2. A 57-year-old CKD 5 patient due to IgA nephropathy received an offer from his 41-year-old cousin. His crossmatch results are shown below. Please answer the following:
- What is his HLA match?
- How would you explain the positive crossmatch?
- Would you accept the offer?
- If yes, how would you manage his immunosuppression?
- If no, what are the other options?
ABO compatible ,Mismatches 120 with 2 mismatches in C and 1 mismatch in DP
FXCM cross match positive in T cells ,negative in B cells >due to No HLA antibodies as it is repeated so lab error excluded
For me I would prefer another donor or paired donor exchange
If we will go for transplantation ,I would do desensitization with plasmapheresis ,IVIG and
Induction with Thymoglobulin +methyleprednisone and maintainence with tacrolimus ,MMF and prednisolone .
Protocol biopsy to detect ABMR early
Other option is paired donor exchange
ABO compatable donor-recipient pair
120 HLA mismatch
FCXM positive for T cell and negative for B cell
This is due to non-HLA antibodies.
I will go for transplantation after doing desensitization as this is a high risk patient due to the positive FCXM, desensitized him by IVIG and plasmapheresis and use ATG as induction therapy and use triple immunosuppressant agent for maintenance (Tac. , MMF , steroid)
With protocol biopsy follow up.
OR
Wait for another donor or paired kidney exchange
The case is ABO compitable,
120 HLA mismatch
A positive T cell FCXM in the presence of negative B cell FCXM, is usually due to technical errors and can be due to autoantibodies or non-HLA antibodies.
I accept this offer and consider this patient as a high risk for rejection and induction therapy with rATG, and maintenance therapy with MMF, tacrolimus and prednisolone .
Another option is paired exchange.
*ABO compatible donor.
* HLA mismatch 120.
*2 HLA mismatches at HLA C , 2 mismatch HLA DQA1 and HLA DPB1 1 mismatch.
*Positive T cell and negative B cell cross match by FXCM mostly due to non HLA antibody .
* no DSA .
*I will accept the offer if no other potential donors are available.
But the transplant is a high risk transplant as FCXM is positive
Protocol for immunosuppression:
Desensitization with IVIG
and plasmapheresis until FCXM is negative as patient is high risk due to T cell FCXM positive. Induction with ATG 1.5mg/kg on day 0 and for 3 days after transplant based on differential count monitoring.
Standard triple immunosuppression needs steroids, MMF and Tacrolimus.
protocol biopsy to detect ABMR due to the non HLA antibodies .
the other option available for the patient is to wait for a more compatible donor or paired kidney exchange.
HLA MATCH:120 mismatches.
positive crossmatch due to non-HLA antibodies .
I will accept but I will give induction with ATG or Alemtuzumab with maintenance therapy MMF+Tacrolimus+Steroids
What is the HLA match?
120
Positive crossmatch is mostly due to none HLA antibodies
Would you accept the offer
I would accept the offer because he is living related donor with good cross matching and no DSAs
I would give induction with ATG with the standard protocol and maintenance immunosuppressive tacrolimus MMF steroids protocol
What is his HLA match?
How would you explain the positive crossmatch?
Would you accept the offer?
If yes, how would you manage his immunosuppression?
If no, what are the other options?
HLA match is 120.
HLA C , DQ mismatch .
ABO compatibility
His cross match results ,
With negative autocross match , no DSAs this would be non HLA antibodies
He is considered high risk , would council the patient about the risks and if he accepted I would transplant him with induction using thymoglobulin and maintain him on tacrolimus MMF and steroids.
If the patient didn’t accept I would offer him paired kidney exchange programe .
ABO matched
HLA 120
Positive T cell ,negative DSA and negative Auto XM denotes non HLA bs
if kidney offered accepted ,it will be as high risk with ATG and triple maintenance therapy with close monitoring for possibility of IgA recurrence
If offer not accepted ,it would be for paired kidney exchange.
There is need to have recent FCXM &DSA.DD of positive T cell XM with negative AB cells XM includes lab error, autoantibodies and non HLA antibodies .Authorization by lab excludes error, negative auto XM, excludes autoantibodies .Low titres of class II antibodies could yield negative B cells. Desensitization will depend on Luninex test; with consideration that we are confronted by high risk case .Also, IgA recurrence possibility should be consider including use of ARB or ACEI if in need for antihypertensive..
HLA 120.
NonHLA antibodies.
No.
Wait for suitable donor or Paired exchange. Plus minus desensitization protocol, center specific.
ABO compatible recipient & donor
120 (HLA-A, -B, -DR) mismatch, in addition to 2 HLA-C mismatch & 1 HLA-DQ mismatch .
FCXM T cell +ve with negative auto FCXm mean presence of non HLA antibodies.
Positive FCXM & high HLA mismatch, it better to put the recipient on paired exchange program, but if the recipient accept this donor he should had induction with T cell depleting agent with maintenance IS including life long steroids to reduce the risk of GN recurrence.
What is his HLA match?
His HLA mismatch is 120 with also 2 HLA C mismatch,2 DQA1 mismatch and 1DPB1 Mismatch.
How would you explain the positive crossmatch?
As autocross match repeated several times
Tcell Fcxm positive and negative Bcell with negative DSA mostly caused by non HLA antibodies or very low titre DSA hadn’t been detected by SAB.
Would you accept the offer? YES, I will as its living related with good matching in DR LOCUS with high probability of matching on multiple levels (allelic matching is highly expected in related donation)
If yes, how would you manage his immunosuppression?
Transplantation outcomes in presence of nonHLA antibodies with or without desensitization still controversial.
Also FXCM positive in both complement fixing and non complement fixing Ab.
repeat anew FCXM, SAB plus doing AHG CDC CM will give us a full current picture with screening of non HLA antibodies in the serum and detection of its type and strength and to be also baseline to be followed post transplant.
If CDC CM is negative and FXCM is negative and DSA is negative induction with basilixmab and triple immunosuppressive tac MMF steroids as his primary disease is IgA nephropathy
If CDC CM is positive and FXCM POSITIVE this patient will need desensitization using pp ,IVIG and rutiximab till become negative
If CDC CM negative ,SAB DSA Screening is Negative and still Fcxm positive i will go for induction ATG plus triple immunosuppressive medications tac mmf steroids with monitoring of non HLA antibodies post transplantation
If no, what are the other options?
Paired kidney donation
What is his HLA match?
1.2.0
With 2 mismatch in C and DQ
How would you explain the positive crossmatch?
Positive T cell cross match with negative DSA this indicate non HLA antibodies
Would you accept the offer?
If yes, how would you manage his immunosuppression?
Yes I will accept this offer but I will consider him as high risk patient due to possible reccrence of previous disease IgA and the presence of non HLA antibodies evidence by positive cross match so the induction would be ATG and to continue with TAC,MMF and predinsilone
If no, what are the other option?
Paired exchange
It is a 120 HLA mismatch. In addition, there are 2 HLA-C mismatch, 2HLA-DQA1 mismatch, 1 HLA-DPB1 mismatches.
T cells express HLA class I antigens and B cells express both HLA class I and class II antigens. Thus, if there is a class I mismatch, both T cell FCXM and B cell FCXM will be positive, and if there is a class II mismatch, a positive B cell FCXM will be expected. Another reason for positive B cell FCXM and negative T cell cross match is a low-level anti class I antibody.
A positive T cell FCXM in the presence of negative B cell FCXM, is usually due to technical errors and can be due to autoantibodies or non-HLA antibodies.
I accept this offer and consider this patient as a high risk for rejection and induction therapy with rATG, and maintenance therapy with MMF, tacrolimus and prednisolone are suggested.
This test between patient and his donor with ABO compatible and 120 mismatch with another mismatch at HLA-C ,HLA- DQA1 and HLA- DPB1 ,negative DSA and positive T cell FXCM and negative B cell FXCM.
Positive T cell with negative B cell results probably due to non HLA Ab ,low class II titer or lab error.
If the test was done for more than 3 months it should be repeated and if DSS is positive or high MFI titer desensitization must be done (plasmapheresis, rituximab and IVIG) if not I will consider him as high risk group patient especially he is a known case of IgA nephropathy and treated him by rATG as induction with prednisolone, MMF and tacrolimus for maintenance regimen with frequent DSA monitoring post transplant.
What is his HLA match?
The mismatch is 1-2-0
How would you explain the positive crossmatch?
Non-HLA antibodies
Would you accept the offer?
No,
1-because the donor is related to the patient. Wang reported a higher graft failure rate in the long term, with the use of allografts from living-related donors, in comparison with unrelated donors , although this observation was not confirmed by others. Besides , familial IgAN carries a markedly increased risk of ESRDand IgA deposits in the donor increased the risk of IgAN recurrence in the recipient.
2- risk of recurrence of IgA nephropathy is high among living-donor if there is ≥1 HLA mismatches . Furthermore, the survival advantage between zero and ≥1 HLA-mismatches in living-donors with IgAN were lost. 1
If yes, how would you manage his immunosuppression?
· I would give him induction with ATG (reduce recurrence of IgAn)2 and keep him on tacrolimus rather than cyclosporine +MMF (ponticelli)+STEROID( avoid steroid free regimen )
· protocol biopsy for AMR due to non HLA and for recurrence
· follow up for IgAn recurrence through urine protin and RBCs 1
If no, what are the other options?
· Exchange donation ( better to be zero mismatch)
· deceased with no DR mismatch1
1-Lionaki, S., Panagiotellis, K., Melexopoulou, C., & Boletis, J. N. (2017). The clinical course of IgA nephropathy after kidney transplantation and its management. Transplantation Reviews, 31(2), 106–114. doi:10.1016/j.trre.2017.01.005
2-erthoux F, El Deeb S, Mariat C, Diconne E, Laurent B, Thibaudin L. Antithymocyte globulin (ATG) induction therapy and disease recurrence in renal transplant recipients with primary IgA nephropathy. Transplantation. 2008 May 27;85(10):1505-7. doi: 10.1097/TP.0b013e3181705ad4. PMID: 18497694.
What is his HLA match?
His HLA mismatch is 120 with also 2 HLA C mismatch,2 DQA1 mismatch and 1DPB1 Mismatch.
How would you explain the positive crossmatch?
Tcell Fcxm positive and negative Bcell with negative DSA mostly caused by non HLA antibodies
Would you accept the offer?
As regard the donor it’s good as he is living related with good matching in DR LOCUS
But he is relating to the pt and the primary disease is IG A nephropathy , so better to reject him
If yes, how would you manage his immunosuppression?
ATG induction
tacrolimus +MMF (ponticelli)+Steroid
If no, what are the other options?
· Exchange donation ( better to be zero mismatch
●1_2_0 mismatch with drb1 /dqb1 mismatches
●positive t cell fcxm and negative bcells fcxm
1:techniques errors
2:non HLA antibody
●if there is no any doner available better HlA I would accept
With aggressive induction with atg and triple maintenance tac/mmf/steroids.
●if no . Looking for paired kideny donation .
Reference .
Hand book of transplantation 6th edition.
HLA mismatch is 120 at A, B and DR
2 mismatches at HLA-C and one mismatch at HLA-DQ and DP
positive T cell FCXM and negative B cell FCXM may be due to non-HLA antibodies or low titer antibodies that was not detected and leaded to negative DSA
lab. error is not probable as repeated several times, auto antibodies are excluded as auto crossmatch is negative
I would ask for Luminex assay, if DSA positive the patient would be for desensitization with plasmapheresis and IVIG till the FCXM becomes negative
if DSA not detected will be considered high immunological risk and will need induction with anti thymoglobulin
induction with antithymoglobulin and maintenance with triple therapy steroids, MMF and Tacrolimus
it is desirable to continue on steroids as it decrease the rate of recurrence of IgA nephropathy
paired kidney donation or waiting for more compatible donor
Moroni G, Belingheri M, Frontini G, Tamborini F, Messa P. Immunoglobulin A nephropathy. recurrence after renal transplantation. Frontiers in immunology. 2019 Jun 19;10:1332.
Not impressed this time Heba
Looks you have not read the scenario very well. No DSA (of course was checked by Luminex SAB)
This is typical on non-HLA antibodies.
There is a confusion regarding your management. Please read how to manage non-HLA antibodies causing positive crossmatch
What is his HLA match?
ABO compatible
HLA match is 1 2 0
HLA C , HLA BW ,HLADQA1 and HLADPB1 mismatch
How would you explain the positive crossmatch?
Positive FCMX ( T-cell) + negative DSA + negative auto reactive antibodies this is most properly due to none HLA antibodies
Would you accept the offer?
I would accept the offer and stratify his immunological risk as high, if there is no other donor options .
If yes, how would you manage his immunosuppression?
The immunosuppressant protocol include desensitization ,induction and maintenance triple TAC
It is better to avoid steroid withdrawal due increased risk of IgA recurrence .
DSA monitoring and protocol biopsy
If no, what are the other options?
Paired exchange is an option .
Reference ;
Lionaki, S., Makropoulos, I., Panagiotellis, K., Vlachopanos, G., Gavalas, I., Marinaki, S., Liapis, G., Michelakis, I., Bokos, I. and Boletis, I., 2021. Kidney transplantation outcomes in patients with IgA nephropathy and other glomerular and non-glomerular primary diseases in the new era of immunosuppression. PLOS ONE, 16(8), p.e0253337.
Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017.
Please tell me what are the criteria required to be fulfilled in order to to carry out desensitisation, what is your cut off level?
What is his HLA match?
This patient has HLA-A 1 mismatch, HLA-B 2 mismatches, HLA-DR 0 mismatch
How would you explain the positive crossmatch?
2017 There was positive T cell on FXCM and Auto FXCM. Since 2019 till 2020 there were only FCXM T cell positive and FCXM Auto negative.
T cell positive But B cell negative crossmatch can be due to:
· Lab error (possibly related to B-cell viability)
· Autoantibodies
· lower immunogenicity of the antibodies or antigens
· Non-HLA antibodies
After auto FCXM it became negative, so possibilities are:
· Non-HLA antibodies
· Low titre of HLA class 1 antibodies
· Low titre of DSA which may give rise to false negative DSA
So, in this scenario, I would like to think about Non-HLA antibodies (HLA C, HLA DQA1 and HLA DPB1). Studies showed that multiple non-HLA mismatches carries risk of graft rejections. The patient need to repeat FCXM and DSA as the last was done a year ago.
Would you accept the offer?
If yes, how would you manage his immunosuppression?
If there is no other potential donor, I would like to do the transplant.
His primary disease was IgA nephropathy
Risk factors for recurrence of IgAN should be considered during induction and maintenance therapy
· Younger age
· maintenance immunosuppression without mycophenolate/ early steroid withdrawal
· less than 3 immunosuppressive agents
· who were corticosteroid-free at one year
· burden of crescents on the native biopsy(crescentric IgAN)
I would like to know about his previous kidney biopsy findings, whether there is presence of crescentic IgAN or FSGS in IgAN which determines the risk of recurrence of his primary disease.
I would choose Thymoglobulin as my induction agent because
· T cell FXCM positive, there is higher chance of graft rejection
· Thymoglobulin induction has been shown delay the reoccurrence of IgAN in transplanted kidneys
For the maintenance therapy, I would choose
· Mycophenolate as it shown to reduce recurrence of IgAN
· Tacrolimus also shown to reduce recurrence of IgAN
· Would avoid early steroid withdrawal strategy
· I personally will avoid mTORi due to evidences of de novo FSGS and its side effect of proteinuria will lead to unnecessary investigation for proteinuria (due to its effect on podocytes)
· Will choose ACEi and ARB as the BP control meds as these drugs are the only proven IgAN therapy for now.
If no, what are the other options?
IF its not feasible to do transplant, I would suggest for much better donor or subject to paired kidney exchange program.
References:
Cazorla-López, J., Wu, J., Villanego-Fernández, F., Naranjo-Muñoz, J., Vigara-Sánchez, L., García-García-Doncel, A., Orellana-Chávez, C., Moreno-Salazar, A., García-Álvarez, T. and Mazuecos-Blanca, A., 2020. IgA Nephropathy After Renal Transplant: Recurrences and De Novo Cases. Transplantation Proceedings, 52(2), pp.515-518.
Lionaki, S., Makropoulos, I., Panagiotellis, K., Vlachopanos, G., Gavalas, I., Marinaki, S., Liapis, G., Michelakis, I., Bokos, I. and Boletis, I., 2021. Kidney transplantation outcomes in patients with IgA nephropathy and other glomerular and non-glomerular primary diseases in the new era of immunosuppression. PLOS ONE, 16(8), p.e0253337.
Thanks Theepa
I agree with you.
* mismatch 1,2,0
*almost due to non HLA AB that will be -ve in auto FCXM
*yes I will go on
*patient consider standard risk (3 mismatch ) HLA C mismatch with HLA B mismatch increase risk for rejection and HLA DQ mismatch also increase risk of AMR so use ATG as depleting agent and standard maintenance protocol (TAC ,MMF ,Cortisol)
cant use cortisol free protocol as IgA is the original kidney disease
What is his HLA match?
120 HLA mismatch in A,B,DR antigens
Tow mismatches at HLA-C
One mismatch at HLA DP and HLA DQ
How would you explain the positive crossmatch?
Positive T FXCM and negative B cell FXCM is caused by Presence of non HLA antibodies
Would you accept the offer?
If yes, how would you manage his immunosuppression?
If I will accept this offer
I will do desensitization of patient with plasmapheresis +IVIG and rituximab
Induction with ATG
Maintenance therapy with Tacrolimus, MMF, Prednisolone.
If no, what are the other options?
I will wait for another more compatible donor
Or arrange for the paired Kidney exchange program.
Excellent answer
But, I disagree with your aggressive desensitization. You need to know what non-HLA antibodies causing the positive T cell crossmatch first
-HLA mismatch is 1-2-0
1 mismatch for HLA A and 2 mismatch for HLA B and no mismatch for HLA DR,
2 mismatch for HLA C, 1 mismatch HLA DQA1 , 1 mismatch HLA DPB1
-Positive T cell and negative B cell can be due to non HLA antigens
the presence of HLA C can lead to poisitive T cell
-it can be accepted if it is the available option
-if No he needs to wait for another donor or paired kidney exchange
Its 1-2-0 mismatches one in HLA-A ,two in HLA-B also thereis onemismatch in HLA-Cw , one in DQA1, , one in DPB1
this first transplant LD , DSA negative , previous postive both FCXM , and autoFCXM crossmatch in 2017 means the possiblity of auto-antibodies (IgM ) ruled out, . lab errors excluded by netaive auto FCXM
persistant positive T cells FCXM with negtaive B cells can be explained by the following:
1- nonHLA abs.
2- low titer of the class11 HLA abs and give negative B cells .
3- negative DSA s due to too low titer
need to ask about the duration between the two tests and if its more than 3 months difference will ask for repeat one by more sepcific test the lumenix SAB assay and according to the cutoff values of theM FI will decide about the need of desesnitaztion prior to transplantation with ( plex , IVIG , Rituximab ), but if repeated test for DSAs still negtaive with above results still i will consider this patient sensitized and will go for high immunological risk induction protocal with either ATG or alemutizemab being followed by triple mainetenance IS , keeping in mind the Iga nephropathy as primary disease even in case of induction with alemutzemab preferrred to continue on steriod plus CNI and MMF as maintenance IS and consider adding ACEI or ARBS as preferred class for BP control with close monitroing for DSAs level and urine p/c ratio , hematuria
in case of not accepting this offer will ask for changing the donor or PKD ( paired kidney donation )
A very impressive answer, properly one of the best answers.
This is a 120 mismatch with added 2 mismatches at HLA-C and HLA-DQA1 and 1 mismatch at DPB1.
A positive T cell crossmatch with a negative B cell crossmatch may be due to lab error, autoantibodies (IgM) or non-HLA antibodies. Lab error is usually ruled out at the lab level itself. Autoantibodies ruled out by autocossmatch which is negative. Hence it seems it is positive due to non-HLA antibodies.
I need more information:
1) Latest FCXM (the last one was done 1 year back)
2) Strength of DSA using solid phase assay – Luminex as screening DSA might be negative in case of low level DSA.
If DSA is negative with solid phase assay and FCXM is negative, we can go ahead with transplant, although it will be a high risk transplant and it is always better to change the donor, if possible.
If DSA present and FCXM positive: Plasmapheresis with IVIG and Rituximab till FCXM negative, then Induction with ATG and maintenance immunosuppression with Tacrolimus, MMF and steroids.
Post transplant close followup with DSA monitoring and protocol biopsy if DSA increasing.
Change the donor. Either some other direct donor, or using kidney paired exchange program for a better donor.
excellent answer
Thanks, Amit
You did not address the non-HLA antibodies in your management plan
If non-HLA antibodies are present, we should try to identify and quantify them. The removal of antibodies using desensitization protocol of plasmapheresis and IVIG with anti CD20 antibody (rituximab) use will be warranted with a close follow-up and monitoring of the titres of those antibodies and protocol biopsies.
I went through these 2 references but I could not get a reference providing a clear-cut answer regarding management of patients with pre-transplant non-HLA antibodies.
References:
1) Philogene MC, Jackson Am. Non-HLA antibodies in transplantation: when do
they matter? Curr Opin Organ Transplant 2016;21:427-432.
2) Kardol-Hoefnagel T, Otten HG. A comprehensive overview of the clinical
relevance and treatment options for antibody-mediated rejection associated
with non-HLA antibodies. Transplantation 2021;105:1459-1470.
Thanks, Dalia
Can you look at desensitization in non-HLA antibodies causing positive crossmatch?
1- His HLA matching is 1 2 0 mismatch
2- + T – B FXCM may be explained by
a- Lab error : unloikely as labs usually recheck the odd results and the same result was obtained several time over subsequent years
b- Non HLA Ab
c- Presence of HLA C may give false +ve T cell cross match
d- Autoantibody : high possibility , as T cells turn negative in autocross match .
3- Would you accept the offer
-His patient has 120 mismatch , no DSA, his first transplantation , positive T cell FXCM ( mostly non HLA or auto ab) , c PRA is unknown
-His primary pathology is Ig A nephropathy and the donor is related
-According to immunological risk this is a high risk patient
-His donor is related ( so must be assessed very carefully to exclude being a carrier of Ig A nephropathy ) . some researchers found high posttransplantation recurrence of Ig A in case of
a- living related donors compared with a deceased donors
b- High degree of HLA matching
c- Ig A deposits in donor kidney.
So, I wouldnot accept this donor.
4- The alternative opition :
Either living unrelated donor with better matching ( paired donation) or deceases donor.
5- If I accepted this patient , treatment protocol:
-Induction with ATG
– Maintenance : triple ( Tac , MMF, steroids).
Wyld, Melanie L. MBBS, PhD, FRACP; Chadban, Steven J. BMed, PhD, FRACP Recurrent IgA Nephropathy After Kidney Transplantation, Transplantation: September 2016 – Volume 100 – Issue 9 – p 1827-1832
Thanks. Sensible plan
As we classically no no obvious reason for T cross-mach positivity alone without positive B FCXM but there are some reasons like HLA-Cw and maybe autoantibodies against T cells
179-P: UNEXPECTED T CELL POSITIVE AND B CELL NEGATIVE FLOW CYTOMETRY CROSSMATCH IN A KIDNEY TRANSPLANT PATIENT https://www.sciencedirect.com/science/article/abs/pii/S0198885912004703
preprint (T Cell Positive B Cell Negative Flow Cytometry Crossmatch (FCXM): Frequency, HLA-Locus Specificity, and Mechanisms Among 3073 Clinical FCXM Tests Prabhakar Putheti,1,2 Vijay K Sharma,1,2 Rex Friedlander,1 Arvind Menon,1 Darshana Dadhania,1,2,3 Thangamani Muthukumar,1,2,3 and Manikkam Suthanthiran.1,2,) https://www.medrxiv.org/content/10.1101/2021.05.20.21257541v1.full.pdf
ın this case we have historical auto crossmatch (2017), followed by a completely negative crossmatch. one explanation for auto crossmatch is trained sensitization (some reasons may be vaccination etc.)
In 2019 and lastly, in 2020 we have only T positive crossmatch but no auto crossmatch, so we can make sure that this is an IgG antibody. No DSA
this surprising result may be due to that T cells express very high class I more than B cells and other is a very low level of DSA
Here we have 120 mismatch but also mismatch to HLA-C, DQA1, DPB1. this patient may have high levels of IgA antibodies as well (although this is not of bad prognosis) (https://journals.lww.com/transplantjournal/Fulltext/1999/01270/IgA_CLASS_ANTIBODIES_AND_FLOW_CYTOMETRIC.22.aspx) this is a high-risk patient (in terms of mismatch and first-degree relative donor) with risk of IgA nephropathy risk of recurrence.
We may accept donor as we may not find a better option, especially from an unrelated donor. after explanation to recipient, we may proceed with this transplantation
as considered high risk but without DSA either basiliximab but preferably rATG could be used. maintenance immunosuppression would be classically steroid/TAC/MMF) with close monitoring of renal function, hematuria and proteinuria followup
Mahmud
Do you think it is due to non-HLA antibodies?
How would you confirm it?
Thank you, Prof. Ahmed. non-HLA antibodies may be either due to antibodies to T cells or B cells. So it is very useful If we can measure. As far as I know, Few labs measure these. If not available I agree with my colleagues to followup clinically by DSA, creatinine, urine analysis, and Urine protein analysis) and confirm any rejection to optimize the treatment when needed
What is his HLA match?
HLA mismatch: 120 at HLA A A, B and DR
How would you explain the positive crossmatch?
T cell positive FCXM
B cell Negative FCXM
-In current scenario with positive T cell and negative B cell FXM indicating there is non HLA antibodies
Some researcher suggest that due to more presentation of HLA Cw on T lymphocytes more than B lymphocytes that cause positive T cell FCXM and negative B cell FXM due to presence of HLA antibodies directed at HLA- Cw locus
-Initially positive autoimmune cross match then negative
Would you accept the offer?
With positive T cell FCXM for Antibody screening with Luminex SAB > not donor-specific or negative (results suggest antibody is not HLA-specific) then considered standard immunologic risk and proceed for transplantation.
If yes, how would you manage his immunosuppression?
In presence of positive T cell FCXM for desensitization and induction with lymphocyte depleting agents. Maintenance with triple immunosuppression prednisolone ,CNI and MMF.
If no, what are the other options?
Wait for another offer with negative cross match or for paired exchange.
Well done
Dear All
I can see excellent answers. Well done. Our efforts has been paid by reading these replies. For those who recommend desensitisation, you need to know the offending antibodies that caused this positive crossmatch.
What is his HLA match?
HLA-match 120
How would you explain the positive crossmatch?
· If T- Positive because of anti-HLA antibody, the B-cell CXM as well, must be positive; which is not the case here. This may raise the possibility of lab error. But, the test had been repeated many times excluding this possibility.
· Positive T FCXM can be because of auto-AB, which in this case is unlikely as the auto-crossmatch was only once positive in 24/11/17. And this may be explained by either (1- the patient had been with autoimmune disease or 2- treated with drug-like rituximab)
· Positive T FXCM could be due to non-HLA antibodies that can be either of IgG or IgM type of low titer.
These non-HLA Ab can give positive FCXM to either T or B or both.
I need to do a solid-phase test to determine the specificity, and strength of the antibodies.
If its IgG more immunological risk, IgM is less risk.
If solid-phase test is negative, a positive FCXM has no impact on graft survival.
For IgM conformation (I need to know whether its non-HLA or HLA and complement-fixing or non-complement fixing)
So do CDC or AHG CDC with DTT treatment of the serum become negative means IgM (non-HLA or HLA)
Generally, positive CDC is a contraindication to transplantation, whereas positive FCXM is not. T-cell FCXM is particularly useful in sensitized and retransplant patients whose antibody levels may have fallen but who can raise a rapid memory response upon challenge. Low levels antibody have a more damaging effect when the deceased donor is older or the kidney quality is uncertain.
I need patient history, especially for Blood transfusion. Even If DSAs are negative
Ø I need to repeat the crossmatch with recent patient serum, the results provided were old. Although, positive historical crossmatch carry an increased post-transplant risk of the potential for memory response but is not CI to transplantation.
Ø Also, repeat DSA
Q- Would you accept the offer?
This offer is risky considering (HLA-mismatch 120 for A-, -B, DR) and HLA C -2, DPB1 -1, DQA1 -2 and positive T-cell FCXM
I will support my decision by the result of solid-phase test, (may need desensitization)
First, as DR negative I could accept
Second, it seems better to search for another donor or paired exchange donor.
Q- If yes, how would you manage his IS?
If yes
Induction with r ATG, methylprednisolone, Tacrolimus, MMF
Maintenance Triple with Tac+ MMF+ Prednisolone (steroid drug I will continue its use as he is IgA)
Q- If no, what are the other options?
Paired donor exchange
Thanks Jamila
The HLA mismatch A, B, DR: 1,2,0
the patient has historical\recent T cell FXCM positive with B cell negative and no DSA (recent) and autocross match is negative. it means that he has a non-HLA antibody. I don’t think this is a technical error as the test repeated over many years.
I will confirm by requesting anti-MICA and anti-ARII
This will depend on the level of mean channel shift of the flow cytometry
If the MCS is ≤250, we offer HLA desensitization depending upon the overall specificity and strength of DSAs. I will do desensitisation by PP, IV igG and Retiximab until the cross match is negative. Then proceed for transplantation.
•
After desensitisation , Induction with ATG or Alumetuzumab and triple therapy(tacrolimus, MMF, prednisolone.
better to repeat the cross match post-transplantation. and protocol biopsy.
other potential donors or KPD
Plan for thinking and decision taking:
HLA match and risk stratification.
Last FCXMwas in Jan. 2020 also DSAs
If they are not class 1 or II are they IgM or IgG
IF they are non HLA and their controversial effect will you go ahead and desensitise untill FCXM is negative.
The fact that the original disease is IgA does this influence your maintenance IS plan
Steroid avoidance protocol is associated with increased risk of IgA nephropathy recurrence , so in this case we need to continue on small dose steroids with TAC and MMF
What is his HLA match?
In the classic HLA antigens, HLA mismatch is120 in HLA-A, -B, -DR loci. Also there are 2 HLA-C antigen mismatches, and 1 HLA DQ mismatch, and 1 HLA DP mismatch.
How would you explain the positive crossmatch?
-Positive T cell cross match means that there are HLA class I antibodies, because HLA class I is not exclusively present on T cells. In this context with negative B cells cross match, non-HLA antibodies or non-IgG antibodies (IgM) could be present. But negative autocross match means that IgM are not the case here. So non-HLA antibodies can explain the crossmatch.
To note that, this patient had positive T cell auto-crossmatch 3 years earlier. So maybe this patient had history of autoimmune disease for which he possibly received treatment, and eventually responded well. This explained the negative T cell crossmatch in the next year.
Would you accept the offer?
Having positive FCXM with T cells and 3 mismatches at classic antigens and 4 mismatches at HLA-C and HLA- DP, -DQ, I would wait for better matching as this mismatch increases the risk of acute rejection and graft loss.
If yes, how would you manage his immunosuppression?
This is a high risk recipient, Having high risk, patient should receive aggressive induction and maintenance immunosuppression to overcome this risk.
Patient should receive rabbit antithymocyte globulin as induction therapy at dose of 1 to 2 mg/kg given intraoperatively followed by 2 mg/kg for 2 more days.
Along with the induction therapy, patient should receive maintenance immunosuppression to prevent acute rejection and the loss of the renal allograft.
Based on large evidence, patient should receive triple maintenance immunosuppressive therapy, CNI based, in addition to MMF and steroids. This combination has been reported to be superior to other combinations.
Desensitization treatments are usually preserved for patients who are highly sensitized, and/or with positive flowcytometry cross match. Positive crossmatch does not always mean to desensitize. Most transplant centers base their decisions whether to or not to desensitize, on median channel shift and relative intensity score to assess the strength of preformed antibodies and their impact on renal outcomes after transplantation. In this case, although crossmatch is positive probably due to non-HLA antibodies, desensitization is not indicated.
If no, what are the other options?
Because of this risk, it is wise to suggest Paired Exchange Program for this recipient. This means that the transplant center may arrange for a kidney exchange from a donor of one pair who is more compatible with the recipient from the other pair. This allows for better matching for both recipients, with lower immunologic risk, and eventually less risk of rejection and graft loss.
Nicely explained, covers all major points.
Q1:
This is 3/6 (120) mismatch and HLA DR & DQ are full-match and HLA- C & DP mismatch.
Q2:
Positive T cell FCXM with negative B cell FCXM is related to development of non HLA antibodies in this case. Because negative autocross match and repeated positivity can excludes auto-antibodies or lab errors as etiology, respectively. In addition DSA is negative.
Q3:
Yes, although there is relative risk of IgA nephropathy recurrence but usually the rate of graft loss is not very high. But due to possibility of non-HLA abs, it may be associated with rejection if perform without desensitization.
Q4:
Desensitization with plasmapheresis, IVIG and rituximab for negative XM. Induction therapy with ATG (due to positive XM and IgA nephropathy as primary disease) and triple therapy with tacrolimus, MMF and prednisolone is recommended.
Q5:
Paired kidney transplantation with a negative XM.
Q1:
This is 3/6 (120) mismatch and HLA DR & DQ are full-match and HLA- C & DP mismatch.
Q2:
Positive T cell FCXM with negative B cell FCXM is related to development of non HLA antibodies in this case. Because negative autocross match and repeated positivity can excludes auto-antibodies or lab errors as etiology, respectively. In addition DSA is negative.
Q3:
Yes, although there is relative risk of IgA nephropathy recurrence but usually the rate of graft loss is not very high. But due to possibility of non-HLA abs, it may be associated with rejection if perform without desensitization.
Q4:
Desensitization with plasmapheresis, IVIG and rituximab for negative XM. Induction therapy with ATG (due to positive XM and IgA nephropathy as primary disease) and triple therapy with tacrolimus, MMF and prednisolone is recommended.
Q5:
Paired kidney transplantation with a negative XM
acceptable
HLA mismatch is 120 in A,B,DR antigens , also there is 2 HLA C antigen mismatches, and one HLA DQ mismatch, and One HLA DP mismatch.
Positive FCXM and negative auto crossmatch with no DSA points to non HLA antibodies.
proceeding with transplantation in patients with positive FCXM is associated with high risk of rejection , so if no other option is available ( another donor or paired exchange transplantation) i would accept the donor , but desensitization should be done before transplantation to get a negative FCXM then to proceed with transplantation.
induction with ATG and maintenance with TAC, MMF, steroids .
finding another donor , or Paired exchange transplantation.
Excellent and up to the point
What is his HLA match?
-HLA is 120 mismatching.
How would you explain the positive crossmatch?
-Positive autocross match means the presence of IgM autoantibodies.
-Positive T cell FCXM and negative B cell crossmatch can be a technical error or non HLA- autoantibodies.
Would you accept the offer?
If yes, how would you manage his immunosuppression?
-I accept this offer with desensitization of patient with plasmapheresis +IVIG and rituximab until FCXM become negative then induction with ATG and Maintenance therapy with Tacrolimus, MMF, Prednisolone.
If no, what are the other options?
– change the donor or put him on the paired Kidney exchange program.
good
1- HLA mismatch is 120
2- positive cross match with negative DSA and negative auto crossmatch indicates presence of non-HLA antibodies
3- if we accept the offer, will do desensitization protocol in the form of plasmapharesis and ivig alternating with hemodialysis for 1-3 weeks until crossmatch becomes negative then will proceed for transplantation with ATG induction and maintained on Tac, MMF, prednisolone.
4- if will not accept will search for paired kidney donation.
what about date of FCMXDo you need an updated DSAs?
yes of course will repeat it
What is his HLA match?
There is 120 mismatching. furthermore, there is HLA-C, HLA-DP mismatching.
How would you explain the positive crossmatch?
It could be due to the presence of non-HLA antibodies, as the auto XM is negative( initially was positive) and the XM is repeated many times so it is unlikely to be a lab error.
Would you accept the offer?
This is a live related donor ( still young age) with 120 mismatching and positive T cell XM, no DSA, don’t know about cPRA, and the presence of non HLA antibodies are known to be associated with rejection, so this is a risky transplantation, but still we can accept the offer.
If yes, how would you manage his immunosuppression?
Desensitization with plasmapheresis and IVIG and may be rituximab till we get negative XM result, then induction with lymphocyte depleting agent ( ATG), and triple immunosuppressive medications for maintenance therapy( Tac, MMF, and steroids).
given the immunological risk of this transplantation and the risk of disease recurrence, early steroid withdrawal can not be applied in this case.
Follow up: DSA monitoring and if possible, protocol biopsy.
If no, what are the other options?
Give the patient a chance of finding a more compatible donor through paired kidney donation program.
References;
Well done remember the last FCXM was in Jan. 2020 so you need to update that slso DSAs
good to mention HLA-C and HLA-DP.
What is his HLA match?
How would you explain the positive crossmatch?
Would you accept the offer? If yes, how would you manage his immunosuppression?
So I will manage this case as high-risk transplantation
If no, what are the other options?
REFERANCES
1. Kuten S, Patel S, Land G, Eagar T, Knight R, Loucks J, Gaber L, Gaber A. Impact of Positive Crossmatch Due to Non-HLA Antibodies on Graft Outcomes in Renal Transplantation [abstract]. Am J Transplant. 2015; 15 (suppl 3).
verygood
Does IgA GN have a say in your maintenance plan.
What is his HLA match?
How would you explain the positive crossmatch?
Would you accept the offer?
I will accept this offer ,putting in mind VXM to be done for further clarification
If yes, how would you manage his immunosuppression?
If no, what are the other options?
Paired kidney donation(Kidney swab).
Referrences
very good but no mention of non HLA ANTIBODIES !
What is his HLA match?
1-2-0
How would you explain the positive crossmatch?
Causes for T cell FCXM positive and B cell FCXM negative are
Lab error – cannot be wrong 3 times.
Auto antibody- ruled out by a negative auto cross match
Non HLA ab
Would you accept the offer?
Prefer an alternate donor or paired kidney exchange .
If no such available and patient is willing to take the risk for this high risk transplant then will go ahead.
If yes, how would you manage his immunosuppression?
Desensitization with
Rituximab D -15
TAC/MMF D -7
Plasmapharesis with ivig 100mg/kg post plasmapheresis from D -7 on alternate day.
Repeat FCXM on D-1 after plasmapheresis and IVIG and go ahead with transplant only if negative .
ATG D0 1.5mg/kg
ATG D1 1.5 mg/kg
Maintenance –
Tac / MMF/ steroids
If no, what are the other options?
Alternate donor or paired kidney exchange .
A Comprehensive Overview of the Clinical Relevance and Treatment Options for Antibody-mediated Rejection Associated With Non-HLA Antibodies
Kardol-Hoefnagel et al
DUAL INDUCTION WITH ANTI-THYMOCYTE GLOBULIN(ATG) AND RITUXIMAB(RTX) IN SENSITIZED KIDNEY TRANSPLANT(KT) PATIENTS
Jin Kong et al