1. A 46-year-old CKD 5 patient secondary to unknown aetiology. He has been on the waiting list for 16 years (highly sensitised due to 2 previous transplants and blood transfusion. His cRF (cPRA) is 95% and MFI is 2230 mainly due to anti-DP3 antibodies He received a kidney offer from a deceased 43-year-old donor. His crossmatch results are shown below.
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Please answer the following:
- Comment on the report below
- Comment on the difference between the broad and the split mismatch?
- What is the impact of split mismatch on graft survival?
- HLA B48 is a rare antigen. How was it managed?
- Will you proceed with the transplantation?
- If yes, what is your immunosuppression protocol?
- If no, what are the other options?
1.split mismatch: 222
broad mismatch:121
ODT default:111
positive B. cell FXM shows class 2 HLA antibody and Luminex indicates that it is related to DP-HLA
2.Broad mismatch shows mismatched based on serological HLA typing but, split is based on molecular methods and is more specific
3.More split mismatches especially more than 3/6 is associated with worse long-term graft outcome
4.It is a rare Ag and is managed as HLA-B40
5.Yes, because of low presentation of HLA-DP on kidney and long waiting time of this patient
6.Induation with basiliximab and then triple immunosuppression with CNI, MMF and prednisolone
7.Pired kidney donation
1. this patient blood group A+ve , Broad mismatch 1.2.1 , highly sensitized.( +ve B cross match ).
2.Split mismatch of value in RTX
3.split mismatch has poor graft function outcome.
4.HLA B48 is a rare antigen. How was it managed : since it is rare Ag , so manage to most similar Ag B40
5.patient highly sensitized so , no .
6.if yes, make desenitization with ATG or may use Anti-IL-6 R., Immunosuppresion protocol : conventional triple therapy : steroids, antiproliferative ( MMF), CNI ( Tacrolimus).
7.other options continue on RRT , waiting for better donor matching , or KPD.
HLA typing and blood grouping and cross matching testing
Donor blood group : A+.but there is no blood grouping for the recipient
Broad mismatch: 1.2.1. Split mismatch : 2.2.2.
flow cytometry cross matching show negative T cell cross match and positive B cross match
when do HLA typing on low resolution we detect difference at antigen level( broad) , while high resolution typing will detect the allelic variant( split)
Opelz G et al.showed that matching for HLA split antigen resulted in better outcome than matching for broad HLA antigen.
No , the patient is highly sensitized
If yes , after consent and do desensitization then proceed to transplantation
induction by ATG /Alemutuzemab : high risk patient
maintenance therapy : Tac, MMF, steroid
if no
wait for more compatible donor
or kidney paired donation
1)Comment on the report below.
Donor blood group : A+.
Broad mismatch: 1.2.1. Split mismatch : 2.2.2.
ODT Default : 1.1.1
FC positive for B cell.
Highly sensitization.
2)Comment on the difference between the broad and the split mismatch?
Split mismatch has higher sensitivity compare to broad mismatch in transplant immunology.
3)What is the impact of split mismatch on graft survival?
Poor allograft survival and outcome.
4)HLA B48 is a rare antigen. How was it managed?
Manage as HLA B40 the nearest common antigen.
5)Will you proceed with the transplantation?
No. But will discuss with the patient the potential high risk of allograft rejection and cost of desentization.
6)If yes, what is your immunosuppression protocol?
Induction : ATG / Alemtuzumab
Maintenance : Tacrolimus, Mycophenolate, steroid,
7)If no, what are the other options?
enrol in pair kidney donation program.
continue RRT.
ABO comptability : not sure as recipient group not m,entioned.
HLA mismatch : 222
high sanitized patient
split mismatch is more important as it is more specific to transplnation.
the more split mismatch , the less the survival of transplanted kidney.
Such somewhat rare antigen are frequently dealt with as most nearest more common ones, HLA B48 should be dealt with as B40.
taking in mind that this is a high sensitized transplantation, i would proceed with the Tx after discussing with the patient.
plasma pharesis , IV Ig for desensitization..
induction therapy using ATG
maintenance therapy using : steroid, MMF.CNI
continue dialysis till find a better matched donor
Comment on the report
Split mismatch on graft survival
Bad outcome for graft – lower rates of survival
HLA B48 management
Since it is a rare antigen, it can make it difficult to get a suitable donor.
Defaulting to the nearest HLA antigen can possibly allow translation with lower risk
Transplantation
I will proceed with patient’s informed consent.
Immunosuppression protocol
Other options
Comment on the report:
ABO: Donor A+, Recipient blood group not mentioned.
HLA:
Broad mismatch: 2.2.0
Split mismatch: 2.2.2
What difference between broad and split mismatch?
Broad mismatch tests for a broad HLA antigen (A, B, DR). While split mismatch tests for more specific antigens split from the broad one.
What’s the impact of split mismatch on graft survival?
It was proven that the lower the split mismatch, the longer the graft survival.
Will you proceed with transplantation?
This is a case of a highly sensitized patient with a high mismatch, transplanting such a patient would carry a high probability of graft rejection.
I’d enroll the patient in a kidney paired exchange program looking for a more suitable donor.
If yes, what is your immunosuppression protocol?
For high-risk recipients;
Desensitization using: IVIG, Rituximab, plasma exchange, or immunoadsorbent.
Induction therapy: Depleting antibodies (ATG).
Maintenance therapy: CNI, MMF, steroid.
If not, what are the other options?
1. Enrol in a paired kidney exchange program looking for a more suitable patient.
2. Desensitizing the patient using one or more of the following protocols: IVIG, Rituximab, plasma exchange, or immunoadsorbent.
3. If in need for renal replacement therapy meanwhile, I’ll initiate peritoneal dialysis as it has better outcomes after transplantation compared to hemodialysis.
ABO group: Donor blood group is A+ve, Patient’s blood group is not available.
Cross match: MM 1,2,1 (broad) 2,2,2 (spit), 1.1.1 (ODT default).
Flow cytometry positive with B-cell (mostly due to DSA against HLA-DP or previous treatment with rituximab) and negative with T-cell.
HLA-A2 has been previously listed as unacceptable at ODT.
Positive DSA against HLA-DP, and against DQB1 cannot be ruled out.
High immunological risk mismatch
HLA antigens classification are developing over many years until today.
Earlier there were a lot of undistinguishable antigens which are reflected now as broad mismatch. With modern techniques, a lot of new antigens were discovered and the level of differentiation among these antigens is currently involving alleles and epitopes for which we use now the term split mismatch
Examples: HLA-A9 Broad (Splits HLA-A23 and HLA-A24), HLA-B5 Broad (Splits HLA-B51 and HLA-B52) and HLA-DR2 Broad (Splits HLA-DR15 and HLA-DR16).
What is the impact of split mismatch on graft survival?
Sapir-Pichhadze et al found higher Class II eplet mismatch was associated with transplant glomerulopathy (TG). 5
Wiebe and colleagues found that higher class II (separately for HLA-DR and HLA-DQ) eplet mismatches are associated with class II de novo DSAs formation. 6
Some antigens are common among specific population, for example HLA B48 antigens are common among the West Pacific Rim, Americas indigenous peoples and Northern Eurasians.
B*4801 is part of a group of alleles including B*4201 that share Intron 1 sequence with B*0702, which is common over the above mentioned population. 8
usually HLA B48 is managed as HLA B40.
Highly sensitized patient with poor match, expected poor outcome and complications post-transplant, young age of patient, long waiting time. All these factors make it a difficult decision; however, I will opt for going ahead for transplantation after proper counselling of the patient with all expected hazards vs limited options in the other hand.
High immunologic risk transplant:
Induction: ATG or Alemtuzumab
Maintenance: Tacrolimus, Mycophenolate, and steroids.
Regular follow up including DSA
The other options include:
1- to stay on Dialysis, on waiting list for better matched donor,
2- If he has a living donor consider kidney paired exchange for better matched donor.
3- Consider desensitization before next transplant.
Q1_ Flow cytometry is positive for B cell and negative for T cell in all remote and new samples.
It is also negative for both B and T cells autoreactivity.
Q2- Broad mismatch here is 2-1-1
Split mismatch is 2-2-2
Q3- Selection of a donor depending on split mismatach has a better graft survival.
Q4- Rare Antigens are usually managed to nearist common antigen which is 40
Q5- This is highly sensitized patient with cPRA of 95% and DSA anti DP3 of MFI 2230, so need special preparation before transplant.
Q6- Induction with ATG or almetuzumab and maintanance therapy with tacrolimus, MMF, and prednoisolone
Q7- Searching for another donor.
Answers from the lecture
Spilt mismatch has better specificity than a broad one, it identified subclasses of the genes .
spilt mismatch is associated with poor graft survival.
it is a high-risk transplant and needs to counsel the patient risk & complications of this offer.
I will proceed with the transplantation as MFI was considered below 5000.of DP3
Induction with ATG or alemtuzumab , maintenance with trible (TAC ,MMF, steroid)
Unfortunately, no other option apart from regular dialysis, as this patient on the waiting list for 16 years, highly sensitized, c PRA95% ,and no live donor
o This an HLA typing and wet cross- matching results of the patient and the potential donor.
o No information is given about the recipient blood group .
o HLA typing is done by FCXM technique.
o There is 1,2,1 mismatch at the level of the broad level and 2,2,2 mismatching at the spit level between the patient the potential donor.
o The result is positive B cell cross matching and negative T cell cross matching, and negative auto-cross match results for both B and T cells.
o The positive B cell cross match is due to the Anti HLA-DP antibody. Moreover, the presence of Anti HLA-DQ antibody cannot be ruled out.
Broad antigens ( super type) have poor specificity and they were identified at an earlier time with serological techniques, but the more advanced molecular DNA technologies enabled us to identify newer antigen subclasses called split antigens(subtype) which are the more refined cell surface antigens in relation to the broad ones
Split mismatching is associated with poor graft survival
Rare HLAB48 is a rare antigen so it is defaulted to the common antigen HLA-B40 to facilitate transplant in this highly sensitized patient
Yes, This highly sensitized recipient and has minimal options for transplantation beside being a long waiter. However, the risks should be clearly explained to the patient due to high degree of mismatching and positive B cell cross matching due to HLA-DP DSA, which constitute a high risk for ABMR, in addition, there is a possibility of HLA-DQ DSA which is associated with a risk of graft loss and and resistance to treatment.
If the patient accepts the risk, then induction with ATG or Alemtuzumab (high immunological risk patient)and maintenance therapy with Tacrolimus (keeping high trough level in the first 3 months between 8- 10 ng/ml) , MMF, prednisolone.
He will require close monitoring of his renal functions, proteinuria, follow of DSA level and if needed transplant biopsy.
If patient refused this cadaveric graft ,Keep the patient on dialysis although the chances to find a more suitable donor are less in view to his high sensitization
1. Comment on the report below:
2. Comment on the difference between the broad and the split mismatch?
4. HLA B48 is a rare antigen. How was it managed?
5. Will you proceed with the transplantation?
6. If yes, what is your immunosuppression protocol?
7. If no, what are the other options?
Q1: Cross Match Report Analysis:
Q 2: Difference between the Broad & Split Crossmatch:
Q3: Impact of split mismatch on graft survival:
Q4: Dealing with Rare Antigen:
Q5: Will you proceed with the transplantation?
Q6: Immunosuppression Protocol:
Q7: Options other than Transplantation:
Blood-group compatibility cannot be evaluated as blood group of recipient not mentioned.
The HLA typing reveals 121 mismatch on broad antigen typing and a 222 mismatch on split antigen typing as HLA A23 and A24 are spilt antigen for broad antigen A9. HLA DRB1*13 and DRB1*14 are split antigens for broad antigen DR6.
FCXM of 6 historical sera of the patient are negative except with B cell FCXM which is positive.
The positive B cell FCXM could be due to anti-HLA-DP antibodies.
* Difference between broad and split mismatch
A broad antigen is HLA molecule with limited specificity and can be divided into two or more split antigens having a more specific cell surface reaction than the broad one. For example, HLA A23 and A24 are spilt antigens for broad antigen A9 and HLA DRB1*13 and DRB1*14 are split antigen for broad antigen DR6.
*Impact of split mismatch on graft survival
Split antigen mismatches had 5 times higher difference in graft survival between 0 and 6 mismatches (31% versus 6%) at 3 years in comparison with broad antigens.
By default to be assigned to nearest HLA antigen ; B40,so considered matching with HLA B40.
*Will you proceed with the transplantation?
Yes
With 16 years waiting, positive B cell FCXM, probably due to anti DP antibodies; class II HLA are less expressed on the renal tissue .Patient acceptance of risk to be obtained .Better outcome than remaining on HD.
*Immunosuppression protocol( high risk)
Induction therapy: ATG 1-1.5 mg/kg per day for 4-6 days ;total dose 6 mg/kg.
Maintenance immunosuppression: triple drug therapy including Tacrolimus: Target trough level of 8-10 ng/ml, Mycophenolate mofetil (MMF): 1000 mg twice a day Corticosteroids: Injection methylprednisolone 500 mg intravenous on the day of surgery, then oral prednisolone 1mg/kg/day for 3 days and then 20 mg/day tapered to 5 mg/day over next 6 to 8 weeks. Close follow-up with clinical and laboratory evaluation: complete blood count, urine examination and serum creatinine, monitoring for proteinuria. In addition, DSA testing: once in first three months, then annually or whenever there is any graft dysfunction, alteration in immunosuppression or nonadherence together with protocol biopsy.
To continue on dialysis and looking for another better matching offer.
References:
Opelz G. Importance of HLA antigen splits for kidney transplant matching. Lancet. 1988 Jul 9;2(8602):61-4.
Yacoub R, Nadkarni GN, Cravedi P, He JC, Delaney VB, Kent R, et al. Analysis of OPTN/UNOS registry suggests the number of HLA matches and not mismatches is a stronger independent predictor of kidney transplant survival. Kidney Int. 2018 Feb;93(2):482-490. doi: 10.1016/j.kint.2017.07.016. Epub 2017 Sep 29.
Takemoto SK, Terasaki PI, Gjertson DW, Cecka JM. Twelve years’ experience with national sharing of HLA-matched cadaveric kidneys for transplantation. N Engl J Med. 2000 Oct 12;343(15):1078-84. doi: 10.1056/NEJM200010123431504. PMID: 11027742.
Wissing KM, Fomegné G, Broeders N, Ghisdal L, Hoang AD, Mikhalski D, et al. HLA mismatches remain risk factors for acute kidney allograft rejection in patients receiving quadruple immunosuppression with anti-interleukin-2 receptor antibodies. Transplantation. 2008 Feb 15;85(3):411-6.
Shi X, Lv J, Han W, Zhong X, Xie X, Su B, et al. What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients. BMC Nephrol. 2018 May 18;19(1):116.
Williams RC, Opelz G, McGarvey CJ, Weil EJ, Chakkera HA. The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts From Deceased Donors. Transplantation. 2016 May;100(5):1094-102.
Wiebe C, Gibson IW, Blydt-Hansen TD, Karpinski M, Ho J, Storsley LJ, et al. Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant. 2012 May;12(5):1157-67.
Opelz G, Döhler B. Association of HLA mismatch with death with a functioning graft after kidney transplantation: a collaborative transplant study report. Am J Transplant. 2012 Nov;12(11):3031-8. doi: 10.1111/j.1600-6143.2012.04226.x. Epub 2012 Aug 17.
Su X, Zenios SA, Chakkera H, Milford EL, Chertow GM. Diminishing significance of HLA matching in kidney transplantation. Am J Transplant. 2004 Sep;4(9):1501-8.
10) 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.
11) 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.
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
HLA typing and crossmatch result of a patient and potential donor .
donor blood group : A+VE recipient blood group : unknown
ABO combatibilty ?
HLA typing done by molecular method .
there 2 2 2 missmatch .
crossmatching (wet type )is performed using flowcytometry method .
T cell FC NEGATIVE .
B cell FC POSITIVE .
Auto B cell crossmatch negative
Auto T cell crossmatch negative
the positive crossmatch is due to DSA against HLA DP .
=================================================
With the modern HLA typing method the previously considered a closely related single antigen, appeared to be more than one ( split ) antigens .
example :HLA-A9 was split into HLA-A23 and -A24, and HLA-A10 was split into HLAA25, -A26, -A34, and -A66.
==============================================================
In one study, the graft outcome is better when HLA typing is performed by split than when it is done by broad HLA TYPING .
In one study the graft survival was 18% difference when typed for split HLA ,in comparison to only 2% difference when broad matched.
these data sugest that HLA split typing is important in renal transplantation .
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4.HLA B48 is a rare antigen. How was it managed?
==============================================
5.Will you proceed with the transplantation?
in this patient with long waiting time, highly sensitized, low chance of getting other better matched donor and in spite of being of high risk for rejection , i will proced with transplantation after explaning the risk for the patient. as the quality of life and survival is better in kidney transplantation than in remaining in hemodialysis .
============================================
6.If yes, what is your immunosuppression protocol?
as this patient is a high risk this needs
induction therapy with ATG and triple immune supressants ( TACROLIMUS , PREDNISOLONE ,MMF ) WITH CLOSE MONITORING .
====================================================
7.If no, what are the other options?
To stay on HD waiting another donor .
References
1-G OPELZ .IMPORTANCE OF HLA ANTIGEN SPLITS FOR KIDNEY TRANSPLANT MATCHING,The Lancet,1988, Vol: 332.
2- Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017.
1. 46 year old recepient with a deceased donor 43 years old blood group A
2 . Broad mismatch 1:2:1
Split mismatch 2:2:2 as HLA A23 and A24 are split antigen of A9
3. Split antigens are more specific and split antigens are immunogenic causing possible graft dysfunction and decrease graft survival
4. HLA B48 rare antigen is defaulted to B40
5. I shall proceed for Tx
6 . This is a highly risk recepient with very high immunological risk for graft rejection
So will need induction(ATG: for 4 to 6 days 1mg/kg per day and high trough level tacrolimus therapy 8-10 ng/ml together with high dose steroids
With strict follow up post transplant for
Kidney function tests , A/C ratio , DSA , and biopsy if required
A23 and A24 are splits here we have 222 mismatch which is very high risk so we need aggressive immune impression with high induction with ATG. split mismatch is more correlated and is associated with worse graft survival; matching at split level is better than the broad. Another option is paired donation if available
seems to be cadaveric (as lymphocytes from spllen were used, so using this transplantation donor can be accepted as better than being on maintenance dialysis. PRAis already high and always there is a risk
1.split ag mismatch 2:2:2,so high risk tx
2.split ag mismatch is more specific than broad
Ag mismatch,so in lower split ag mismatch,
there will less ab formation and greater graft
Survival.
3.more the split ag mismatch, poor the graft
survival.
4.Hla B28,is a rare ag and default to nearby B40
ag.
5.yes, I will proceed with tx with high induction
treatment.
6.ATG induction with 6mg/kg
Tacrolimus 0.15mg/kg with target level of 12
MMF 2gm/day
Corticosteroid.
7.if no, then can go for ABOi tx,or wait for
match and continue hd.
1.Comment ON THE REPORT BELOW:
Abo Blood Group Of The Recipient Un Known.
Hla Typing Broad 1:2:1, Split 2:2:2,( Not Good For Graft Survival) Default Odt 1:11.
Mentioned That Patient Has Previous Two Trx Plus Blood Transfsion Not Mentioned At Which Year Before 90 Or After.
Dsa Positive Against Hla Dp3 Less Likly To Be Expressed In Kidney Tissue.
Patient Cosidered Highly Sensetized Which Make Graft Survival Is Less
2. Comment ON THE DIFFERENCE BETWEEN THE BROAD AND THE SPLIT MISMATCH?
Whether MATCHING FOR Hla ANTIGEN SPLITS RESULTS IN BETTER TRANSPLANT OUTCOME THAN MATCHING FOR BROAD That Shows No Actual Specificty For The Cell As Broad Can Be Devided Into 2 Or More More Specific To Cell Surface.
3.What IS THE IMPACT OF SPLIT MISMATCH ON GRAFT SURVIVAL?
Split Mismatch Has Agreat Role In Trax As It Is Associated Wit Poor Graft Survival .
4.Hla B48 IS A RARE ANTIGEN. How WAS IT MANAGED?
As Report Shows Hla B48 Arare Antigen So It Is Defaulted To The Nearest Common One Which Is Hla B40 Wich Is Considered Amatch.
5. Will YOU PROCEED WITH THE TRANSPLANTATION?
For Me Yes As For Others It Is Associated With Graft Survival Due To Missmatch And High Sensitaization But Patient Has Nothing To Lose As He Is On Waiting List For The Last 16 Years And This Adeceased Donor.
6.If YES, WHAT IS YOUR IMMUNOSUPPRESSION PROTOCOL?
For Desentization I Will Ask For Plasmapharesis Plus Ivig Followed By Aggressive Induction Therapy Atg Plus Maintenance With Tacrlimus And Mmf Plus Ccs.
7. If No As Others May Prefer He Will Keep On Waiting List Plus Rrt Till Another Opportunity.
1)Given the history of previous 2 transplantations and blood transfusion , cPRA 95% , DSA + for DP3 ; the patient is highly sensitized .
positive XM for B cells only ( DSA against class II ) & Negative for T cells.
HLA mismatch 2.2.2
This patient has high immunologic risk
2) Broad HLA Ag is comprises 2 or more split Antigens , so split mismatches are more specific .
3) split mismatch refers to each of HLA A , B , DR pair of allleles mismatch .
the fewer the mismatches the better transplant outcome .
4) currently I am not sure about it
5) Yes , as the patient has been on the waiting list for 16 years , this might be his best offer after all this period .
6) desensitisation therapy , as having a deceased donor graft that is subjected to ischemia and therefore might get marked expression of class II ( mainly DP here) on the graft . ATG induction then standard triple therapy .
7) Hemodialysis and wait for another graft with a less mismatch .
Broad HLA typing mismatch is 1:2:1. Split HLA typing: 2:2:2. Note that the broad HLA-A results, despite being differnt, are described as 1 mismatch. This indicates that theres a split somewhere there: A-23 and A-24are splits of A9.
3.Impact of split mismatch on gratf survival: Studies have shown a difference in graft survival when the kidneys are matched for split HLA- antigens. G Opelz in his study on the Importance of HLA antigen splits for Kidney transplant matching showed a marked difference in graft survuival when there was matching for split HLA- antigens.
4.HLA-B48 is a rare antigen, and it was, in this case, defaulted for an antigen similar to it, in this case HLA-B40. This explains why in the ODT typing result it is 1:1:1. The B-48 matches B40.
5.I will continue with the transplantation.
6.Immunosuppression will involve induction with ATG or Alentuzumab, and maintenance with Tacrolmus, prednisolone and Mycophenolate mofetil.
7.Other options if i don’t proceed with the transplantation: Continue hemodialysis.
1. Comment on the report below:
2. Comment on the difference between the broad and the split mismatch?
3. What is the impact of split mismatch on graft survival?
4. HLA B48 is a rare antigen. How was it managed?
5. Will you proceed with the transplantation?
6. If yes, what is your immunosuppression protocol?
7. If no, what are the other options?
This crossmatch report demonstrates the opposite of what was expected for a patient with as much risk of sensitization as this one. The performance of 2 previous transplants and blood transfusions would make this recipient at high risk for HLA antibodies, which we can see in the panel reactivity (cPRA = 95%) and also the presence of a specific antibody (Anti-DP3) with MFI close to the cut-off point. However, their FCMX was negative for T lymphocytes and autoantibodies , positive for B lymphocytes, representing that we have titers of DSAs for HLA II that can be managed with immunosuppressants.
On the other hand, your HLA typing with broad 1:1:1 and split 2:2:2 would tell us that you are moderately risky.
· Comment on the difference between the broad and the split mismatch?
There is a huge polymorphism of the HLA system due to its epitopes. Each carried on individual HLA specificities. The difference between “broad” and/or “split” is expressed through the size of their units, where the “split” is a subunit of broad. Trials have shown that crossing smaller portions (“splits”) is more specific for missmatch than broad portions (“broads”).
The identification of split mismatch allows a better choice of graft, increasing the percentage of graft survival and also allowing better immunosuppression.
HLA rare antigens are compared to their more common equivalentes. So that patients with rare tissue types match with more donors. In the HLA B48, your equivalent is HLA B40.
Yes, I ´ll
I would use a protocol with strong induction (Thymoglobulin) and maintenance with corticosteroids + ICN + MMF
HLA Broad mismatch- 1 2 1, HLA split mismatch 222,,
Flow cytometry cross match negative for T cell and and positive for B cell.
DSA – +ve due to anti DP3 antibodies with MFI 2230
On the back ground of 2 previous TX and blood transfusion , with cPRA- 95%, he is highly sensitized.
A broad antigen is HLA molecule with a poor specificity and it can be divided into 2 or more split antigens having a more specific cell surface reaction .
For example:
HLA A23 and A24 are spilt antigen for broad antigen A9
Split antigens are more specific then broad antigen for HLA typing and split antigen mismatch leads to poorer graft survival.
HLA B48 is a rare antigen present by default where assigned nearest HLA antigen is B40 so considered as match for HLAB40 of donor.
Yes, survival of patient and quality of life is better even with this much of mismatch compared to be on MHD. HLA DP is less expressed in kidney tissue and DSA against it would not be of that significance. Refusing this patient of kidney Tx would be ethically wrong.
Induction with ATG, and triple immunosuppression with prednisolone, MMF, Tacrolimus
Search for swap donor or to continue on MHD
Comment on the report below :
Highly sensitised patient due to history of previous two transplantation and previous one blood transfusion , primary disease not known and also ABO blood group of recipient unknown.
HLA Broad mismatch is 121 and HLA Split mismatch is 222 as HLA A9 ( broad antigen) is split into HLA A23 and HLA A 24 and HLA DRB6 ( broad antigen) split into HLA DR13 and HLA DR14.
DSA positive for HLA- DP
Flow cytometry crossmatch negative for T cell and auto-crossmatch also negative
Comment on the difference between the broad and the split mismatch?
Broad antigen – HLA molecule which can be divided into two or three split antigens which are more specific. Example- HLA A23 and HLA A24 are split antigens of HLA A 9 ( broad antigen)
HLA DR13 and HLA DR14 are split antigens of HLA DRB6 ( broad antigen).
What is the impact of split mismatch on graft survival?
The higher the HLA match, lower the incidence of delayed graft function as well as acute rejection rate in first year and higher the 10-year graft survival. Studies have shown that the number of HLA match in the recipient-donor pair is a strong predictor of graft kidney survival. Split antigen mismatches had 5 times higher difference in graft survival between 0 and 6 mismatches (31% versus 6%) at 3 years, signifying the importance of split antigen typing in renal transplantation.
LA B48 is a rare antigen. How was it managed?
HLA B48 is a rare antigen and can be managed by defaulting it to HLA B40
Will you proceed with the transplantation?
Yes , to allow her better quality of life than on HD , and also positive cross match to HLA_DP is less expressed on kidney tissue than tested lymphocytes in vitro.
If yes, what is your immunosuppression protocol?
Immunosuppressant medications include
1-depleting induction using high dose ATG 6-8mg/kg in our setup or Almutuzumab
2-tacrolimus 0.15 mg/kg targeting trough level 10-12ng/ml initially
3-MMF
4-Steroids
Patients having HLA-DP DSA can be transplanted successfully without prior antibody removal strategies
If no, what are the other options?
If no, then the only option available for the patient is to continue on dialysis and wait for another donor.
REFERENCES:
1– Yacoub R, Nadkarni GN, Cravedi P, He JC, Delaney VB, Kent R, et al. Analysis of OPTN/UNOS registry suggests the number of HLA matches and not mismatches is a stronger independent predictor of kidney transplant survival. Kidney Int. 2018 Feb;93(2):482-490. doi: 10.1016/j.kint.2017.07.016. Epub 2017 Sep 29. PMID: 28965746
2-Wiebe C, Gibson IW, Blydt-Hansen TD, Karpinski M, Ho J, Storsley LJ, et al. Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant. 2012 May;12(5):1157-67. doi: 10.1111/j.1600-6143.2012.04013.x. Epub 2012 Mar 19. PMID: 22429309
3-Margarita Rufino Hernández, E.. Cabello Moya, J.M.. González-Posada, D.Hernández Marrero, L.. Pérez Tamajón, D.. Marrero Miranda, S.. García Rebollo, B.Martín Urcuyo, A.. Rodríguez Hernánde ,et al.Induction treatment by combining immunoglobulins, plasmapheresis and rituximab in hypersensitive patients receiving cadaveric renal allograft.Nefrologai.Vol.30.issue.2.March 2010: pages 143-269
***Comment on the report below :
•••Highly sensitised patient due to history of previous two transplantation and previous one blood transfusion , primary disease is unknown, on waiting list for 16 years and unknown ABO .
••• ABO for donor is A positive and for recipient is unknown.
••• HLA Broad mismatch is 121 and HLA Split mismatch is 222 as HLA A9 ( broad antigen) is split into HLA A23 and HLA A 24 and HLA DRB6 ( broad antigen) split into HLA DR13 and HLA DR14.
••• Flowcytometry crossmatch negative for T cell and positive for B cell most probably due to Anti-HLA-DP3
••• Auto Flowcytometry is negative for B and T cells .
*** Comment on the difference between the broad and the split mismatch?
Broad antigen is HLA molecule with less specificity and divided into two or three split antigens which have more specific cell reactions.
As HLA A 9 ( broad antigen) splits into HLA A23 and HLA A24 and HLA DRB6 ( broad antigen) splits into HLA DR13 and HLA DR14.
*** What is the impact of split mismatch on graft survival?
Despite of split mismatch has many characteristics but immunological outcomes between and split and broad mismatch is different. Study by Oplez in Lancet on 1998 is shown that there is a difference in survival at three years between graft with 0 to 6 mismatches for HLA-A, HLA-B and HLA-DR which was 31 % when antigen split investigated in comparison to the 6 % difference with broad.
• Other studies shown that the specificity of broad
HLA-A OR HLA-B mismatch affected by their split mismatch while there is no discrepancy for HLA-DR split mismatch.
*** HLA B48 is a rare antigen. How was it managed?
HLA B48 is a rare antigen present by default where assigned nearest HLA antigen is B40 so considered as match for HLAB40 of donor.
***Will you proceed with the transplantation?
Yes, he is awaiting for 16 years and highly sensitised due to one previous blood transfusion and two previous kidney transplantation.
cPRA 95% and MFI 2231 due to Anti-HLA-DP3.
*** If yes, what is your immunosuppression protocol?
Aggressive induction by ATG
maintenance triple therapy is steroid , MMF and tacrolimus.
If no, what are the other options?
Long term dialysis until find suitable donor.
the patient is highly sensitized as he had 2 previous renal transplants
HLA typing is done by molecular method.
HLA broad mismatch 1.2.1
the split mismatch is 2.2.2
T lymphocyte and T&B auto FSXM was -ve
DSA positive against HLA DP
A broad antigen is an HLA molecule with poor specificity, and it can be divided into 2 or more split antigens having a more specific cell surface reaction. Matching for HLA antigen(splits) results in better transplant outcome than matching for (broad) HLA antigen
The split mismatch is associated with poor graft outcomes.
It defaults to the common antigen ( HLA-B40).
Yes,I will proceed, although it’s a high-risk transplant.
1)Induction therapy: ATG in dose of 1-1.5 mg/kg per day for 4-6 days (total dose 6 mg/kg).
2) Maintenance immunosuppression: Triple drug therapy including
-Corticosteroids
– Tacrolimus
– Mycophenolate mofetil
With regular follow up post-transplant with proteinuria, DSA, and protocol biopsy
If no, what are the other options?
For pair exchange or another donor.
Comment on the difference between the broad and the split mismatch?
There is no information about the patient blood group ,the donor blood group A
HLA typing is done by molecular method.
There is 1,2,1 mismatching (broad ) 2.2.2 (split ) between the patient the potential donor.
Flow cytometry method shows positive B cell negative T cell crossmatching, and negative auto-crossmatch results for both B and T cells.
become important in the prognosis and graft survival in kidney transplantation . Split is more sensitive than broad ,split is the component of broad which done by DNA testing while broad done by serology eg : 6 to 13 -14 .
What is the impact of split mismatch on graft survival?
The degree of HLA match affect the graft outcome and rejection possibility . When patients had high level of HLA-DR load had less 1-year graft survival. The effect is more in DR locus than A and B .The split mismatch associated with poor graft outcome .
· HLA B48 is a rare antigen. How was it managed?
It defaults to the common antigen ( HLA-B40).
· Will you proceed with the transplantation?
Although it’s a high-risk transplant with 2.2.2 mismatching and positive B cell crossmatching due to HLA-DP DSA, which constitute a high risk for ABMR and also a possibility of HLA-DQ DSA which increase the risk of graft loss I will accept because she is waiting for 16 years and she may die from dialysis complication .
· If yes, what is your immunosuppression protocol?
Induction with ATG ( 1.5mg/kg) (available in my country ) , pulse steroid, and maintenance therapy with Tacrolimus , MMF, prednisolone with monitoring the graft with protocol biopsy and DSA level .
· If no, what are the other options?To look for anther donor or pair exchange .
* Comment on the report below:
This patient is highly sensitized due to 2 previous renal transplantation and one blood transfusion and unknown cause of primary disease, on HD for long time ,his blood group unknown.
The donor is deceased with A Rh positive blood group.
HLA broad mismatch is 1.2.1 and split mismatch is 2.2.2
T lymphocyte and T/B auto FCXM was negative
B lymphocyte was positive FCXM
DSA +ve against HLA DP
* What is the impact of split mismatch on graft survival?
Typing for HLA antigens split is very important in renal transplantation.
Doing matching at a higher resolution like when we do split matching specificity for HLA-A, -B and -DR. and molecular matching at allelic level for HLA-DRB1 and considering additional loci like HLA-C, -DQ and -DP will lead to decrease rate of rejection episodes and improved graft survival.
So many well matched grafts at the broad level specificity may contain a significant number of mismatches when a higher level at matching like split level specificity or allele matching are used .
So matching of private or public antigens plays a great role in decreasing graft rejection .
Patients with at least one matched private antigen had equal or better graft survival when there’s matched public antigens.
Typing for split antigens is more expensive and more difficult than typing for broad antigens.
For cadaveric renal matching, split is not necessary.
It is easy to find good match for broad antigens than for split antigens, because small numbers of antigens specificity done .
* HLA B48 is a rare antigen. How was it managed?
As it is rare Ag it defaulted to the nearest Ag .
* Will you proceed with the transplantation?
Yes I will.
* If yes, what is your immunosuppression protocol?
ATG as induction and triple immunosuppressant as maintenance (Tacrolimus , MMF ,PRD) putting in mind that HLA DP Ags are less expressed in kidney tissue but it always associated with DQ Ags
* If no, what are the other options?
Return to HD while searching other more compatable donor by (if possible) epitope high resolution crossmatching
Comment on the report below
1-The blood group of the recipient not given , so we can’t comment regarding compatibility of blood group.
2- The HLA typing revealed 222 mismatch on split antigen and 121 on broad .as HLA 9 (broad )was split into A23 and A24 , also HLA DR6 ( broad) was split into DRB1*13 and DRB1*14
3-T lymphocyte and T/B auto FCXM are negative
B lymphocytes FCXM are positive
The positive B cell FCXM is probably due to anti-HLA-DP antibodies.
Comment on the difference between the broad and the split mismatch?
A broad antigen is HLA molecule with a poor specificity and it can be divided into 2 or more split antigens having a more specific cell surface reaction .
For example:
HLA A23 and A24 are spilt antigen for broad antigen A9.
What is the impact of split mismatch on graft survival?
split mismatch causing immune stimulation leads to graft injury and rejection with poorer outcomes.
HLA B48 is a rare antigen. How was it managed?
If a rare antigen is present, it is defaulted by the nearest HLA antigen which is B40
Will you proceed with the transplantation?
As the pt on waiting list for more than 16 years ,the cross match FCXM is positive for B cell which is due to anti DP antibodies. Class II HLA are less expressed on the renal tissue, especially DQ and DP, so it is better to accept the donor
If yes, what is your immunosuppression protocol?
High risk protocol :
1) Induction therapy: ATG in dose of 1-1.5 mg/kg per day for 4-6 days (total dose 6 mg/kg).
2) Maintenance immunosuppression: Triple drug therapy including
-Corticosteroids
– Tacrolimus
– Mycophenolate mofetil
With regular follow up post transplant with proteinuria , DSA and protocol biopsy
If no, what are the other options?
continue on dialysis and wait for another offer
Dear All
To conclude
We can not proceed with the paired exchange as there is no living donor. The options available are:
I transplanted this patient with aggressive induction (this is one of the cases discussed in part 3 of the lecture). The kidney is still functioning with eGFR 26 mls/mins.
A 46-year-old CKD 5 patient secondary to unknown aetiology. He has been on the waiting list for 16 years (highly sensitised due to 2 previous transplants and blood transfusion. His cRF (cPRA) is 95% and MFI is 2230 mainly due to anti-DP3 antibodies
The donor :
43 years old deceased donor, Blood group is A+ve (the blood group of the patient isn’t mentioned
HLA broad mismatch is 1.2.1 and HLA split mismatch is 2.2.2
T lymphocyte and T/B auto FCXM are negative
B lymphocytes FCXM are positive due to DSA against HLA DP.
Human leucocytic antigens (HLA) were identified using antisera from multipara women, however; with the advance of medical technology and research, techniques were evolved to split the formerly known (broad antigens) into narrower specificities.
For example, HLA-A9 was split into HLA-A23 and -A24 [1]
What is the impact of split mismatch on graft survival?
HLA mismatching has a significant effect on graft function, 0 mismatch has the perfect outcome. the degree of HLA mismatches at the A, B, and DR loci has a significant effect on the fade of a kidney transplant. More HLA mismatches are associated with more undesirable graft function and shortened patient survival after kidney transplantation. HLA has a crucial function in the immunity system by moderating immune responses through the presentation of the antigen and recognizing “self” from “non-self”. New antigens were discovered occasionally which resulted in the splitting of what was know before as ‘broad’ antigens into two or more antigens, named ‘split’ antigens.
Analysis report from the Collaborative Transplant Study (CTS) and more recently from the Australia and New Zealand Dialysis and Transplant (ANZDATA) has shown an important junction between HLA-matching at the HLA-A, B, and DR loci and allograft and patient survival, regardless of the donor type, starting immunosuppressive medications[2].
A recent retrospective single-center study of live and deceased donor renal transplants has explained that HLA-mismatch is still the cornerstone as a risk of acute rejection in kidney allograft recipients taking four immunosuppressive medications including IL-2 receptor antibody induction, tacrolimus, mycophenolate mofetil, and corticosteroids[3].
If a rare antigen is present, it is, by default, assigned the nearest HLA antigen (which is B40), hence it is considered as a match with the HLA B40 (of the donor).
No
If yes, what is your immunosuppression protocol?
This transplant has 2 risk factors which direct me to put it in high-risk transplantation as the scoring system of high immunological risk equals 2; the presence of split HLA mismatch 222 (including DR) and the presence of DSA; therefore I will use the following protocol:
A) Induction using depleting antibody using anti-thymocyte globulin (ATG)
B) maintenance by tacrolimus + MMF + prednisolone
If no, what are the other options?
If I choose not to proceed with this transplant, we can use paired exchange donor program, in which can use the donor of this scenario for another patient more compatible and less mismatched with no DSA and use another donor for our patient in this scenario to be more suitable as well.
Advantage: more favorable outcome regarding the graft and patient survival and on other hand, less aggressive immunosuppressive regimen so can lessen the adverse effects of immunosuppression and cost as well
Disadvantages: needs more time and needs a well-organized system.
References:
[1] Gabriel M. Danovitch, Handbook of kidney transplantation, sixth edition, pg. 55
[2] Lim W, Chadban S, Clayton P, et al. Human leukocyte antigen mismatches associated with increased risk of rejection, graft failure, and death independent of initial immunosuppression in renal transplant recipients. Clin Transplant 2012; e-pub.
[3] Wissing K, Fomegné G, Broeders N, et al. HLA mismatches remain risk factors for acute kidney allograft rejection in patients receiving quadruple immunosuppression with anti-interleukin-2 receptor antibodies. Transplantation 2008; 85 (3): 411.
Thanks, Michael
We can not proceed with the paired exchange as there is no living donor. The options available are:
I transplanted this patient with aggressive induction (this is one of the cases discussed in part 3 of the lecture). The kidney is still functioning with eGFR 26 mls/mins.
1-blood group of donor A
blood group of recepient not mentioned
broad mismatch 4
but spilit mismatch 6
B lymphocyte postive due to DSA aganist HLA DP
T lymphocyte negative
2-broad antigene is aless specific than spilit as in this case broad mismatch 1-2-1 but in spilit (more specific )2-2-2 mismatch .example broad antigene A10 has spilit AG A25-A26-A34-A66 so spilit more specific so more reduction of risk for graft rejection and increase its survive
3-reduce risk of rejection
increase graft survival
4-I dont know
5-for me NO
6- if yes he need desenstization first with Retuximab and IVIG
also start TAC &MMF early before operation
heavy induction with depleting agent ATG
maintenance Tac,MMF ,corticosteroid
7-continue on hemaodialysis waiting for better crossmatch&also make desenstization with Retuximab to reduce PRA
I transplanted this patient with aggressive induction (this is one of the cases discussed in part 3 of the lecture). The kidney is still functioning with eGFR 26 mls/mins.
Comment on the report below
In this case recipient is 46 year old with history of two renal transplants and blood transfusion- Blood group not mentioned and is highly sensitized . The donor is 43 year old with Blood group A positive.
T lymphocyte and T/B auto FCXM are negative
B lymphocytes FCXM are positive due to DSA against HLA DP.
HLA broad mismatch is 1.2.1 and HLA split mismatch is 2.2.2
Comment on the difference between the broad and the split mismatch?
Broad HLA molecules detected by traditional serological methods can have split antigens e.g A9 has A23 And A24. which can be detected by newer molecular techniques. HLA DP is better expressed on lymphocytes but less expressed on kidney tissues like other class 11 HLA .Here HLA broad mismatch is 1.2.1 and HLA split mismatch is 2.2.2
What is the impact of split mismatch on graft survival?
HLA split mismatches are associated with poor patient and graft survival. Matching split antigens provides better graft survival
HLA B48 is a rare antigen. How was it managed?
It can be managed by defaulting as B40
Will you proceed with the transplantation?
Patient is awaiting for 16 year and is highly sensitised due to previous transplants and blood transfusion and had cPRA of 95% and MFI of 2230 due to anti DP3 antibodies. I will proceed with renal transplant with modified immunosuppressants as studies have shown successful outcome in such cases
If yes, what is your immunosuppression protocol?
Induction with Antithymocyte globulins- ATG and maintenance with tacrolimus, mycophenolate mofetil and steroids. Post transplant will require monitoring with DSA
If no, what are the other options?
Long term renal replacement therapy or search for suitable donor
Excellent
I transplanted this patient with aggressive induction (this is one of the cases discussed in part 3 of the lecture). The kidney is still functioning with eGFR 26 mls/mins.
Well done Professor
a) The prospective recipient is a 46-year-old male (blood group not given) being offered a kidney from a 43-year-old deceased donor with blood group A positive. Hence the blood-group compatibility cannot be commented upon.
b) The HLA typing of the pair in HLA A B and DR reveals a 121 mismatch on broad antigen typing and a 222 mismatch on split antigen typing. This is because HLA A23 and A24 are spilt antigen for broad antigen A9. Similarly, HLA DRB1*13 and DRB1*14 are split antigen for broad antigen DR6.
c) The report shows a flowcytometry cross match (FCXM) with six historical sera of the patient, all of which are negative except with B cell FCXM which is positive with all the sera.
The positive B cell FCXM is probably due to anti-HLA-DP antibodies.
A broad antigen is HLA molecule with a poor specificity and it can be divided into 2 or more split antigens having a more refined or specific cell surface reaction than the broad antigen. The HLA typing of the pair in HLA A B and DR reveals a 121 mismatch on broad antigen typing and a 222 mismatch on split antigen typing. This is because HLA A23 and A24 are spilt antigen for broad antigen A9. Similarly, HLA DRB1*13 and DRB1*14 are split antigen for broad antigen DR6.
As a broad antigen has poor specificity while the split antigens are more specific, a split mismatch will have different response to immune stimulation causing graft injury and rejection leading to poorer outcomes. One of the initial studies assessing split antigen versus broad antigen showed that as compared to broad antigen mismatches, split antigen mismatches had 5 times higher difference in graft survival between 0 and 6 mismatches (31% versus 6%) at 3 years, signifying the importance of split antigen typing in renal transplantation.(1) HLA typing and mismatch determination between the potential transplant recipient and donor pair is an important factor for prognostication in kidney transplantation. Studies have shown that the number of HLA match in the recipient-donor pair is a strong predictor of graft kidney survival.(2) The higher the HLA match, lower the incidence of delayed graft function as well as acute rejection rate in first year and higher the 10-year graft survival.(3,4) HLA mismatches have been shown to be associated with poor transplant outcomes.(5) UNOS registry showed that the risk of renal graft failure increased with the number of mismatches (13% in 1/6 mismatch and 64% in 6/6 mismatch).(6) Increased formation of DSAs is seen in case with Class II HLA mismatch (HLA-DQ, DR) thereby ultimately leading to poor graft survival.(7) Increased risk of death with a functioning kidney graft has been seen in recipients with increased HLA mismatch.(8) So, if we rely only on broad antigen typing, we will not be able to undrestand the risks involved.
Of note is a study by Su et al which deduced that due to availability of better and more potent immunosuppression, HLA mismatch has lost much of its relevance.(9)
If a rare antigen is present, it is, by default, assigned the nearest HLA antigen (which is B40), hence it is considered as a match with the HLA B40 (of the donor).
The patient has been on a waiting list for last 16 years. He has been offered a donor with a positive B cell FCXM, presumably due to anti DP antibodies. Class II HLA are less expressed on the renal tissue, especially DQ and DP. Hence I will proceed with the transplant.
Since this patient is a high immunological risk category patient, the patient will require induction immunosuppression and tacrolimus based triple drug maintenance immunosuppression.(10)
1) Induction therapy: Injection Anti Thymocyte Globulin (ATG) in dose of 1-1.5 mg/kg per day for 4-6 days (total dose 6 mg/kg).
2) Maintenance immunosuppression: Triple drug therapy including
a. Tacrolimus: Target trough level of 8-10 ng/ml
b. Mycophenolate mofetil (MMF): 1000 mg twice a day
c. Corticosteroids: Injection methylprednisolone 500 mg intravenous on the day of surgery, followed by tablet prednisolone 1mg/kg/day for 3 days and then 20 mg/day, to be tapered to 5 mg/day over next 6 to 8 weeks.
Post-transplant, patient requires close follow-up with clinical and laboratory evaluation.(10)
i) Complete blood count, urine examination and serum creatinine.
ii) To look for proteinuria: Spot urine protein-to-creatinine ratio.
iii) DSA testing: Once in first three months, then annually or whenever there is any graft dysfunction, alteration in immunosuppression or suspicion of non-adherence.(11,12)
iv) Protocol biopsy: Once in first three months.(11) If the biopsy shows features of AMR, it should be treated.
If no, then the only option available for the patient is to continue on dialysis and and wait for another offer.
References:
1) Opelz G. Importance of HLA antigen splits for kidney transplant matching. Lancet. 1988 Jul 9;2(8602):61-4. doi: 10.1016/s0140-6736(88)90001-3. PMID: 2898695.
2) Yacoub R, Nadkarni GN, Cravedi P, He JC, Delaney VB, Kent R, et al. Analysis of OPTN/UNOS registry suggests the number of HLA matches and not mismatches is a stronger independent predictor of kidney transplant survival. Kidney Int. 2018 Feb;93(2):482-490. doi: 10.1016/j.kint.2017.07.016. Epub 2017 Sep 29. PMID: 28965746.
3) Takemoto SK, Terasaki PI, Gjertson DW, Cecka JM. Twelve years’ experience with national sharing of HLA-matched cadaveric kidneys for transplantation. N Engl J Med. 2000 Oct 12;343(15):1078-84. doi: 10.1056/NEJM200010123431504. PMID: 11027742.
4) Wissing KM, Fomegné G, Broeders N, Ghisdal L, Hoang AD, Mikhalski D, et al. HLA mismatches remain risk factors for acute kidney allograft rejection in patients receiving quadruple immunosuppression with anti-interleukin-2 receptor antibodies. Transplantation. 2008 Feb 15;85(3):411-6. doi: 10.1097/TP.0b013e31816349b5. PMID: 18322434.
5) Shi X, Lv J, Han W, Zhong X, Xie X, Su B, et al. What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients. BMC Nephrol. 2018 May 18;19(1):116. doi: 10.1186/s12882-018-0908-3. PMID: 29776389; PMCID: PMC5960106.
6) Williams RC, Opelz G, McGarvey CJ, Weil EJ, Chakkera HA. The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts From Deceased Donors. Transplantation. 2016 May;100(5):1094-102. doi: 10.1097/TP.0000000000001115. PMID: 26901078; PMCID: PMC8086563.
7) Wiebe C, Gibson IW, Blydt-Hansen TD, Karpinski M, Ho J, Storsley LJ, et al. Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant. 2012 May;12(5):1157-67. doi: 10.1111/j.1600-6143.2012.04013.x. Epub 2012 Mar 19. PMID: 22429309.
8) Opelz G, Döhler B. Association of HLA mismatch with death with a functioning graft after kidney transplantation: a collaborative transplant study report. Am J Transplant. 2012 Nov;12(11):3031-8. doi: 10.1111/j.1600-6143.2012.04226.x. Epub 2012 Aug 17. PMID: 22900931.
9) Su X, Zenios SA, Chakkera H, Milford EL, Chertow GM. Diminishing significance of HLA matching in kidney transplantation. Am J Transplant. 2004 Sep;4(9):1501-8. doi: 10.1111/j.1600-6143.2004.00535.x. PMID: 15307838.
10) 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.
11) 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.
12) 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.
Excellent Amit
I transplanted this patient with aggressive induction (this is one of the cases discussed in part 3 of the lecture). The kidney is still functioning with eGFR 26 mls/mins.
1- Comment on the report ;
Donor is A + blood group , recient blood group ( not mentioned)
Broad antigen mismatch 1.2.1 while slit antigen is 2.2.2 mismatch
negative T , positive B lymphocytes FCXM.
2- Some of the antigens (broad antigens ) detected by early serological techniques used for tissue typing were found to have one or more subtypes that could be detected by more advance molecular techniques ( spit antigens).
3- Split antigen mismatch has a prognostic value for graft outcome with better matching carring better graft survival.
4- This is a high immunological risk patient as
Highly sensitized
High degree of mismatch
However , as quality of life is better for transplanted patient compaired with patients whom remain on dialysis , also modern IS drugs allow transplanting high risk patients , so I would proceed for transplantation.
Immunesuppression regiemen :
Induction with ATg
Maintanance with triple ( CNI, MMF, steroid)
Frequent monitoring of DSA.
Excellent
I transplanted this patient with aggressive induction (this is one of the cases discussed in part 3 of the lecture). The kidney is still functioning with eGFR 26 mls/mins.
Dear all candidates
Very encouraging start
Let’s raise the bar with the following questions:
All the best
1.Yes I would accept this option. Although not commonly used in deceased donor transplantation due to time constraints that would NOT allow for effective desensitization,BUT there are successful ABOi deceased donor transplants with plasmapharesis done shortly before transplant..Amti ABO isoaggluinin should be low.Hyper acute rejection is not common but the rate of ABMR is higher than ABOc trnsplant.PE could also be done folloing such transplantation
2.I am NOT SURE but sounds attractive ,I would rather prefer to use it together with TPE,not alone
3.bcz she is highly sensitized/previous transplant/blood transfusion.and the MFI level
4.preformed anti-HLA-DP DSA are as deleterious as anti-HLA A/B/DR/DQ DSA. It justifies their inclusion in kidney allocation programs and in immunological risk stratification algorithms.IF time constraints would allow i would check for matching at this location with the deceased donor
A realistic approach for the first question.
The recipient is Male, so this antibody is not a response to pregnancy but maybe a genuine preformed DSA with his story of previous 2 transplaants
1- still we can go with ABOi donor prefered LD and offer him desentiztion with plex ,IVIG and rituximab ,aswith the ABOi DD the desensitization will be abig challenge with high surgical risk of bleeding heamtoma and wound related infection, earlly rebound of DSA s antibodies
2-Till date thereis no standradized desensitization protocal its all depened on local centre expreince and policy , in my opinion IVIG alone not enough ,class11 DSA increased the risk of noncomplement mediated AMR not like class1 DSA
3- being have isolated anti DP ABs which means class11 ABs with less kidney tissue expression
4-in highly sensitized candidate prefered to do epitope-eplete base cross match with high resolution 4 digits matching which refere to antigens -antibodies binding sites this will help in detection of acceptable and non-acceptable Ags and to screen for the crossreactive antigens
Reference:
prof ahmed Halwa lecture module 2
Good response for Question 4, thank you
I would accept the ABO incimpatable donor, as the ABO desensetization protocol with Rituximab and PE might be of benefit to down regulate the anti HLA antibodies as well.
IVIG adminstration is indicated as it might reduce the anti HLA antibody titer. We need to assess the DSA titer before and after the IVIG.
HLA Dp is significant here as its reciprocally expressed predominantly in Lymphocytes and not in the kidney tissues, encouraging us to proceed with transplantation in this highly sensitized patient. However, close monitoring of DSA is indicated.
Assessment of anti HLA Dp DSA with Relative mean flouresence RMF is indicated in higly sensitized patient like this patient to assess the level of positivity after assessing for MFI. RMF cut off is 1.48 for T lymphocyte and 1.88 for B lymphocyte.
Reference:
Uptodate transplantation.
Dr. Ahmad Halawa lectures
1-for me it will be very risky (prefare combitable blood group)as in this case increase risk for rejection mush more .plasmapharesies will done before operation
2-its agood option but may be insufficent alone may need retuximab and plasma exchange with.
3-as this patient has high cPRA with DSA MFI >2000 so high risk paient
4- patients on transplant waiting lists are regularly monitored for changes in their alloimmune status. In this retrospective analysis, their is a dynamic changes in anti-HLA antibodies over time in patients on a kidney transplant waiting list. the kinetics of alloimmunity are highly individualized and do not appear to correlate with the interval between measurements. However, the magnitude of alloimmune status change increased significantly in patients with a previous transplant versus those without such a history. This suggests that an individualized strategy for alloimmune status monitoring of patients on organ transplant waiting lists on the basis of their alloimmunization history might be preferable to current recommendations for regular monitoring.MFI may increase with time.
References:
ABOi transplant is definitely another option for this patient however he would require Rituximab , ivig and plasmapharesis or immunoadsorption. I think a single dose of IVIg won’t be enough.
As expression of Dp is more on lymphocytes than kidney tissue so a lymphocyte cross match can mislead us.
Better to go for Eplet base cross match .
Comment on the report below
-Donor blood group A Rh-positive / patient blood group is not mentioned.
-FCXM is positive due to DSA against HLA-DP
– T lymphocytes FCXM
– T/B auto FCXM are negative.
Comment on the difference between the broad and the split mismatch?
– Broad antigens 1.2.1
– Split antigen 2.2.2
What is the impact of split mismatch on graft survival?
-HLA mismatches are associated with poor patient and graft survival in kidney transplantation. The increased number of HLA mismatches associate with a higher risk of rejection and graft failure.
HLA B48 is a rare antigen. How was it managed?
HLA B48 is a rare antigen and should be defaulted to HLA B40.
Will you proceed with the transplantation?
– Yes, renal transplantation is better than continuing on hemodialysis ( better quality of life and patient survival)
– It is necessary to make the patient aware that he is at high risk for graft rejection, requiring important immunosuppressive therapy to increase the chances of a successful transplant.
If yes, what is your immunosuppression protocol?
– Consider Desensibilization (rituximab, IVIG)
– Lymphoablative therapy (ATG or Alentuzumab)
– Triple maintenance immunosuppression (Tacrolimus, MMF plus prednisone)
– Scheduled DSA dosages and on-demand biopsy protocol
If no, what are the other options?
Searching for a more compatible donor, despite having been waiting 16 years for an opportunity
Well-structured answers.
Need references!
Suppose you mean by scheduled DSA dosages, DSA monitoring! So, how frequently are you going to test during the first year?
Is it an on-demand biopsy ??
I would do DSA monitoring as shown every three months. Depending on the clinical evolution, assess the best moment for the graft biopsy
Cherukyru et al Kidney International 2019 96, 202-213
Thanks for the comments. I will get better
I think we need to do frequent monitoring of DSA every 3 months in such highly sensitized patient and do protocol biopsy for detection of subclinical rejection
Tissue typing shows 121 HLA mismatch for broad Ag, 222 mismatch for split Ag & 111 mismatch for default Ag.
Blood group for donor is known (A+ve) but its unknown for recipient. Cross match done by flow cytometry ( +ve for B cells & negative for T cells & auto cross match) with DSA against HLA-DP.
Split Ags are serological subtypes of broad Ags, and it is more commonly used in HLA matching, because split mismatch is more important than broad mismatch ( split mismatch associated with poorer graft outcome).
HLA-B48 is a rare Ag compromised around 1% & it is a default of common Ag.
This patient is highly sensitized due to previous transplantation & blood transfusion. Due to high HLA mismatch with positive FCXM & +ve DSA against HLA-DP he considered high immunological risk patients.Although HLA-DP Ag had low renal tissue expression it may had a deleterious effect on graft outcome. But this patients had long waiting list time with high cPRA & chance of having more suitable donor is low, so I will proceed transplantation from this donor if the recipient accept the risk.
The recipient should be induced by ATG & triple ( CNI, MMF & steroids) IS regime, with close monitoring of DSA level & protocol graft biopsy to detect early signs of rejection.
Thispatienthighlysensitized due to previous two transplantation , and blood transfusion withlonglistwaited,cPRA 95% means difficult to find compatible LD or even DD.HLA matching for allocation of compatible donor can be done by using the Low resolution antigen level for three HLA loci (HLA-A, HLA-B, and HLA-DR) and this have been allocating donor kidneys for transplant since the 1970s, while now we are moving toward the high resolution molecular genetic testing which is more sensitive and specific to determined donor –recipient HLA mismatch at the eplit antigen level and help in predicting the risk of denovo DSA ABS formation (2).
HLA -mismatch by the broad antigen which refer to parent antigen 2digit and 222 mismatch by more specific split antigen used to identify those with acceptable mismatch which can impact the kidney graft outcome especially in re- transplant . All antibodies that react against all loci except for DPA Can be listed as unacceptable antigens for DD program in US (5) In one study review found that the Isolated HLA-DP DSA are rare, high-risk eplet mismatches maybe associated with increased risk HLA-DP DSA formation. Therefore, in this study they recommend HLA-DP typing to perform HLA-DP DSA analysis before transplantation. HLA-DP DSA with high MFI were not always correlated with positive cross match results ( 1).
The impact of HLA-DP mismatches on kidney allograft outcome is still indeterminate and based on available evidence from retrospective studies it shows less effect as compared to other HLA loci like DR, DQ , combination of DP with DQ DSA may associated with high risk of Denov DSA s activation from the memory cells and trigger acute rejection.Unacceptable antigens refers to a donor HLA antigen against which the recipient has performed Abs and should be avoided because of an increased risk of ABMR , like in this case his CPRA 95% almost 95% chance of having preformed Abs and he have very low chance to get compatible donor in current scenario the CDCXM was negative with persistent Positive B FXCM , but auto FXCM was negative , so this can be still due to presence of true DSA to class 11 HLA abs or false positive due to non HLA abs
HLA B 48 is rare < 1% can be defualted to HLAB40.
will go ahead with the transplant as high immunological risk , being DD transplantation so no time for desensitization , induction can be done either by ATG with high dose 6-8mg /kg ( total accumulative dose ) or alemutezmab which is even more potent depleting agent for both T and B lymphocytes followed by triple conventional therapy with tacrolimus targeting higher trough level 8-10 in first 3 months plus MMF and steroids , with frequent monitoring with DSA level in first 3-12 months post transplantation with low threshold for biopsy with any increased in creatinine or DSA level , protineuria
Other induction option for this case may consider as part of desentization with B cell depleting monoclonal AB anti CD 20 may be in modified dose of 200 mg but should balance with increasing risk of infection this type of induction recently increased use in ABOI transplantation from local centers with promising results .
Other option is to keep him on waitlisted dialysis with the higher risk of mortality and morbidity, very low chance to allocate donor in paired kidney donation, he is waiting for 16 years.
References:
1-The impact of HLA-DP mismatches on renal allograft outcome is still poorly understood and is suggested to be less than that of the other HLA loci. The common ass
2-Senev A, Coemans M, Lerut E, et al. Eplet Mismatch Load and De Novo Occurrence of Donor-Specific Anti-HLA Antibodies, Rejection, and Graft Failure after Kidney Transplantation: An Observational Cohort Study. J Am Soc Nephrol. 2020;31(9):2193-2204. doi:10.1681/ASN.2020010019
3-Class II HLA Eplet Mismatch Is a Risk Factor for De Novo Donor-Specific Antibody Development and Antibody-mediated Rejection in Kidney Transplantation Recipients H Kishikawa 1 , T Kinoshita 2 , M Hashimoto 2 , S Fukae 2 , A Taniguchi 2 , K Yamanaka 2 , M Nakagawa 2 , K Nishimura 2
4-Heidt S, Haasnoot GW, Witvliet MD, et al. Allocation to highly sensitized patients based on acceptable mismatches results in low rejection rates comparable to nonsensitized patients. Am J Transplant. 2019;19(10):2926-2933. doi:10.1111/ajt.15486.
5- Kidney transplant in adult: Overview of HLA sensitization and cross match testing, Up to date 2022.
Excellent response Dr. Saja, although it needs to be in a better structure to reduce distraction of the reader.
It is better to write the references in the proper way, Vancouver style
If you have the luxury to go for an advanced Lab test, what you should go for to decide about this Anti-DP Ab? and whether they are important alone or because of being detected with Anti-DQ regardless of the trigger by infection.
Thank you Prof Ala for the feedback I will pay attention to my references order
regarding the better advanced labtest its prefered in such highly sensitized patient to go for epitope-eplete base cross match with high resolution 4 digits matching which refere to antigens -antibodies binding sites this will help in detection of acceptable and non-acceptable Ags and to screen for the crossreactive antigens but offcourse with more cost ,so its use limited for highly sensitized recpients like our presented case and another limitaion is still no standradazid cutoff values of significance.
DP- antibodies related to class11HLA abs ( DR,DQ,DP ) with variable kidney tissue expression , espcially DP have lower kidney expression and its presences in isolation with the given MFI cutoffvalue will not preculde this patient to go ahead with the transplant as high immunological risk.with agressive induction and coventional triple immunotherapy with close FU by DSA level, Kidney function test , protienuria , kidney biopsy once indicated or as part of protocal biopsy based on centre policy .
Thank you
This is high risk patient,, with high cRF 95%positive with positive DP3antibidy of 2230 MFI. The cross match with potential donor showed HLA mismatch of 222 split and 121 on broad HLA, as the broad antigen is consistant of more subunit antigen. The split antigen mismatch is directly related sucess of allograft rather than broad HLA antigen. B48 antigen was defaulted to B51 antigen. As far as the anti HLA antibody is mainly anti DP3 which is less prevalent in kidney tissues, I would proceed with transplant given thatless risk of having rejection. I will recommend ATG induction with 6.6 mg/kg body weight or Alemtuzomab and a maintenance course with Tacrolimus based immunosuprresants protocol keeping high normal teough level of Tacrolimus for the first 3 months post transplant.
Thank you, Dr. Wael
What minimum Tac level are you aiming for at 12 months?
Do you think it is only for the first month of transplantation? With such history!
Thank you Dr. ALa.
I wiuld suggest trough Tacrolimus level of 6_8 ng/ml for the first 12 months rather than the first 3 months
Comment :
The patient’s blood group is not mentioned
HLA typing (molecular method).
There is 222 mismatch. Cross matching by flow cytometry method shows positive B cell and negative T cell cross matching along with negative auto cross match .The possibility of the presence of Anti HLA-DQ antibody and non HLA ones cannot be ruled out , solid phase assays are missing as well.
The difference between the broad and the split mismatch:
Split mismatch is more accurate than broad cross matching ,split mismatch indicates adverse effect on graft and have worse graft survival time and it provides better idea on the cross matching better than broad cross matching , there are a group of closely related antigens which were previously considered as a single (broad) antigen, now they can be distinguished as multiple (split) antigens.
Impact of split mismatch on graft survival:
Split mismatching is associated with worse graft outcomes.
HLA B48:
It is related to the more common antigen HLA-B40.
Yes, I would proceed with the transplantation after fulfilling all the missing data
Induction with ATG (1.5mg/kg) 3-5 doses pulse steroids, and maintenance therapy with Tacrolimus, MMF, prednisolone with monitoring of DSAs level.
If no :
paired kidney donation program.
References:
The possibility of the presence of Anti HLA-DQ antibodies and non-HLA ones cannot be ruled out!
What are the implications of AntiHLA-DQ and NON-HLA antibodies in such a case?
I think in the context of highly sensitized recipient with presence of preformed DSA, the coexistence of non_ HLA antibodies will carry a risk for acute rejection and worse graft outcome
Comment on the report below
-Donor blood group is A Rh-positive while the patient blood group is not mentioned.
-B lymphocytes flow cytometry crossmatch ( FCXM) is positive due to DSA against HLA-DP, while T lymphocytes FCXM and T/B auto FCXM are negative.
-This patient has 1.2.1 mismatches on HLA-A, B, DR on broad antigens while his mismatch is 2.2.2 on split antigens.
Comment on the difference between the broad and the split mismatch?
-The difference between the broad antigens (1.2.1) and the split antigen(2.2.2) mismatches may be due to A9 split into(A23, A24) and DR6 split into(DR13, DR 14).
What is the impact of split mismatch on graft survival?
-HLA mismatches are associated with poor patient and graft survival in kidney transplantation, especially at HLA-A,-B, and DR loci. The increased number of HLA mismatches associate with a higher risk of rejection, graft failure, and all-cause mortality.
HLA B48 is a rare antigen. How was it managed?
HLA B48 is a rare antigen and defaulted to HLA B40.
Will you proceed with the transplantation?
Yes, renal transplantation is better than continuing on hemodialysis ( better quality of life and patient survival)
If yes, what is your immunosuppression protocol?
He is a high-risk recipient, so induction with ATG, and maintenance immunosuppression TAC, MMF, and prednisolone
If no, what are the other options?
Search for another donor.
No blood group for donor, though Cross blood group transplant can be done,now
successfully.
Patient is HLA Mismatch 121 Broad, 222 Split with Positive FCXM against B.
The effect of DSA 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.(1,3).
Broad antigen is parent antigen, split is more specific as recently shown.
matching for HLA antigen “splits” results in better transplant outcome than matching for
broad.(2).
Managed by defaulting it to B40.
Patient waiting for longtime as our patient for deceased allograft with HLA-DP positive
FCXM can be transplanted with reasonable outcome as shown in some centers.
Depleting antibody (ATG) or Alemtuzumab induction THEN standard
immunosuppression, keeping ATG at high trough. (3)
Desensitization treatment (4) consisted of:
1. First day after transplant: rituximab 375mg/m2 , repeated with the same dosage on the
seventh day.
2. Plasmapheresis on days 3, 5 and 7 post-transplant, with IV immunoglobulin infusion
dosed at 0.5g/kg body weight following each session, with dose reinforcement of 1g/kg
on days 10, 11 and 30 post-transplant.
References:
1- YazinMarie ,TimKeyAhmedHalawaa .Renal transplantation against a positive
crossmatch due to HLA-DP donor-specific antibodies without prior antibody removal –
Casereport.Transplantation ReportsVolume 6, Issue 3, September 2021, 100076.
2-GerhardOpelz.IMPORTANCE OF HLA ANTIGEN SPLITS FOR KIDNEY TRANSPLANT
MATCHING. The Lancet:Volume 332, Issue 8602, 9 July 1988, Pages 61-64.
4- J. Margarita Rufino Hernández, E.. Cabello Moya, J.M.. González-Posada, D..
Hernández Marrero, L.. Pérez Tamajón, D.. Marrero Miranda, S.. García Rebollo, B.
Martín Urcuyo, A.. Rodríguez Hernánde ,et al.Induction treatment by combining
immunoglobulins, plasmapheresis and rituximab in hypersensitive patients receiving
cadaveric renal allograft.Nefrologai.Vol.30.issue.2.March 2010: pages 143-269.
Comment on the report below: This patient is highly sensitised because of previous 2 kidney transplant and blood transfusion.
patients has HLA A, B, DR mismatch; he has HLA 48 is very rare split antigen and can matched with nearsed split A 40
Comment on the difference between the broad and the split mismatch?
Split antigen more specific and effecfive in matching than broad. Split is more immunological difference than broad in outcome of graft survival.
for example spilt of A23, A24 are the broad of A9.
What is the impact of split mismatch on graft survival?
HLA matching are very important in successfully of long term graft .
Matching with HLA-DR more strong and associated with the successful survival than HLA-A $ HLA-B, but Matching of those 3 HLA Are still tested. Split mismatch are associated with poor outcome graft within one year but due to successfully adherence to immunosuppressive agents help to increase chance of survival graft.
HLA B48 is a rare antigen. How was it match? it’s HLA 48 is a rare Antigen & can matched with the nearest one HLA 40 which are the broad of B12.
Will you proceed with the
transplantation?
Yes, I will proceed kidney transplant and will treat him aggressively with induction therapy by ATG (Anti Thymocyte Globulin) & maintenance by tacrolimus MFF (mycofenolate moftile )& steroid .
References:
1. Xinmiao Shi, Jicheng Lv etal ; What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients: BMC Nephrology volume 19, Article number: 116 (2018).
-patient 1.2.1 mismatch for broad ,2.2.2 ( split mismatch).
-flow cytometry
negative for T lymphocyte ,
positive for B lymphocyte ,
T and B auto Ab negative
high cPRA due to anti DP3Ab (DSA)
Donor blood group A Rh positive
patient blood group ? but I think compatible since deceased donor transplantation
-split antigen specific site reaction on cell(active part ) but broad is major antigen that shar group of parts (split ) with advanced technology more detail and information’s about antigen parts EX (molecular technique).
– split antigen mismatch associated with adverse graft outcome than broad antigen.
-HLA B48 IS rare antigen to minimized risk and complete work we managed by defaulted to near one HLA B40.
-Ithink proceed for transplantation because :
1-with modern and potent immunosuppressive successful transplantation of highly sensitized patient possible .
2-patient survival and quality of life is better than stay on dialysis.
3-patient has anti DP3 Ab although risky but less than anti B OR anti DR
may be related to gene expression on kidney less that on lymphocyte
-immunosuppressive protocol include
ATG
TAC
STEROID
MMF
*Comment on the report below?
There is no information about the other blood group
-This patient is highly sensitized due to previous blood transfusion and 2 previous renal transplantions
-Broad HLA mismatch in (A,B,DR) (1-2-1)
Split mismatch (2-2-2)
If default(1-1-1)
-CPRA 2230 mainly due to anti-DP3 antibodies
Positive flow cytometery to B-cell
*Comment on the difference between the broad and the split mismatch?
HLA tissue typing can be done by several methods in the past serologically done as broad Ag later on advancing molecular methods used as split Ag which is subunit of broad Ag ex (A23 and A24) are split from A9
*What is the impact of split mismatch on graft survival?
HLA matching in split Ag gives more accurate result than matching in broad one,so better clinical out come and high graft survival time
*HLA-B 48 is a rare antigen how was it managed?
HLAB 48 is a rare Ag can be manage by defaulting in to the nearest HLA Ag (B 40) to allow translatability with minimal immunological risk
* Will you proceed with the transplantation?
Yes , i will proceed with transplantion
* What is your immunosuppression protocol?
Induction therapy with ATG and methyle prednisolone and maintenance therapy(Tacro ,MMF ,Prednisolone)
cPRA is 95% can you comment on that with reference to unacceptable Antigens how does compromise the transplant ability and waiting time.?
How does the MFI mentioned rank the risk of this patient?
1) CPRA for allocation of kidneys in the US: More candidates ≥98% CPRA, lower positive crossmatch rates and improved transplant rates for sensitized patients
Lee Ann Baxter-Lowe et al. Hum Immunol. 2016 May.
Show details
Abstract
In 2009 calculated panel reactive antibody (CPRA) replaced PRA as the metric for HLA sensitization in the US kidney allocation system. During the next four years, registrants with at least one unacceptable antigen increased (34-40%) and registrants with ≥98% PRA/CPRA increased from 7% to 9% of the waitlist. These changes were accompanied by a reduction in kidney offers refused for positive crossmatch: 14,137 (1.7%) in 2009 and 3,310 in 2013 (0.4%). Registrants with ≥98% PRA/CPRA had highest rates of refusal but also showed substantial improvement (20% in 2009 vs 8% in 2013). For registrants with ≥98% PRA/CPRA, 45% of accepted offers in 2009 were not transplanted into the intended recipient compared to 11% in 2013. Transplant rates remained low for these patients (∼50/1000 active patient-years), but rates improved for patients with 80-97% PRA/CPRA (223/1000 active patient-years in 2009 vs 354/1000 in 2013). In 2013, 40% regraft candidates had CPRA ≥98% compared to 4% of primary graft candidates. More females than males were ≥98% CPRA (14% vs 7%) and more females had CPRA above 0 (50% vs 28%). In the CPRA era, listing of unacceptable antigens increased, positive crossmatches were diminished and transplant rates for sensitized patients improved.
2) The MFI in this patient less than 5000 so we can transplant this patient with aggressive immune induction.
Results: In total, 61/174 patients had pre-transplant DSA. We found a strong correlation between the presence of DSA against class I and II HLA and DSA MFI greater than 10 000. Both DSA patterns independently predicted an increased risk of early AMR (odds ratio 4.24 and 4.75, respectively, P < 0.05). The risk for AMR in patients with intermediate MFI (3000-10 000) gradually increased with increasing MFI but group sizes were too small to allow for final conclusions. The risk for AMR was comparable to nonsensitized patients in patients with only class I or II HLA-DSA or MFI below 3000. 5-year allograft survival was lowest in patients with simultaneous presence of class I and II HLA-DSA and MFI above 10 000 (45%) but was comparable between patients with only HLA class I or II or no DSA (90.0, 90.0 and 88.1%, respectively). AMR was the only independent predictor of graft loss. Undetectable DSA 14 days post-transplant predicted excellent long-term outcome.
Conclusion: . The favourable outcome in the majority of DSA-positive patients despite non-depleting antibody induction and the poor outcome in patients with class I and II HLA-DSA and high DSA strength call for a differentiated therapeutic approach in this patient population.
The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
Dear All
Bear in mind that the donor is a cadaveric donor. There is no time for desensitization and also PES (PAIRD EXCHANGE SCHEME) is not applicable to cadaveric transplantation.
Dear Colleagues
Dear Colleagues
Please listen to the lecture, especially part 3. There is a unique feature of HLA DP and the rest of class II antigens. Please consider it in your answer. This may give you a clue why I transplanted this patient
Dear All
Apology, there was a typo in the scenario which I corrected. The cRF (cPRA) 95% and the MFI is 2230. This is a real case I have transplanted few years back
The mismatch at the HLA-A.B.DR level is 2.2.2 at the broad level and 1.2.1 at the split level.
In flow cytometry, the XM is negative for TCells and positive for B cells (this is most likely owing to antibodies against DP), and negative for T cells. (The cPRA code is 2230).
Comment on the difference between the broad and the split mismatch?
The split antigen is described as an antigen that elicits more distinct particular cell surface reactions than wide antigen when compared to broad antigen. Separated antigens: Separation of a single antigen into subtypes; an antigen that produces a more particular cell surface response in comparison to a more general antigen. (For example, the HLA-B5 broad antigen is divided into the HLA-B51 and HLA-B52 subtypes.).
A broad antigen that is identical to another broad antigen may contain distinct split antigens, and these tiny changes may elicit an immunological response and rejection.
Therefore, matching on split antigens has a better transplantation result than matching on wide antigens in terms of outcomes.
HLA B 48, which is an uncommon antigen, may be substituted with HLA B 40.
I will explain the risk of rejection to the patient. If he accepted the risk, I will proceed as a high immunological risk patient.
induction ATG or Alemtuzumab(if available). maintenance on triple therapy(tacrolimus, MMF and steroid). I will monitor the DSA regularly and do protocol biopsy.
paired exchange(if he has an available living donor) or continue on the waiting list for a better match.
-Takemoto S, Gjertson DW, Cecka JM, Terasaki PI: HLA matching for local pools using fewer HLA factors. Transpl Proc 27:675, 1995.
-Helman S W.etal, Interpretation of HLA Typing Results for Entry into UNet. Organ Procurement and Transplantation Network, Jan 2003.
-Gabriel M. Danovitch, MD. Handbook of Kidney Transplantation
Seam you by mistake switched the broad and split antigens.
Considering the MFI 2230 for the class 2 DSA how does this rank his risk
You can Liston to the lecture it will make matters easier and if not come back to us.
Please note that when you by default consider 48as 40 then the match will be 111