last recommendation of the group is to consider preemptive treatment for patients who appear at risk to develop PTLD (rising EBV viral load).
Will you accept this offer?
This young patient who is highly sensitized with a history of previous 2 failed transplants due to antibody mediated rejection, in addition to history of PTLD, 222 mismatch with donor, and kidneys from expanded criteria donor carry many risk on graft survival and overall survival ranging from DGF and acute rejection to the development of malignancy and mortality. The context of high risk recipient, taking in consideration history of failed transplants, mismatch, kidney from ECD, mandated the use of aggressive induction therapy including r-ATG. But r-ATG induction is associated with a higher risk of PTLD and its aggressive form (monomorphic PTLD and Hodgkin lymphoma). So this transplantation carries high risk for the patient not only in terms of rejection but also in terms of overall survival. I would not proceed with this offer.
What induction immunosuppression can be used?
This is a highly sensitized recipient not only because of 2 previous grafts, but because the cause of the previous grafts is antibody mediated rejection which means that the patient has already preformed antibodies which could be donor specific for the offered allograft.
If kidney transplantation has been considered, then desensitization of the recipient should be performed initially with IVIG, plasmapheresis and rituximab. Rituximab is the standard treatment for PTLD if the reduction in immunosuppression failed to reverse the disease. But is not used as prophylaxis for PTLD.
The EBV status of the donor should be considered as we should avoid EBV positive donor which carry in this case higher risk of developing PTLD.
Based on the evidence of decreased risk of rejection in high risk group, Induction therapy should be with r-ATG, and maintenance therapy with standard dose CNI/MMF/steroids. The regimen containing low dose CNI/ m-TOR I (Everolimus), MMF , AND steroids owing to the antiproliferative effects of m-TORi, combination of TAC/+ mTORi was shown to increase the risk of PTLD and this was reported in few studies.
Would your management differ if the mismatch was 000 and FXCM showed weak positive B cell with negative autocrossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500)?
In tis settings with full match and weak positive B cell, negative auto crossmatch and anti-HLA DP3:
The weak positive B cell crossmatch could be explained by the previous treatment with anti CD20, which causes false positive B cell crossmatch.
The presence of anti-HLA DP3 with MFI 2500 is associated with reduced graft survival in subsequent transplantation. Although the MFI is not too high but with 2 previous failing kidneys, recommendations are to desensitize the recipient with plasmapheresis and rituximab.
To minimize the risk of PTLD, I would suggest Induction therapy with anti IL2, as the higher risk here is not acute ACR, but ABMR. Maintenance therapy with CNI/MMF/steroids.
Antiviral prophylaxis according to seropositivity of EBV, but I would avoid the donation from EBV positive donor, because of the strong corelation with PTLD.
Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells?
In this scenario the induction therapy should be anti-IL2 based without induction and maintenance therapy with CNI/MMF/steroids, with performing protocol biopsy as the patient has 2 previously failed kidneys because of antibody mediated rejection and ABMR could be subclinical and needs immediate treatment.
References
-UpToDate
-Medscape
-ASNRT lectures
-Hatem Ali, Karim Soliman, Ahmed Daoud, Ingi Elsayed, Tibor Fülöp, Ajay Sharma, and Ahmed Halawa. Relationship between rabbit anti-thymocyte globulin and development of PTLD and its aggressive form in renal transplant population. Ren Fail. 2020; 42(1): 489–494.
-Marcelo Santos Sampaio 1, Yong W Cho, Tariq Shah, Suphamai Bunnapradist, Ian V Hutchinson. Association of immunosuppressive maintenance regimens with posttransplant lymphoproliferative disorder in kidney transplant recipients. Transplantation. 2012 Jan 15;93(1):73-81.
EXELLANT
Exellent
PTLD is a serious and fatal complication of renal l transplantation due to
Although EBV negative cases and T cell lymph proliferative disease can occur
Prevention
Treatment
The prognosis of a patient with PTLD is poor with overall survival of 25-35%
Will you accept this offer? What induction immunosuppression can be used?
Would your management differ if the mismatch was 000 and FXCM showed weak positive B cell with negative autocrossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500)?
Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells?
Exellent Sherif
wise to turn down the first graft offer.
correct explanation of the positive Luminex ,week positive FCXM and negative autocrossmatch previous Reuximab.
Initial induction protocol is acceptable.
your last one with ATG induction with PTLD is not.
This means that even if the patient has PRA> 80 % I will consider him low risk and i should use basiliximab. am I right ?, thanks a lot
exactly your first planfor desensitisation was wiser.
So the correct answer is
First scenario I will not accept offer
Second desensitization then IL2RA induction
3rd scenario basiliximab induction
Will you accept this offer?
I will not accept for the followings:
What induction immunosuppression can be used?
Supposing that transplantation is accepted:
I will consider desensitization protocol( PLEX,IVIG AND Rituximab for induction )
In maintenance Immunosuppression : TAC,MMF and Prednisolone.
Would your management differ if the mismatch was 000 and FXCM showed weak positive B cell with negative autocrossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500)?
Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells?
Although this offer is good for the patient in away that he may not need high doses at maintenance Immunosuppression but
management will be the same because of the previous transplantation and sensitization.
Referrences:
1- S. Y. Choo, “The HLA system: genetics, Immunology, clinical testing, and clinical implications,” Yonsei Medical Journal, vol. 48, no. 1, pp. 11–23, 2007.
Welldone
many questions should be asked first.
A-regarding pt its self.
1-what is his blood group?
as an example if pt with blood group o he will wait for longer time to be allocated akidney offer with history of sensitization so his chance is very low to get acomaptible kidney.
2-what is the cause of his cAMR?
is it non comapliance to medication or under immunsuprrseion , or the prevoius two kidnies were high risk transplants with high dsa and positive cross match requried desentization.
3-what is his cPRA now ?
4-any avilable living donor under workup now for him?
B-regarding the cadaveric offer its self.
1-is the donor diabetic ?and if yes for how long , what is his last acr.?
2-is the donor HTN? if yes how many medications he was on to control his blood pressure.
3-what is the size of his kidnies in us ?
4-what is the cause of his death?
collecting the data from this question will make me decide wether to accept the offer or not.
the cadaveric kidney transplantion is an art allocating suitable kidnies for suitable donors .
Will you accept this offer?
if no avilable living donor and after assesing the donor carfully putting in considerations the questions which have differnt answers above , i will accept the offer rand may be for DUAL KIDNEY TRANSPLANT.
What induction immunosuppression can be used?
i will go for atg 6 mismatches with past hitory of failed 2 grafts and cAMR .high risk tranplantion.
Would your management differ if the mismatch was 000 and FXCM showed weak positive B cell with negative autocrossmatch and Luminex-SAB identified DSA (HLA DP3 with MFI 2500)?
with zero mismatch and fxcm only positive weak b i can ask the HLA lab to repeat the cross match again , if came with the same result i will accept as Kidney transplantation with low level DSA with or without a low positive XM is a reasonable option for highly sensitized patients and may be advantageous compared to waiting for a negative XM deceased donor. The risk for CAMR is low in patients with no DSA even if the XM is positive. Patients with cPRA≥80% are at risk for CAMR even if no DSA is detected
Would your management differ if the donor was his brother with negative DSA and negative FXCM for both B and T cells?
for the induction immunosuprresion, with this scenario i will go for basilixmab putting in considertion his history of his ptld, and maintinace immunosupression with fk, mmf , pred and i may offer for him prtocol biobsies to be sure that there is no underlying subacute rejection going on.
refeences
1-Transplantation. 2017 October ; 101(10): 2422439.doi:10.1097/TP.0000000000001619
REMEMBER labs when faced with anegative Luminex with positive weakFCXM;
an autocrossmatch is done
repeat automatically the test before sending the results
there the posobility of Retuximab antibodies used for his PTLD
Sure, but does it make adifference in our descion?
If Luminex lysate DSA crossmatch is negative will accept the offer.
If Luminex lysate DSA crossmatch is positive will reject the offer.
Evaluation of Crossmatch Techniques for Deceased Donor Transplant Program – Need of the Hour
Ankit Mathur et al
Basiliximab
for cadaver donor – reject
for live donor
Desensitization with Rituximab, alternate day plasmapheresis plus ivig 100mg/kg post plasmapheresis
Induction- Basiliximab
Maintenance- Tacrolimus, MMF, Prednisolone .
Induction-Basiliximab
maintenance -Tacrolimus, MMF, Prednisolone
******Prior to consider the patient for retransplant his PCR EBV should be negative and EBV serology should be positive for EBV IgG.
Retransplantation after post transplant lymphoproliferative disorder: overcoming the obstacles! Pallavi Prasad et al .