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1. A 31-year-old CKD 5 patient due to FSGS received a kidney offer from a deceased 29-year-old donor.
- Comment on the report.
- Comment on the difference between the broad and the split mismatch.
- What is the impact of split mismatch on graft survival?
- Explain how the presence of DSA influences graft survival would.
- Will you proceed with the transplantation?
- If yes, what is your immunosuppression protocol?
- If not, what are the other options?
- What is the impact of the primary disease on graft survival in the indexed case?
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1. Compatible blood grouping
HLA matching at broad antigen level 110
At split antigen level 111
Negative crossmatch for B and T cells
2. Broad antigens can split to split antigens, split antigen are more specific.
A9 broad antigen split into A 23 and A 24.
3.split mismatch is more specific and has negative impact on graft survival.
4. Presence of DSA means previous desensitization as previous transplantation, blood transfusion and pregnancy
Lead to antibody mediated rejection and graft loss
5. Yes , ATG for induction followed by maintenance therapy ( Tac,MMF and steroids)
6. Waiting for more compatible donor, living donor، kidney paired donation
7. FSGS has risk of recurrence about 30% and risk of graft loss in 50% of cases
Comment on the report.
The cadaveric donor is 29 years with O negative blood group and the recipient has B positive blood group. Serologic HLA matching shows 110 mismatches (broad mismatch). But DNA profiling results in 111 mismatches (split mismatch).There are no DSAs.
Comment on the difference between the broad and the split mismatch.
Mismatch at the major antigenic loci tested serologically at HLA-A, HLA-B & HLA-DR is called broad mismatch. Split mismatch is how similar the subdivisions of HLA-DR, i.e DRB1, DRB2, DRB3, DRB4, etc tested gene
What is the impact of split mismatch on graft survival?
Split mismatch can result in formation of anti-bodies against that antigen and graft dysfunction although we may have assumed that rejection for that parent locus by broad mismatch would not have occurred.
Explain how the presence of DSA would influence graft survival.
Presence of DSA may lead to antibody mediated rejection and catastrophic outcomes if not aggressively managed.
Will you proceed with the transplantation?
Yes
If yes, what is your immunosuppression protocol?
Induction: Basilixumab
Maintenance: Prednisolone, Tacrolimus, MMF
If not, what are the other options?
Other donors from donor pool may be considered.
What is the impact of the primary disease on graft survival in the indexed case?
FSGS can recur with possible graft loss and chronic allograft nephropathy
Comment on the report.
The above donor has 110 broad antigen typing mismatch with the above recipient and 111 split antigen mismatch –Donor is ABO blood group compatible and has no DSA with negative flow cytometry for T and B cells.
Comment on the difference between the broad and the split mismatch.
Broad antigen is an HLA molecule with less specificity and is divided into two or more split antigen .while split antigen is specific .As A9 broad antigen is split into A23 and A24 split antigens.Similarly in the above case ,DR2 is split into DR15 and DR16.
What is the impact of split mismatch on graft survival?
Better graft and patient survival is associated with split antigen match and has prime importance wile selecting donors for renal transplantation. If mismatches are identified, large difference was observed within 03 years between 0 (31%)and 6 mismatches (6%)
·Explain how the presence of DSA influences graft survival.
Chances of ABMR with graft loss and poor survival are more if DSA are present.
Will you proceed with the transplantation?
Yes, I will proceed with the transplantation as quality of life will be improved with transplantation rather than remaining on dialysis .
If yes, what is your immunosuppression protocol?
Patient will be inducted with basilixmab and pulse methylprednisolone for 3 days then tapered off ,followed by maintenance therapy with low dose steroids and tacrolimus 0.15mg/kg /day in divided dose twice a day with trough level 8-10ng/ml ,mycophenolate mofetil (MMF)1g/BD.
If not, what are the other options?
Living donor or paired kidney exchange program,
Wait for another better matched deceased donor.
What is the impact of the primary disease on graft survival in the indexed case?
One of commonest cause of steroid resistant nephrotic syndrome is FSGS that leads to ESRD and even if patients undergo renal transplant , chances of recurrence are around 10% to 47% and 30-50% chance of graft loss . Young patients who belongs to white and asian ethnic group and having a living donor ,who presents early with nephrotic syndrome and progress rapidly to ESRD ,having lower BMI ,having HLA DR-7, DR-53 and HLA-DQ 2,biopsy showing mesangial hyercellularity and patients undergoing third or fourth transplant with previous history of recurrence in previous transplant are more prone to develop recurrence post transplant.
Post transplant FSGS recurrence can be treated with optimization of immunosuppression ,PLEX and cyclophosphamide/Rituximab
REFERENCES:
1-Handbook of kidney transplantation-6th edition
2- 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
3- Uffing A, Pérez-Sáez MJ, Mazzali M, et al. Recurrence of FSGS after Kidney Transplantation in Adults. Clin J Am Soc Nephrol. 2020 Feb 7; 15(2):247-256.
This patient is having 1:1:0 mismatch with no DSA
will go with transplant using ATG ,will recommend to have split DSA for better survival
will proceed with ATG induction then triple tmmunuspressent
Patient need close monitoring as there is risk for rescuerence of primary disease
Comment on the report.
Donor is having O blood group and Recipient is having B blood group .So it is a ABO compatible Transplant. Broad mismatch is 110 and split is 111. No DSA present
Comment on the difference between the broad and the split mismatch
Typing for HLA antigens can be done for so-called broad antigen specificities or for their subunits which are commonly called antigen splits.! For example, individuals possessing the HLA antigen HLA-A9 can be characterised further as possessing either HLA-A23 or HLA-A24, two subunits or “splits” of HLA-A9.
What is the impact of split mismatch on graft survival?
Survival is better if HLA is matched for split antigens.
Explain how the presence of DSA influences graft survival would.
It increases the risk of ABMR. The type of DSA (preexisting or de novo) may also be a predictor of worse outcomes in patients with ABMR. ABMR in patients with a de novo DSA, which is thought to be mostly related to medication nonadherence or inadequate immunosuppression, has been associated with poorer outc.omes compared with ABMR in patients with preexisting DSA (ie, presensitized patients) .
Will you proceed with the transplantation?
YES
If yes, what is your immunosuppression protocol?
Considering his immunological risk ,i will go with ATG induction.Then triple immunosuppression.
What is the impact of the primary disease on graft survival in the indexed case?
There can be recurrence of FSGS in kidney graft and graft can be lost. To help detect early recurrence posttransplantation, all patients with primary FSGS as the cause of ESKD in the native kidneys should be screened for proteinuria. We obtain a random or spot urine protein-to-creatinine ratio on the first postoperative day, the day of scheduled hospital discharge, weekly for four weeks, and then monthly for one year after transplantation . If the ratio is >0.5 g/g, we obtain a 24-hour protein collection to confirm the result obtained with the random urine protein-to-creatinine ratio.Protein excretion from native kidneys decreases significantly within one month of transplantation; thus, proteinuria that is detected more than one month after transplantation is most likely derived from the allograft and should trigger further investigation.A kidney biopsy to exclude other causes of proteinuria should be performed if posttransplantation proteinuria exceeds 1 g/day and should include electron microscopy to detect early features of FSGS.
The report shows ABO compatible transplantation with no DSA.
The different between broad and split antigens is non-significant in this case … reflects good matching considering HLA groups.
The higher split match provides better graft survival, less antigenic, lower probability of exposure to rejection episodes.
The presence of DSA poses the renal graft to higher incidence of rejection if not treated properly it decreases the graft survival.
The exposure to DSA either preformed or Denovo affects the graft survival, consequently eGFR decline. Special concerns to complement fixing types, IgG4, IgG 3 are associated with vascular and cellular rejection with worse prognosis.
Proceeding for transplantation process is accepted.
Immunosuppressive regimen is:
Induction by basiliximab (as they are of good matching, no DSA)
Triple immunosuppression regimen including tacrolimus, MMF, and steroids), noting that the original disease is FSGS which has high tendency for recurrence.
Other options include haemodialysis or paired kidney donation or deceased donation programs.
FSGS show high tendency for recurrence average 50% ,so regular frequent monitoring of proteinuria , protocol biopsies according to the centre schedule are mandatory for
such cases.
Given that the probable receiver is B and the potential donor is O, this is an ABO-compatible situation.
Rh(D) is not significant since non-erythroid cells lack it.
Broad mismatches of HLA 110 and split mismatches of HLA 111, DR2 Broad (Splits DR15 and DR16; 1995), NO DSA found.
The last time FCXM for both B and T cells was negative was in 2020; however, FCXM with DSA level has to be repeated.
HLA antigen classifications have changed over time as assay progress has made it possible to identify antigen variations that were previously undetectable (“broad” categories; “split” categories).
Testing for cell surface antigens is known as broad antigen, which is also known as an antigen with two or more splits and a serological specificity that is low or broad in comparison to other specificities.
Split Antigen has a more specialised or refined cell surface response.
When compared to broad antigens, the outcome is better when matching split HLA antigens. Compared to HLA-DR, it is more clinically significant for HLA-A and HLA-B.HLA-DR split specificities have a considerable impact on re-transplant survival but have little effect on first transplants.
Pre-transplant DSA was substantially associated with an increased risk of ABMR, graft loss, and accelerated eGFR decline.
Certain characteristics of DSAs have been linked to poor outcomes among ABMR patients.
Will you proceed with the transplantation?
Before making a decision, perform another cross match and DSA level.
Yes, we will go through with the transplantation as long as the following conditions are met:
If yes, what is your immunosuppression protocol?
Basiliximab for induction and triple maintenance therapy (steroid +tacrolimus +MMF).
If not, what are the other options?
Look for better HLA matching living donor
What is the impact of the primary disease on graft survival in the indexed case?
The FSGS recurrence rate ranges from 17% to 60%, with the strongest data coming from the TANGO cohort study, which reported a 32% recurrence risk.
It could begin as early as 3 months or as late as 3 months post-transplantation, typically in patients with primary or idiopathic disease.
Consider preventative strategies to reduce the risk of recurrence; plasmapheresis, rituximab. Monitor the recurrence by urine PCR beginning on the very first postoperative day. If the proteinuria is significant, an allograft biopsy is required to corroborate the recurrence of FSGS or the presence of another pathology.
References:
– Opelz, Gerhard1; Scherer, Sabine; Mytilineos, Joannis. ANALYSIS OF HLA-DR SPLIT-SPECIFICITY MATCHING IN CADAVER KIDNEY TRANSPLANTATION: A Report of the Collaborative Transplant Study. Transplantation 63(1):p 57-59, January 15, 1997.
– Nguyen, H. D. , Williams, R. L. , Wong, G. , Lim, W. H. . The Evolution of HLA-Matching in Kidney Transplantation. In: Rath, T. , editor. Current Issues and Future Direction in Kidney Transplantation [Internet]. London: IntechOpen; 2013 [cited 2023 Jan 16]. Available from: https://www.intechopen.com/chapters/42879 doi: 10.5772/54747.
– Hata, Yoshinobu2; Cecka, J. Michael3; Takemoto, Steven; Ozawa, Miyuki; Cho, Yong W.; Terasaki, Paul I.. EFFECTS OF CHANGES IN THE CRITERIA FOR NATIONALLY SHARED KIDNEY TRANSPLANTS FOR HLA-MATCHED PATIENTS1. Transplantation 65(2):p 208-212, January 27, 1998.
– Zhang R. Donor-Specific Antibodies in Kidney Transplant Recipients. Clin J Am Soc Nephrol. 2018 Jan 6;13(1):182-192. doi: 10.2215/CJN.00700117. Epub 2017 Apr 26. PMID: 28446536; PMCID: PMC5753302.
– Uffing A, Pérez-Sáez MJ, Mazzali M, Manfro RC, Bauer AC, de Sottomaior Drumond F, O’Shaughnessy MM, Cheng XS, Chin KK, Ventura CG, Agena F, David-Neto E, Mansur JB, Kirsztajn GM, Tedesco-Silva H Jr, Neto GMV, Arias-Cabrales C, Buxeda A, Bugnazet M, Jouve T, Malvezzi P, Akalin E, Alani O, Agrawal N, La Manna G, Comai G, Bini C, Muhsin SA, Riella MC, Hokazono SR, Farouk SS, Haverly M, Mothi SS, Berger SP, Cravedi P, Riella LV. Recurrence of FSGS after Kidney Transplantation in Adults. Clin J Am Soc Nephrol. 2020 Feb 7;15(2):247-256. doi: 10.2215/CJN.08970719. Epub 2020 Jan 23. PMID: 31974287; PMCID:
Comment on the report.
· This report showed an ABO matching compatible as the donor has blood group O(universal donor) and can safely donate his organ to blood group B recipient.
· RH incompatible, but in renal transplantation the RH antigen is not an important antigen, being present on red blood cells surface only but not on the parenchymal graft cells.
· The HLA FXCM is negative for both B and T cells. However, it is old and need to be updated.
· HLA mismatch is 1:1:0 at the broad level, while the split:1:1:1 as DR 2 is split into DR 15 and DR 16.
· No encountered DSA
Comment on the difference between the broad and the split mismatch.
· The antigens can be classified into broad antigens and split antigens.
· 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.
· Accordingly, the older broad antigens can split into 2 or more antigens. In the above case DR2 broad is split to DR 15 and DR 16.
· Broad antigens have the ability to bind 2 or more antibodies, while split antigens can only bind 1 antibody(1,2).
What is the impact of split mismatch on graft survival?
Matching for the broad antigens increase the chances of finding a more suitable donor especially with the lack of available organs for transplantation; However, it was found that HLA split cross-match can impact the transplantation outcome.
Split HLA matching is associated with better graft survival. This appear to be more important for HLA-A, B compared to HLA-DR.. HLA-DR split matching is more important for re-transplantation (3).
Explain how the presence of DSA influences graft survival.
The presence of DSA indicates previous sensitization from previous transplantation or multiple pregnancies in case of female recipients or blood transfusions.
Preformed DSA were associated with an increased risk for AMR and graft loss in kidney transplantation, which was greater in living than in deceased donation. Even weak DSA <3000 MFI were associated with worse graft survival.
Will you proceed with the transplantation?
Yes, immunologically low risk patient
If yes, what is your immunosuppression protocol?
Immunologically low risk patient
Induction with Basiliximab, and maintenance with Tacrolimus, MMF, and Prednisolone.
If not, what are the other options?
Enroll in a living kidney-exchange program or look for a more suitable donor.
What is the impact of the primary disease on graft survival in the indexed case?
Following renal transplantation, FSGS carry a risk of recurrence around 30 % and causes graft loss in 30-50%.Risk factors for recurrence include, a living donation, white ethnicity, lower BMI, , heavy proteinuria, , and prior recurrence of FSGS
References:
1. Mahdi B. A glow of HLA typing in organ transplantation. Clinical and Translational Medicine. 2013; 2(6).
2. Tinckam KJ et al. . Re-Examining Risk of Repeated HLA Mismatch in Kidney Transplantation. J Am Soc Nephrol. 2016; 27(9): 2833–2841.
3. Opelz G. Importance of HLA antigen splits for kidney transplant matching. Lancet. 1988;9(2):61-4.
4. Zhang R. Donor-Specific Antibodies in Kidney Transplant Recipients. Clin J Am Soc Nephrol. 2018 Jan 6;13(1):182-192.
5. Chadban SJ, Ahn C, Axelrod DA, Foster BJ, Kasiske BL, Kher V, et al. KDIGO Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation. Transplantation. 2020 Apr;104(4S1 Supp 1):S11-S103.
6) Cosio FG, Cattran DC. Recent advances in our understanding of recurrent primary glomerulonephritis after kidney transplantation. Kidney Int. 2017 Feb;91(2):304-314.
1- This is HLA report demonstrating compatible blood group matching , the patient is blood group B positive and the donor is blood group O negative.
The mismatch is 1:1:1.
2- Split mismatch is more accurate and depends on the sequential analysis of the alle epitope .
3- Split mismatch would reduce the risk of antibody reduction and improved graft survival rate.
4- Presence of DSA will put the transplantation at risk of acute antibody rejection and consequently graft loss.
5- Yes I will proceed with this transplantation because no DSA, and the flow cross match is negative.
6- Induction with methylprednisolone injection followed by tacrolimus, mycophenolate mofitel and prednisolone triple therapy.
7- Other options like paired exchange donation.
8- There is high recurrence of the original disease up to 60%.
Comment on the report.
The report is crossmatch negative
Comment on the difference between the broad and the split mismatch.
The serological supertypes are the broad specificities while split is subtypes comprising of finer specificities giving a better insight of immunogenic potential (Tait BD, 2011)
What is the impact of split mismatch on graft survival?
Split mismatch has a negative impact and can lead to graft failure
Explain how the presence of DSA influences graft survival would.
Presence of Donor specific antibodies negatively impacts the graft survival as they work against donor antigens. A significantly increased risk of ABMR, graft loss, and accelerated eGFR decline (hyperacute or acute rejection) were associated with the presence of pre-transplant DSA
Will you proceed with the transplantation?
Yes, I will proceed with the transplantation
If yes, what is your immunosuppression protocol?
Induction with ATG- 3mg/kg bodyweight
Tacrolimus- 0.1 to 0.15mg/kg body weight
MMF- 1 gram body weight
Steroids
If not, what are the other options?
What is the impact of the primary disease on graft survival in the indexed case?
The main concern is the reoccurrence of FSGS post-transplant.
References
1. Tait BD. The ever-expanding list of HLA alleles: changing HLA nomenclature and its relevance to clinical transplantation. Transplant Rev (Orlando). 2011;25(1):1-8.
ABO compatible
Broad HLA matching 1 1 0, split HLA matching 1 1 1, no DSA, negative FXCM for both T& B cells.
Split antigen typing is more expensive and challenging than broad antigen typing.
Splitting is not required for cadaveric kidney matching.
Because there are fewer specific antigens, it is simpler to identify a suitable match for broad antigens than for split antigens.
When a higher degree of matching is utilized, such as split level specificity or allele matching, many well-matched grafts at the broad level specificity may contain a considerable number of mismatches.
Therefore, private or public antigen matching is very important in reducing graft rejection.
The HLA-A and HLA-B loci were matched for both wide and split antigens.
By including HLA-DR Antigens in the mismatching computation, the antigen split effect is potentiated.
Consequently, typing HLA-DR split will enhance the correlation of HLA matching with 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 .
When a higher degree of matching is utilized, such as split level specificity or allele matching, many well-matched grafts at the broad level specificity may contain a considerable number of mismatches.
Therefore, private or public antigen matching is very important in reducing graft rejection.
When there are matched public antigens, patients with at least one matched private antigen had transplant survival that was on par with or superior.
Split antigen typing is more expensive and challenging than broad antigen typing.
Splitting is not required for cadaveric kidney matching.
Because there are fewer specific antigens, it is simpler to identify a suitable match for broad antigens than for split antigens.
DSA is predictive of poor graft survival and graft loss as well as poor patient survival.
Yes.
Induction by basiliximab, maintenance by triple IS
Desensitization
PKD
Recurrence is the main concern.
Comment on the report.
ABO compatible (Donor has O blood group), HLA matching showed 110 broad mismatch and 111 split mismatch. No DSA and negative flow cytometry for T and B cells on five occasions.
Comment on the difference between the broad and the split mismatch.
Broad antigens splits into two or more antigens, termed ‘split’ antigens. For example, the A9 broad antigen was split to A23 and A24 split antigens, whereas the DR2 broad antigen was split to DR15 and DR16 split antigens. Split antigen matching is more clinically important compared to broad antigen matching as it’s more specific and associated with better allograft function and survival.
What is the impact of split mismatch on graft survival?
split mismatch was significantly associated with increased risks of overall graft failure. In one of the studies graft survival was significantly decreased if a split mismatch was defined although no broad mismatch (P=0.04) and also in grafts with two split mismatches, which showed only one mismatch according to the broad definition (P=0.03).
Explain how the presence of DSA influences graft survival would.
Pre-transplant DSA were associated with a significantly increased risk of ABMR, graft loss, and accelerated eGFR decline (hyperacute or acute rejection). As well as, De novo donor-specific HLA antibodies reduce graft survival rates and increase the risk of kidney transplant rejection and often accompanied by C4d deposition (Chronic transplant glomerulopathy).
Will you proceed with the transplantation?
Based on the previous report I will proceed with the transplantation.
If yes, what is your immunosuppression protocol?
Induction with Basiliximab and Methylprednisolone.
Maintenance with Tacrolimus, Prednisolone and MMF.
What is the impact of the primary disease on graft survival in the indexed case?
FSGS associated with high recurrence rate (30%) which can occur sometimes early after transplant (hours to days) and cause graft loss in about third of the cases.
Opelz G, Scherer S, Mytilineos J. Analysis of HLA-DR split-specificity matching in cadaver kidney transplantation: a report of the Collaborative Transplant Study. Transplantation. 1997 Jan 15;63(1):57-9. doi: 10.1097/00007890-199701150-00011. PMID: 9000661.
Uffing A, et al. Recurrence of FSGS after kidney transplantation in adults. Clin J Am Soc Nephrol 2020; 15:247–256. doi: 10.2215/CJN.08970719
Comment on the report
* ABO compatible transplantation
* Broad antigen typing is 110
While split antigen typing is 111
* Flow cytometry is negative in 5 occasions
* DSA is negative
Broad mismatch is less specific while split antigen is more specific
Where Broad antigen can be splited into 2 or more split antigens
As DR2 is split into DR 15,16
Split mismatch can cause poor graft outcome
Presence of DSA can lead to ABMR and acute graft loss or chronic allograft nephropathy.
I shall proceed with transplantation as negative cross match and negative DSA
Split antigen mismatche is 111
Induction immunosuppression with basilximab followed by triple immunosuppression Tacrolimus, MMF and Stetoids.
Alternatives is to enroll the patient in paired kidney donation
FSGS as a primary renal disease is liable for recurrence by 30 to 40 % with a risk of 30 % graft loss
Assalam o Alaikum
1. COMMENT ON THE REPORT:
ABO compatible due to O group donor. Rh not relevant in consideration for renal transplantation. HLA matching shows 110 broad and 111 split mismatch, which is good considering it is a deceased donor. Manual Flowcytometry is negative for both T & B cells multiple times over 26 months period. No donor specific antibodies could be detected.
Overall a very good report with probably the biggest concern being the primary disease.
2. Comment on the difference between the broad and the split mismatch.
Serological HLA typing will give us broad mismatches whereas molecular HLA typing will give us split mismatches which can give us better insight into immunogenic potential. The finer the differentiation, the better chance it gives us of identifying higher risk cases for rejection and transplant glomerulopathy. Chopra et al found a mean discrepancy rate of 19.5 % between broad and split mismatches.
3. What is the impact of split mismatch on graft survival?
According to the study by Nguyen et al Broad mismatch has a linear association with acute rejection whereas split mismatch has a non-linear but exponential association. The presence of higher split mismatches is associated with development of de novo DSA and transplant glomerulopathy. Although not superior to serological testing, split mismatch by molecular method can serve as an important adjunct to predicting high risk cases.
In another study by Opelz the difference in graft survival was 31% (split mismatches) vs 6% (broad mismatches). Molecular testing for split antigen mismatches can and does improve transplant outcomes.
4. Explain how the presence of DSA influences graft survival
ABMR remains the leading cause of graft dysfunction and graft loss post-transplant. Donor specific antibodies can be classified into preformed and de novo categories. Preformed antibodies are present as a consequence of blood transfusions, pregnancy, previous transplant (in short any episode of exposure to HLA antigens). De novo DSA formation is associated with higher HLA mismatches, poor immunosuppression (low dose vs poor compliance) and inflammation (viral, bacterial, ischemic, cellular injury). Presence of DSA (both preformed and de novo) is associated with poorer graft survival. Preformed DSA can lead to hyperacute and acute rejection episodes as well as graft loss. De novo DSA can lead to acute or chronic antibody mediated rejection as well as transplant glomerulopathy.
5. Will you proceed with the transplantation?
Yes. On basis of this report we can proceed for transplantation as a standard case after repeating cross match as the last report is from January 2021.
6. If yes, what is your immunosuppression protocol?
I would advise Basiliximab alongwith IV methylprednisolone as induction therapy. Standard CNI (Tac) with MPA and steroids as maintenance therapy.
Although a few studies have been done with regards to Plasmapheresis +/- Rituximab for prevention of recurrent FSGS post-transplant but no definitive proven benefit for either strategy has been found. However I would keep a very close eye on proteinuria in the immediate post-transplant phase.
7. If not, what are the other options?
N / A
8. What is the impact of the primary disease on graft survival in the indexed case?
There is a 30 % risk of recurrent FSGS post-transplant with 30-40 % of those affected having graft loss. The recurrence rate varies from 17-55% in various studies, this difference in part is due to failure in differentiating between primary and secondary FSGS as primary diagnosis.
REFERENCES:
· Chopra GS, Diwan RN, Mehra NK. Role of Molecular Typing in Live Related Donor Renal Transplantation. Med J Armed Forces India. 2002 Jul;58(3):201-4. doi: 10.1016/S0377-1237(02)80129-0. Epub 2011 Jul 21. PMID: 27407382; PMCID: PMC4925343.
· Nguyen, Hung & Wong, Germaine & Chapman, Jeremy & Mcdonald, Stephen & Coates, Patrick & Watson, Narelle & Russ, Graeme & DʼOrsogna, Lloyd & Lim, Wai. (2016). The Association Between Broad Antigen HLA Mismatches, Eplet HLA Mismatches and Acute Rejection After Kidney Transplantation. Transplantation Direct. 2. 1. 10.1097/TXD.0000000000000632.
· Opelz G. Importance of HLA antigen splits for kidney transplant matching. Lancet. 1988;2(8602):61-64. doi:10.1016/s0140-6736(88)90001-3
· Boonpheng B, Hansrivijit P, Thongprayoon C, et al. Rituximab or plasmapheresis for prevention of recurrent focal segmental glomerulosclerosis after kidney transplantation: A systematic review and meta-analysis. World J Transplant. 2021;11(7):303-319. doi:10.5500/wjt.v11.i7.303.
· Uffing A, Pérez-Sáez MJ, Mazzali M, et al. Recurrence of FSGS after Kidney Transplantation in Adults. Clin J Am Soc Nephrol. 2020 Feb 7;15(2):247-256. doi: 10.2215/CJN.08970719. Epub 2020 Jan 23. PMID: 31974287; PMCID: PMC7015092.
Comment on the report.
Comment on the difference between the broad and the split mismatch
The split antigen tests the cell surface antigens, an antigen with a more refined cell surface reaction (e.g HLA B51, HLA52 as split antigen of HLA5 relative to a broad antigen. For instance e.g HLA B51, and HLA52 as split antigens of HLA5 which is the broad antigen
What is the impact of split mismatch on graft survival?
Explain how the presence of DSA influences graft survival
The DSA could be those found pretransplant or de-novo. The presence of either has a negative impact on the survival of the graft.
Positive donor-specific antibodies mean the donor has developed antibodies against the donor antigen and this could result in acute rejection or ABMR if desensitization is not done before proceeding with the transplantation.
These antibodies are usually developed by the potential recipient through blood transfusion, pregnancy, or previous transplantation
Will you proceed with the transplantation?
YES,
What is your immunosuppressive protocol?
If not, what are the other options?
What is the impact of the primary disease on graft survival in the indexed case?
The recurrence rate of primary FSGS following kidney transplantation is between 30-50%, while the rate of graft loss is 200-30% and this could be as high as over 50% in collapsing variant of FSGS. This recurrent rate has been found to be at an increasing rate in subsequent transplants if the first one failed
References
1) Comment on Report:
No ABO incompatibility issue.
HLA matching is quite good.
B and T cell cross matching is negative.
No DSA is detected.
2) Broad and Split mismatch:
Split antigen mismatch is more precise than broad antigen mis match and uses PCR based study.
3) More split mismatch confers the chances of more change of acute and chronic rejection and less long term graft survival.
4) DSA on graft survival:
Presence of DSA confers chances of acute and chronic graft rejection. Donor needs to be desensitized.
5) Overall there is good compatibility and Tx can be done.
6) Immunosuppressive:
Induction: Basiliximab and
methylprednisolone.
Maintenance: Oral prednisolone, Tacrolimus,
MMF.
7) Other Options:
Tx from living kidney donor.
Dialysis: Peritoneal or,
Hemodialysis
8) Impact of primary disease on graft :
FSGS can recur in graft on 30-40% cases.
Manifested as proteinuria and graft
dysfunction .Recurrent disease causes
decreased graft survival. Needs regular follow
up after Tx.
Comment on Report :
As Donar is O-ve and Recipient is B +ve so No ABO Compatibility issue
HLA Matching is reasonable and Flow Cross match is negative multiple times so
It’s a Good match and Transplant can be done with ease
Comment on the difference between the broad and the split mismatch:
Split mismatch is advanced test than Broad mismatch as it allows the detection of differences in antigens that were indistinguishable from broad mismatch
What is the impact of split mismatch on graft survival:
Better Mismatch results means better compatibility. Better compatibility means better graft survival
Explain how the presence of DSA influences graft survival :
Donar specific antibodies before transplant is a major risk factor for early loss of graft and early rejection especially humoral one
Will you proceed with the transplantation:
Yes, As it is ABO Compatible and match is good but’ll check level of FSGS and proteinuria before transplant and’ll monitor after transplant
If yes, what is your immunosuppression protocol :
Induction : ATG 1.5 mg/kg
Maintainance : MMF, Steroids and Tac
If not, what are the other options :
Others Options are Peritoneal dialysis, Hemodialysis or Live kidney transplant
What is the impact of the primary disease on graft survival in the indexed case :
There are chances of recurrence of FSGS post Kidney transplant so i’ll monitor proteinuria initillay daily than weekly than monthly and than 3 monthly and’ll treat if recur
Comment on the report:
ABO compatible
HLA match 11/18; Class1 A-B-C 3/6 – haplo-match; class2 8/12 match; DR 3/4 match
broad mismatch 210; split mismatch 211
Flowcyto X match negative repeatedly, with absence of DSA
=> over all, wel-matched pair, like a living sibling / parental donor
Comment on the difference between the broad and the split mismatch.
HLA Broad antigen detected on serology can be further subclassified into 2 or more splits of allele as detected on SAB analysis, expressed on the cell surfaces.
example : HLA A5 can have A5.1 and A5.2 or further 3rd digit subclassification
Split mis match is more precise, can be detected with newer technology like PCR (Single antigen bead)
HLA -DR antigen mis match has more impact than HLA class1 antigen mismatch on 1st year post transplant rejection; how ever no significant difference on long term graft survival.
What is the impact of split mismatch on graft survival?
higher the split matching means better histo-compatible pair – thus higher split mis-macth can have bearing on long term allograft survival, acute and chronic rejection.
Explain how the presence of DSA influences graft survival would.
Positive Donor Specific Antibody can cause acute and chronic antibody mediated rejection (AMR), transplant glomerulopathy and early graft loss. High level of DSA especially against HLA class 1 antigen of the donor can cause accelerated AMR or hyperacute rejection – so, may have to decline from accepting that particular donor; and shall need prior desensitization in case of live donor transplant.
Will you proceed with the transplantation?
Yes, as it is a well-matched young donor, with multiple X match negative and DSA negative.
If yes, what is your immunosuppression protocol?
Being Low immunological risk
1.Induction with Basiliximab x20mg 2 doses – [1st dose on day0 (1 hour prior to declamping) and 2nd dose on Day4]
or Low dose Thymoglobulin 3mg / kg in infusion over 4hours
2.Methyl Prednisolone Injection – 3days (1gm – 500mg – 250mg), then oral prednisone 0.4mg/ kg daily x 3 weeks — then reduction dose 5mg/ week up to a maintenance dose of 5mg daily
MMF and Tacrolimus to be started 6 hours post operation or immediately patient is allowed orally.
If not, what are the other options?
patient can go for a suitable live donor, as the immediate post transplant complications are less and long term graft survival better with live donor transplant than from even a matched deceased donor.
What is the impact of the primary disease on graft survival in the indexed case?
high risk of recurrence of FSGS after transplantation have been reported – varying from immediate post op period to as late as many years.
Younge patients with heavy proteinuria, history of nephrotic syndrome, rapid progression to ESKD are high risk factors.
Some patients with early recurrence may present immediately post-transplant (day3-7) with oligo-anuria, massive proteinuria, fluid overload, bloated appearance and rapidly rising creatinine.
Initial slow / delayed graft function which is common in cadaver donor renal transplant may complicate the clinical picture.
We have be vigilant with high index of suspicion for immediate or early recurrence, if the patient retains fluid and keeps increasing weight, with heavy proteinuria. Graft renal biopsy for early detection and treatment with Plasma exchange and Retuximab can salvage the kidney, although less effective for long term.
Comment on the report:
SO overall it is a good matching
Comment on the difference between the broad and the split mismatch
I searched for this issue because I didn’t have an informations……overall split mismatch was more precise and clinically significant than broad ones for deciding renal transplantation.
Explain how the presence of DSA influences graft survival would.
the presence of DSA adversely affect & trigger rejections and poor graft survival
Will you proceed with the transplantation?
yes ,because the crossmatch was good and acceptable
if yes, what is your immunosuppression protocol?
induction…..basiliximab
maintenance…..CNI.MMP & steroid
If not, what are the other options?
What is the impact of the primary disease on graft survival in the indexed case?
there is risk of recurrence original disease and affecting graft survival
ABO compatible donor.
HLA typing: 110 mismatch for broad antigen and 111 mismatch for split antigen.
5 times FCXM for both T & B cell were negative. Need recent cross match report.
No DSA was detected.
So there is low immunological risk for transplantatation.
Broad antigen can be divided into 2 or more split antigen which have more specific cell surface reaction than broad antigen (Example- HLA A9 has been split into A-23 and A-24).
So split mismatch is newer technique and more specific than broad mismatch perspective of HLA matching for organ transplantation.
Higher the split antigen match, higher the histocompatibility and higher the graft survival.
So there is negative impact of high split mismatch on long term graft surviaval and increase chance of acute rejection & delayed graft function.
Anti- HLA antibodies(DSA) present in the recipient at the time of transplantation may cause aggressive rejection, particularly if directed against particular HLA antigen in the transplanted kidney. Sensitization (i.e development of Anti-HLA antibody) occur when patient exposed to non- self HLA antigen during previous pregnancy (directed against paternal HLA antigen) or previous blood transfusion or previous organ transplantation ( a ‘000’ mismatch is less likely to become sensitized).
Yes i will proceed for transplantation as there is low immunological risk.
Induction: Basiliximab 20mg IV on day 0 & day 4 of transplantation and methyl prednisolone for 3 days.
Maintenance: Tripple drug therapy include
a.Tacrolimus : Target trough level 3 – 7 ug/L
b. MMF : 1gm 12 hourly
c. Prednisolone
Can wait for living donor transplantation because living donor transplants are superior to those of deceased donor transplants, even for recipient of HLA matched kidneys.
Primary FSGS have a high incidence of recurrence after transplantation, reported 20 – 40%. The odds of recurrence are increased in the following patients-
Younger, history of heavy proteinuria & clinical nephrotic syndrome, rapid progression to ESKD, collapsing variant & mesangial hypertrophy.
Recurrence may present immediately post-transplant with oliguria & graft dysfunction from acute tubular injury. Plasma exchange before transplantation and in the early post- transplant period has been suggested but less effective.Recurrence after 1 year is unusual.
Comment on the report.
1.Patient/Donor ABO:compatible considering that the donor is O negative =universal donor.
2.HLA typing : Boad Ag mismatch: 110
Split Ag mismatch:111
3.physical crossmatch using flow cytometry shows repeatedly negative results for both B and T cells.
4.DSA screen result is negative=no detected DSA.
Comment on the difference between the broad and the split mismatch.
Broad Ag is like the parent Ag or supertype older Ag that were detected using serological tests
Split Ag is the subtype or subdivision the tge parent supertype broad Ag that were newly discoverd through molecular methods.
Split Ag is more refined or specific cell surface reaction relative to a broad antigen. (Example: HLA-B51 and HLA-B52 are split antigens of HLA-B5)
What is the impact of split mismatch on graft survival?
HLA Matching criteria may vary with regards to
Consideration of broad or split antigens.
Split Antigen matching appears to be more common
and clinically important for HLA-A and-B
antigens than for HLA-DR antigens
utilization of matching for broad
antigens increases the probability of identifying
HLA-matched recipients for any given donor.
Typing for HLA antigen splits is Important in renal transplantation,and results in better transplant outcomes
Explain how the presence of DSA influences graft survival
The presence of high levels of pre-transplant class I (HLA-A and B) ± II (HLA-DR) donor-specific antibodies
Is associated with poorer graft outcomes, including the development of acute AMR, chronic AMR, transplant glomerulopathy and late graft loss . but do not Affect the risk for T cell-mediated rejection
few studies have suggested that the association between pre-transplant DSA and graft survival was restricted to recipients who had developed early AMR, within the first 30-days post-transplantation
Will you proceed with the transplantation?
Yes,I will. The patient has negative flow cytometry and and no detected DSA i.e. has a low immunological risk
If yes, what is your immunosuppression protocol?
Considering the patient’s low immunological (_ve flow cytometry and no DSA)
We can give basiliximab as an induction agent and use triple drug regemine immunosuppressive medications (prednislone+CNI+MMF)
Although in real life the choice of medications is ruled by the availability of certain drugs in that given centre among other issues.
If not, what are the other options?
Options other than this donor could include:
1. waiting for another deceased donor which can jeopardize the patient’s health. And he might even require starting scheduled hemodialysis while waiting for a more suitable deceased donor
2.finding a suitable willing living donor
3.desenitization
4.Paired exchange program.
What is the impact of the primary disease on graft survival in the indexed case?
FSGS is is not a specifc disease entity but a Histopathological “’pattern of injury” seen on light Microscopy that primarily targets podocytes.
Multiple Underlying etiologies that lead to podocyte loss have Been identifed, including :systemic, genetic, and Medication induced and those mediated by adaptiveKidney responses.
When no secondary cause (genetic, viral, drug-associated, or adaptive can be identified and the patient presents with a clinical history of nephrotic syndrome, FSGS is termed primary or idiopathic.
Distinguishing between idiopathic and secondary FSGS is especially important in patients being considered for kidney transplantation because idiopathic forms frequently RECUR in the graft with a substantial rate of subsequent graft loss.
Reported rates of recurrence are wide, ranging from 17% to 55%in smaller studies and from 9% to 15% in registry-based studies
The accurate distinction between idiopathic and secondary causes, however, remains challenging, particularly if ultrastructural evaluation of the kidney biopsy or genetic testing are missing.
Comment on the report.
• ABO-compatible.
• Donor is Blood group O which is universal donor so no mismatch at ABO group.However, they are different in the Rh factor where we can see that the donor is Rh negative and the patient is Rh positive, Rh incompatibility is not an obstacle for transplantation because Rh-D is absent on non-erythroid cells.
• DSA – not detected
• Tissue typing: There is 110 mismatch at broad antigen level as DR 15 and 16 was considered as single antigen & 1:1:1 at split antigen typing.
• The Flow cytometry cross match was -ve for both T cell & B cell being done 5 times over 4 years.
this is standard immunological risk.
Comment on the difference between the broad and the split mismatch.
• Split antigens are antigens which were discovered with the development of molecular technology resulting from split of previously undistinguishable broad antigens which was detected with serological methods.
• That means broad antigens can occasionally be divided into two or more subtype antigens, known as “split” antigens.
• In other words, split antigens are those antigens which can be defined from other antigens in the broad group by unique epitopes.
• Example:
• HLA-A9 is a broad antigen —-> split antigens HLA- A23 and HLA-A24.
• HLA-B is a broad antigen —-> split antigens HLA-51 and HLA-52.
• HLA-DR2 is a broad antigen—-> split antigens HLA-DR15 and HLA-DR16.
What is the impact of split mismatch on graft survival?
• In kidney transplantation, matching at the level of split antigens yield better results than matching at broad level regarding graft function and survival and lower incidence of rejection.
• Matching at split level is more significant for HLA A and B when DR is more significant in case of retransplantation. As split antigens are more specific than a broad antigen, a split mismatch will have different response to immune stimulation causing graft injury and rejection leading to poorer outcomes.Higher number of split mismatches have a higher risk of developing DSA post transplantation and a higher risk of graft loss.
Explain how the presence of DSA influences graft survival would.
• DSA are IgG antibodies targeted against HLAs specifically corresponded to a mitchmatched antigen of donor.
• DSA may be anti-class I and anti-class II.
• The presence of preformed DSA is strongly associated with increased graft loss in kidney transplants, related to an increased risk of AMR.
• Pre-transplant DSA with MFI >1000 significantly reduced graft survival, with patients who had cumulative DSA MFI >5000 experiencing the worst results.
• Even DSA in patients with an MFI of 500 to 1000 were linked to a noticeably higher incidence of ABMR than in those without DSA.
• Patients are ‘sensitized’ (i.e. develop anti-HLA antibodies) when previously exposed to non-self HLA antigens.
• Key Sensitization –
1. Previous organ transplant
2. Previous pregnancy (directed against paternal HLA antigens).
3. Previous blood transfusion.
4. Unknown (possibly caused by cross-reactivity with microbial antig
• Present of donor-specific antibodies(DSA) in sensitized patients can trigger
1. hyperacute rejection
2. acute cellular rejection
3. early acute antibody-mediated rejection.
• De novo donor-specific antibodies are associated with late acute antibody-mediated rejection, chronic antibody-mediated rejection, and transplant glomerulopathy.
Will you proceed with the transplantation?
• Yes, I will proceed for transplantation.
• This patient carries low immunological risk, but there is risk of primary disease recurrence.
If yes, what is your immunosuppression protocol?
• Induction with basiliximab two doses on day 1 and 4 and methylprednisolone for 3 days
• Induction with basiliximab two doses on day 1 and 4 and methylprednisolone for 3 days.
• Maintainance with Tacrolimus, Mycophenolate and Prednisolone.
• If not what are the other options?
1. living donor.
2. Waiting for another deceased donor
3. Paired kidney donation.
What is the impact of the primary disease on graft survival in the indexed case?
• Primary FSGS have a high incidence of recurrence after transplantation, reported between 20% and 40%.
• Recurrence occurs commonly within two-year after transplant .
• Recurrence may present immediately post-transplant with oliguria and graft dysfunction from acute tubular injury. Proteinuria may develop within days – weeks post-transplantation.
• Risk factors for recurrence include:
1. Young aged patients
2. Non-African-American ethnicity
3. Rapid progression to ESKD
4. Collapsing variant
5. Heavy proteinuria
6. Nephrotic syndrome
7. Initial biopsy showed mesangial hypertrophy
8. History of recurrent FSGS hypertrophy in initial biopsy.
• The strongest predictor of recurrence is a history of recurrence in a previous transplant.
• Recurrence may occur in weeks, months or even immediately in which delayed graft function may occur.
• The 5-year graft survival is 81% -88%in FSGS recipients and non-FSGS recipients, respectively. The 5-year graft survival is 52% -83% in recipients with FSGS recurrence and recipients without FSGS recurrence, respectively.
Comment on the report
compatible ABO as a universal donor
broad antigen 110 mismatch
split antigen 111 mismatch
FCXM which is negative for both T & B cells
DSA negative
Comment on the difference between the broad and the split mismatch
Split antigens are more specific cell surface reactions relative to broad antigens
What is the impact of split mismatch on graft survival?
As more refined it offers better allocation of transplanted organs,with better outcomes
Explain how would the presence of DSA influences graft survival
Donor-specific anti-HLA antibodies (DSAs) cause hyperacute rejection,antibody-mediated rejection (ABMR) and reduced graft survival
De novo donor-specific antibodies are associated with late acute antibody-mediated rejection, chronic antibody-mediated rejection, and transplant glomerulopathy.
Will you proceed with the transplantation?
Yes
If yes, what is your immunosuppression protocol?
being low to moderate risk, Basiliximab seems a suitable induction
then the patient will be maintained on TAC regimen
If not, what are the other options?
waiting for another offer or PKD if a relative is ready to donate
What is the impact of the primary disease on graft survival in the indexed case?
(FSGS) is a histologic pattern of injury in the kidney that may have variable etiologies, including genetic factors, infection, toxins, and obesity, as well as previous injury resulting in hyperfiltration of remaining viable nephrons.Recurrent FSGS affects up to 60% of first kidney grafts and exceeds 80% in patients who have lost their first graft due to recurrent FSGS.a circulating permeability factor is the supposed culprit in the pathogenesis of the primary and recurrent disease. . In addition to plasma exchange, proposed treatment options for the management of recurrent FSGS are B-cell depleting antibodies as the activity of the postulated circulating permeability factor(s) may be B-cell related
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.
1.ABO compatible, split mismatch 111 broad mismatch 110, FCXM negative, DSA negative. So, standard immunological risk.
2. Split mismatch is the more detailed & modern technique than broad mismatch.
3. Split mismatch is associated with higher risk of graft rejection.
4.Presence of DSA is associated with high risk of hyperacute rejection & reduced graft survival.
5.Yes, as there is moderate to low immunological risk.
6.Induction( basiliximab & methyl prednisolone).Maintenance ( steroid, MMF & TAC).
7. Paired kidney donation.
8. Risk of recurrence of FSGS.
ABO compatible as O is universal donor.
split mismatch 1 1 1 broad mismatch 1 1 0
DSA negative T cell B cell negative So standard immulogical risk
2.What is the difference between split and broad mismatch?
In this case, the broad HLA is 110, while the split is 111 in DRB1.
-The Spilt mismatch is associated with a high risk of developing rejection, it is a more advanced technique to study HLA typing.
3.What is the impact of split mismatch on graft survival?
-Worse graft outcome had been found in a recipient with HLA-DR split mismatches.
-Decreased allograft survival is found in re –transplanted recipients with HLA-DR split mismatches.
4. Explain how the presence of DSA influences graft survival would?
-Present of donor-specific antibodies in sensitized patients can trigger hyperacute rejection, acute cellular rejection, and early acute antibody-mediated rejection.
-De novo donor-specific antibodies are associated with late acute antibody-mediated rejection, chronic antibody-mediated rejection, and transplant glomerulopathy.
5.-Will you proceed with the transplantation?
Yes.
This patient carries low immunological risk, but there is risk of primary disease recurrence.
6.If yes, what is your immunosuppression protocol?
-Induction Therapy; (Basilixmab)
-Maintenance triple (Steroids. MMF, tacrolimus)
7.If not, what are the other options?
Kidney paired donation.
8.What is the impact of the primary disease on graft survival in the indexed case?
Recipients known to have primary FSGS have a high incidence of recurrence after transplantation, reported between 20% and 40%. recurrence are increased in patients who are younger,those with a history of heavy proteinuria and clinical nephrotic syndrome, those who had a rapid progression to ESKD, those with the collapsing variant, and those whose showed mesangial hypertrophy in initial biopsy.
ABO compatible as O is universal donor
split mismatch 111 broad mismatch 110
FCXM. Negative with No DSA
So standard immulogical risk
Survival is better with split mismatch
Explain how the presen
ce of DSA influences graft survival would.
· The development of DSAs following renal transplantation is a specific marker of antibody-dependent vascular injury.
· The primary histopathologic feature is microvascular inflammation, which may be accompanied by the deposition of complement in the graft .
· DSA production also identifies transplant recipients at risk of chronic allograft rejection.
– Yes, I will proceed for transplantation as a standard immunological risk.
– Patients should be forewarned of the possibility of recurrence.
If yes, what is your immunosuppression protocol?
– Induction with basiliximab & methylprednisolone.
– Maintenance with triple therapy steroid+MMF+tacrolimus
· transplant candidates with primary FSGS have a high incidence of recurrence after transplantation, reported between 20% and 40%.
· The odds of recurrence are increased in patients who are younger ,those with a history of heavy proteinuria and clinical nephrotic syndrome, those who had a rapid progression to ESKD, those with the collapsing variant, and those whose initial biopsy showed mesangial hypertrophy. The strongest predictor of recurrence is a history of recurrence in a previous transplant.
1-Comment on the report?
– ABO-compatible; donor group O+ (a universal donor), Rhesus status does not matter in kidney transplantation while the recipient is group B+,
-DSA – not detected,
-HLA mismatches are 1 1 0 at broad level and 1 1 1 at split level,
-Flow cytometry crossmatch – negative T cell and negative B cell
2-What is the difference between split and broad mismatch?
-Split antigen is an antigen that has a more refined or specific cell surface reaction relative to a broad antigen.
-In this case, the broad HLA is 110, while the split is 111 in DRB1.
-The Spilt mismatch is associated with a high risk of developing rejection, it is a more advanced technique to study HLA typing.
3-What is the impact of split mismatch on graft survival?
-Worse graft outcome had been found in a recipient with HLA-DR split mismatches .
-Decreased allograft survival is found in re –transplanted recipients with HLA-DR split mismatches .
-Also in cadaveric kidney transplantation split mismatches are found to be associated with decreased graft survival .
4-Explain how the presence of DSA influences graft survival would?
-Preformed donor-specific antibodies in sensitized patients can trigger hyperacute rejection, accelerated acute rejection, and early acute antibody-mediated rejection.
-De novo donor-specific antibodies are associated with late acute antibody-mediated rejection, chronic antibody-mediated rejection, and transplant glomerulopathy.
5-Will you proceed with the transplantation?
Yes;
Although;This patient carries low immunological risk, but there is risk of primary disease recurrence.
6-If yes, what is your immunosuppression protocol?
-Induction Therapy; (Basilixmab)
-Maintenance triple TAC (Steroids. MMF, CNIs (tacrolimus)
7-If not, what are the other options?
–Kidney paired donation (KPD)
8-What is the impact of the primary disease on graft survival in the indexed case?
-The reported recurrence rate of FSGS after kidney transplant is 10-56% . Genetic testing should be performed in a young kidney transplant candidate and those with steroid resistant,
-Recipients known to have primary FSGS have a high incidence of recurrence after transplantation, reported between 20% and 40%.
-The odds of recurrence are increased in patients who are younger,those with a history of heavy proteinuria and clinical nephrotic syndrome, those who had a rapid progression to ESKD, those with the collapsing variant, and those whose showed mesangial hypertrophy in initial biopsy.
-The strongest predictor of recurrence is a history of recurrence in a previous transplant.
Patients should be forewarned of the possibility of recurrence.
-If a living donor is being considered, both the transplant candidate and the potential donor should be aware of the risk for graft loss from recurrent FSGS.
-Plasma exchange before transplantation and in the early posttransplantation period has been suggested to reduce the risk for recurrent disease, but its effectiveness has been difficult to prove. -Rituximab, abatacept, and Belatacept have been used as part of immunosuppression to prevent or treat FSGS but their results are less than satisfactory.
-Some patients with FSGS continue to have heavy proteinuria (more than 10 g daily) while on dialysis. In these cases, native kidney nephrectomy may be indicated both for nutritional consideration and because persistent massive native kidney proteinuria makes the evaluation of post-transplant proteinuria very difficult.
9-References;
1-Analysis of HLA-DR split-specificity matching in cadaver kidney transplantation ;a report of the collaborative transplant study ,G Oplelz et al ,Transplantation,1997.
2- Dantal J, Baatard R, Hourmant M, et al. Recurrent nephrotic syndrome following renal transplantation in patients with focal glomerulosclerosis. A one-center study of plasma exchange effects. Transplantation. 1991; 52: 827-831.
3-Danovitch G.M .Handbook of kidney transplantation. sixth edition. Wolters Kluwer .Press:2017.
*Compatible ABO, HLA 1-1-1 mismatch, -ve CM, -ve DSA, this is standard immunological risk.
*Split mismatch is more accurate in predicting graft outcome
*+ve DSA is a risk for hyper acute rejection, early graft survival and long term outcome.
*Yes would proceed to transplant.
*Induction with Basiliximab, maintenance with Prednisone, MMF, Tacrolimus.
* Risk of recurrence determined by sub-type of FSGS wether it is primary, familial, or secondary
– Compatible blood grouping (O is a universal donor)
– Tissue typing: mismatch 1:1:1 broad antigen typing & 1:1:1 split antigen typing
– Crossmatch is negative (4 times, last on 30/1/2020)
– No DSA detectable
What is the impact of split mismatch on graft survival?
– Split Ags are more specific as broad Ag can be divided into 2 or more split AGs, example: HLA-DR2 (DR2) is a broad antigen serotype that is now preferentially covered by HLA-DR15 and HLA-DR16 serotype group.
– Split Ag typing is more specific & associated with better outcomes & graft survival.
– Presence of DSA means the presence of Abs specific to the recipient HLA molecules. it may be preformed before transplantation o De-Novo post-transplantation. it is associated with ABMR & graft loss.
– Yes, I will accept for transplantation as a moderate immunological risk.
– Induction with basiliximab & methylprednisolone.
– Maintenance with steroid+MMF+tacrolimus
– FSGS as the primary disease is associated with a risk of recurrence & graft loss, mTORi should be avoided in the presence of proteinuria .
Comment :
-Our recipient is young , suffering from FSGS ( either genetic , 1ry or 2ry ) CKD class 5 , either on dialysis or not .
He receives an acceptable kidney offer from deceased young donor .
-The attached report reveals a ABO compatibility as the donor is a universal blood group donor .
-The HLA cross match shows a broad mm of 110 and a split mm of 111
-The Flow cytometry cross match was -ve being done 5 times over 4 years but we definitely need a new one
-No DSAs are present
-Split mismatch is more specific than the broad one based one previous studies in anticipating graft survival and future outcomes
-The presence of donor specific antibodies increased the risk of graft failure , survival and antibody rejection .
-Our potential recipient suffers from FSGS, the risk of recurrence of FSGS is around 20-40% post-transplant .
Risk factors for recurrence include:
o Young aged patients
o Non-African-American ethnicity
o Rapid progression to ESKD
o Collapsing variant
o Heavy proteinuria
o Nephrotic syndrome
o Initial biopsy showed mesangial hypertrophy
o History of recurrent FSGS
-Recurrence may occur in weeks, months or even immediately in which delayed graft function may occur.
-Yes i will accept this donor with rATG induction ( although no DSA’s and acceptable matching , but our donor is deceased we need to decrease the CNI’s doses earlier , as well as our donor is FSGS ) so i will go with the rATG rather than Simulect ,along with MMF , Tac and prednisolone .
-If this offer was cancelled , will put the patient of the KDP list and wait for another acceptable offer .
References :
1-Handbook of kidney transplantation-6th edition
2-Matsuda Y, Sarwal MM. Unraveling the role of allo-antibodies and transplant injury. Frontiers in immunology. 2016 Oct 21;7:432.
3-Otten HG, Verhaar MC, Borst HP, van Eck M, van Ginkel WG, et al. The significance of pretransplant donor-specific antibodies reactive with intact or denatured human leucocyte antigen in kidney transplantation. Clin Exp Immunol. 2013 Sep;173(3):536-43.
4-Kienzl-Wagner K, Waldegger S, Schneeberger S. Disease recurrence—the sword of Damocles in kidney transplantation for primary focal segmental glomerulosclerosis. Frontiers in immunology. 2019 Jul 17;10:1669.
Comment on the report.
Blood group: compatible D/R match-à D/R= O-ve/B+ve.
Compatible ABO donation because the donor blood group is O which is a universal donor, so it accepted to donate to a blood grouped B patient. However, they are different in the Rh factor where we can see that the donor is Rh negative and the patient is Rh positive, Rh incompatibility is not an obstacle for transplantation because Rh-D is absent on non-erythroid cells.
HLA mismatch: Broad 1-1-0, split 1-1-1
Negative cross match 5 times over 2 years and 2 months
DSA: not detected.
This is a low-moderate immunological risk offer.
Comment on the difference between the broad and the split mismatch.
Classifications of HLA antigens have developed gradually over many years when modern techniques allowed formerly undistinguishable antigens (Broad Antigens) to be subclassified into new antigens depending in differences in alleles.
In other words, split antigens are those antigens which can be defined from other antigens in the broad group by unique epitopes.
Example:
HLA-A9 is a broad antigen—–>> split antigens HLA- A23 and HLA-A24.
HLA-B is a broad antigen—->> split antigens HLA-51 and HLA-52.
HLA-DR2 is a broad antigen—->> split antigens HLA-DR15 and HLA-DR16.
What is the impact of split mismatch on graft survival?
Many studies had tested the effect of HLA-eplet mismatch on allograft outcome especially in renal transplantation. Sapir-Pichhadze et al found higher Class II eplet mismatch was associated with transplant glomerulopathy (TG).
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.
The eplet load concept could be useful in post-transplant follow up as new measurable indicator for de novo DSA and antibody mediated rejection even without eplet based mismatching.
HLA Match Maker is a computer program that was started in Australia and proposed in Brazil to improve access to transplant, reduce waiting time and help financial savings for highly sensitized patients.
Explain how the presence of DSA influences graft survival would.
Presence of circulating DSA make the recipient at high risk of hyper acute rejection or accelerated rejection. sensitized patient should wait for a cross match compatible kidney.
In index case the recipient doesn’t have DSA against donor’s antigens with a negative cross-match so he can proceed for kidney transplantation from this donor.
Presence of DSA will determine the immunological risk of the recipient according to the following algorithm.
blob:https://worldkidneyacademy.org/d5352103-7917-4766-915d-8ba28169ab58
Will you proceed with the transplantation?
Yes, I will proceed with the transplantation.
If yes, what is your immunosuppression protocol?
This is a low immunological risk offer, I will choose basiliximab as induction and maintenance therapy with CNI+MMF+ steroids.
If not, what are the other options?
Kidney paired donation scheme
What is the impact of the primary disease on graft survival in the indexed case?
If the primary renal disease in this case is secondary FSGS to reflux nephropathy, obesity and drug toxicity, usually doesn’t reappear after transplantation.
The recurrence of primary FSGS after transplantation was reported 10%-56%.
Graft loss on top of recurrent primary FSGS is recorded in 30-50%.
Data from ANZDATA showed that 5-year graft survival in recurrent FSGS was 52% compared to 83% in those without recurrence.
And higher rate of recurrence was observed in younger patient, heavy proteinuria, non-white ethnicity, clinical nephrotic syndrome and those with collapsing variants. The most powerful risk factor for recurrence is recurrence in previous transplant.
Some studies proposed using Soluble Urokinase Plasminogen Activator Receptors as an indicator for recurred FSGS.
The chance of recurrent FSGS in those with graft failure secondary to recurrence is more than 80%.
Plasma exchange is the usual treatment option in recurrent FSGS according to some case reports and series, Rituximab is another proposed option of treatment without randomized controlled trials.
*Comment on report: young deceased donor, compatible blood group, HLA 1,1,1 mismatch, -ve CM, this is standard immunological risk.
*Split mismatch more accurate to determine graft survival than broad mismatch.
*presence of DSA can cause hyper acute AMR, DGF, early graft dysfunction and decrease graft survival
*Yes, will proceed to transplant.
*Basiliximab for induction, prednisone, Tacrolimus& MMF for maintenance.
*Impact of FSGS on transplant depends on its sub-type wether it is primary, hereditary or secondary
ABO COMPATIBLE
FLOW CYTOMETRY CROSS MATCH IS NEGATIVE
NO DSA
ABOUT HLA – SPLIT IS BETTER THAN BROAD IN VIEW OF PERFECT MATCHING
IN BROAD 3 ANTIGEN WAS MATCHED OUT OF TOTAL 6 , WHICH IMPROVED AFTER SPLIT MATCHING OF 4 OUT OF 6 ,
THIS IS A GOOD MACTH
WE CAN PROCEED WITH KIDNEY TRANSPLANT
ATG AS INDUCTION AND FOLLOWED BY
TRIPLE DRUG LIKE STEROID, CNI AND MMF AS MAINTENANCE
IF SPLIT HLA MATCHINH IS DONE THEN GRAFT SURVIVAL WILL IMPROVE
PREFORMED ANTIBDY LIKE DSA IS INVITE AMR IN RECEPIENT AND THIS MAY OR MAY NOT GIVE POSITIVE CROSS MATCH
IN PRENCE IF POSITIVE DSA, TRANSPLANT IS VERY RISKY AND NEED PRIOR PLEX OR RITUXIMAB THERAPY
FSGS IS LIKELY TO RECUR IN GRAFT SO COUNSELLING NEED TO BE DONE PRIOR TO SURGERY
DURING FOLLOW UP PROTEINURIA IS TO BE MONITERED AND GRAFT BIOPSY IS PLANNED IF RENAL FUCNTION IS DETERIORATING
This recipient had Compatible blood group with negative crossmatch.
2. Comment on the difference between the broad and the split mismatch.
The matching is 210 for broad and 211 for split
Identifying new MHC molecules has split the currently known antigens, while the broad specificity group can capture antigens that are more functionally matched to the recipient; therefore, the mismatch rate is lesser. Our patient has a split match at broad DR 2 locus (DR 15 and 16).
Matching HLA “splits” antigens gives better transplant results than matching for “broad” HLA antigens. This has been studied in 30,000 first cadaveric kidney transplant recipients. At three years, better allograft survival was noticed among transplants recipients typed for HLA-A and B splits antigen than transplants typed for broad antigens (18% versus 2% respectively). Additionally, an analysis of HLA-A, B, and DR antigens in the same study, showed even a more prominent advantage for matching split antigens (31%) vs. (6%) for broad antigens between grafts with 0 or 6 mismatches.
Alternatively, Hata Y et al. reported no negative impact of split DR mismatches in HLA-matched first renal transplants, compared to broad HLA-DR, unlike other HLA mismatches.
The significance of DR splits in the re-transplanted recipients is probably due to repeated DR mismatches, as the risk of alloimmune sensitization and developing HLA-specific alloantibodies following rejecting first kidney transplant increments steadily with the total number of mismatches at all HLA loci, resulting in donor incompatibility.
Patients can develop specific HLA antibodies following exposure to HLA alloantigens due to blood transfusion, pregnancy, or a rejected kidney. Pre-transplant donor-specific anti-human leukocyte antigen antibodies (DSA) have been related to ABMR and inferior graft outcomes. Moreover, DSAs with higher MFI threshold and C1q-binding DSAs have been closely correlated to TMA, microangiopathy, C4d deposition, glomerulopathy, tubular atrophy, and extensive interstitial fibrosis, all of which can influence allograft prognosis and reduce allograft survival.
Yes, I will proceed with this transplant. Avoiding mismatch grafts can reduce donor opportunities, with subsequent long waiting lists.
I will use aggressive induction therapy with ATG and tacrolimus-based maintenance immunosuppression (tacrolimus, MMF, and steroids) to decrease early and late alloimmune injury in the presence of 6-mismatches and to monitor DSA levels.
Primary FSGS has a high recurrence rate of 34% to 56% in the first transplant, accelerating graft loss and 75% in the subsequent transplant when relapse has already occurred. Risk factors associated with a high rate of recurrence include; younger age upon presentation, rapid progress from the disease diagnosis to development of end-stage kidney disease (ESKD) (≤ 3 years), recurrence in the previous transplant within a year post-transplantation (in this condition, the chance can be up to 80%) and diffuse mesangial proliferation on original kidney biopsy. It is not yet known whether living donor recipients are at high risk of recurrence compared to deceased donor recipients.
References:
1. Gao Y, Twigg AR, Hirose R, Roll GR, Nowacki AS, et al. Association of HLA antigen mismatch with risk of developing skin cancer after solid-organ transplant. JAMA dermatology. 2019 Mar 1;155(3):307-14.
2. Opelz G. Importance of HLA antigen splits for kidney transplant matching. Lancet. 1988 Jul 9;2(8602):61-4.
3. Hata Y, Cecka JM, Takemoto S, Ozawa M, Cho YW, Terasaki PI. Effects of changes in the criteria for nationally shared kidney transplants for HLA-matched patients. Transplantation. 1998 Jan 27;65(2):208-12.
4. Opelz G, Mytilineos J, Scherer S, Dunckley H, Trejaut J, et al. Analysis of HLA-DR matching in DNA-typed cadaver kidney transplants. Transplantation. 1993 Apr 1;55(4):782-5.
5. Matsuda Y, Sarwal MM. Unraveling the role of allo-antibodies and transplant injury. Frontiers in immunology. 2016 Oct 21;7:432.
6. Tinckam KJ, Rose C, Hariharan S, Gill J. Re-Examining Risk of Repeated HLA Mismatch in Kidney Transplantation. J Am Soc Nephrol. 2016 Sep;27(9):2833-41.
7. Otten HG, Verhaar MC, Borst HP, van Eck M, van Ginkel WG, et al. The significance of pretransplant donor-specific antibodies reactive with intact or denatured human leucocyte antigen in kidney transplantation. Clin Exp Immunol. 2013 Sep;173(3):536-43.
8. Lefaucheur C, Suberbielle‐Boissel C, Hill GS, Nochy D, Andrade J, et al. Clinical relevance of preformed HLA donor‐specific antibodies in kidney transplantation. American Journal of Transplantation. 2008 Feb;8(2):324-31.
9. Kienzl-Wagner K, Waldegger S, Schneeberger S. Disease recurrence—the sword of Damocles in kidney transplantation for primary focal segmental glomerulosclerosis. Frontiers in immunology. 2019 Jul 17;10:1669.
10. Uffing A, Pérez-Sáez MJ, Mazzali M, Manfro RC, Bauer AC, et al. Recurrence of FSGS after kidney transplantation in adults. Clinical Journal of the American Society of Nephrology. 2020 Feb 7;15(2):247-56.
This is a 29years old, deceased donor, donating to a 31 year old recipient.
Compatible blood group O to B.
The match is 110 broad
111 split
No DSA detectable.
Cross match is negative 5times before, latest one 30/01/2020
The split mismatch is much more specific for HLA antigen typing than broad one. It is a new method for HLA antigen detection.
the difference in survival at three years between grafts with 0 or 6 mismatches for HLA-A, B, DR was 31% when antigen splits were analysed, in contrast to a 6% difference.
DSA is associated with acute antibody mediated rejection, more risk of infection and more grafts loss.
Yes, he is negative cross match and no DSA.
Induction with basiliximab and maintenance with triple immunosuoresive medications ( tacrolimus, cellcet and prednisolone)
If this donor offer did not proceed, for positive final cross match or what ever reasons, then waiting for another donor, going for paired exchange or continue on dialysis.
It is known that FSGS may recur after transplantation. This can happen in 50-80% of cases and lead to graft loss in 50% of cases. Recurrence risk increased with living donation, history of recurrence in previous transplant and certain HLA antigens like HLA DR7, DR 53.
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-KDIGO guidelines for kidney transplantation evaluation and management 2020
■ COMMENT ON THE REPORT:
● ABO compatible blood grouping
Recipent B +ve – Donar O – ve
●Broad mismatch : 1 1 0 – Split mismatch : 1 1 1
Dr 15 & 16 are considered single antigen ( split ones)
Both are splits of the the broad antigen DR2.
●Historic FCXM of T & B cells : negative over the past 3 ys.
●DSA is negative ( not mentioned the method of measuring it)
● Recipient and donar age : young.
■ Differences between Broad & split antigens
●The split has a specific cell surface protein that is not present in the Broad rendering it a cause of a later rejection that could be missed pre-tx.
■ Impact of split antigen in graft survival:
●Analysis of HLA-A & B & DR antigens showed a greater advantage of matching for antigen splits:
The difference in survival at three years between grafts with 0 or 6 mismatches for HLA-A, B, DR was 31% when antigen splits were analysed, in contrast to a 6% difference with broad antigens.
● These results indicate that typing for HLA antigen splits is important in renal transplantation.
■ How DSA influence graft survival ?
●It is associated with higher incidence of graft loss
That is higher in living than deceased ones.
●It is even present in low MFI DSAs
DSAs with MFI < 3000 ( i.e. weak) have worse graft survival than those with no DSA.
● It could be preformed or denovo
Preformed cause : hyperacute or early acute rejection or early ABMR
Denovo cause:
Late acute and chronic ABMR as well as transplant glomurulopathy.
● The sole independent predictor of antibody mediated rejection (AMR) incidence was DSA strength (HR = 1.07 per 1000 increase in MFI, P = 0.034).
●DSA-Cw are associated with an identical risk of AMR and impact on graft function in comparison with class I DSA.
■ Would you proceed with this TX.?
Yes
■If yes, what is your standard protocol ?
He is of low immunological risk, thus:
Induction with Basiliximab & methyl prednisolone
Maintainance with triple immunosuppressive ttt;
Tacrolimus, MMF & steroids
■ IF not, what are the other options ?
Kidney paired donation.
Hdx ( the worse option).
■ What is the impact of the primary disease on graft survival in the indexed case?
●The risk of recurrence of FSGS is high post kidney transplantation (30-80%).
●It is associated with poor graft survival (50%).
● High risk of recurrence in:
_ Older age at the 1ry
disease onset
_ White
_ Native nephrectomy
_ History of previous graft
recurrence
_ BMI (HR, 0.89 per
kg/m2).
● Plasmapheresis and rituximab were the most frequent treatments (81%).
Both are used if the tx time < 3 months. If > 3 months check for 2ry causes at first, if all negative–> give rituximab +/- plasmapheresis.
Partial or complete remission occurred in 57% of patients and was associated with better graft survival.
■ REFERENCES
●https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(88)90001-3/fulltext
● Ziemann, Malte et al. Preformed Donor-Specific HLA Antibodies in Living and Deceased Donor Transplantation: A Multicenter Study. CJASN 14(7):p 1056-1066, July 2019. | DOI: 10.2215/CJN.13401118
●Alasfar S, Matar D, Montgomery RA, Desai N, Lonze B, Vujjini V, Estrella MM, Manllo Dieck J, Khneizer G, Sever S, Reiser J, Alachkar N
SO
Transplantation. 2018;102(3):e115.
●https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015092/
Comment on the report.
Donor is Blood group O which is universal donor so no mismatch at ABO group
There is 110 mismatch at broad antigen level as Dr 15 and 16 was considered as single antigen
There is 111 mismatch at split antigens
There are no DSAs and the FCXM was negative for both T and B cells .
Comment on the difference between the broad and the split mismatch.
A broad antigens were early defind as big antigens that were divided later into more specific antigens with the development of advanced typing techniques.
split antigen has more specific cell surface reaction.
Such as HLA-B5 that was spilited to HLA-B51 and HLA-B52 and DR15 and DR16 which were split from the broader antigen DR2.
What is the impact of split mismatch on graft survival?
Matching at split antigens level is more specific,
As this split antigens has different immune response than the broad one and detecting AB at a specific more refined level will help in better matching and better graft survival
Explain how the presence of DSA would influences graft survival.
Preformed donor-specific antibodies in sensitized patients can trigger hyperacute rejection, accelerated acute rejection, and early acute antibody-mediated rejection.
De novo donor-specific antibodies are associated with late acute antibody-mediated rejection, chronic antibody-mediated rejection, and transplant glomerulopathy.
The pathogeneses of antibody-mediated rejection include not only complement-dependent cytotoxicity, but also complement-independent pathways of antibody-mediated cellular cytotoxicity and direct endothelial activation and proliferation.
The novel assay for complement binding capacity has improved ability to predict antibody-mediated rejection phenotypes.
C1q binding donor-specific antibodies are closely associated with acute antibody-mediated rejection, more severe graft injuries, and early graft failure, whereas C1q nonbinding donor-specific antibodies correlate with subclinical or chronic antibody-mediated rejection and late graft loss.
IgG subclasses have various abilities to activate complement and recruit effector cells through the Fc receptor.
Complement binding IgG3 donor-specific antibodies are frequently associated with acute antibody-mediated rejection and severe graft injury, whereas noncomplement binding IgG4 donor-specific antibodies are more correlated with subclinical or chronic antibody-mediated rejection and transplant glomerulopathy.
Will you proceed with the transplantation?
If yes, what is your immunosuppression protocol?
Yes I will proceed with transplantation
As the crossmatch is negative but we need new one before transplantation
No DSA
It is low risk transplantation induction can with basiliximab, methyl prednisolone for 3 day and triple maintenance immunosuppression on Tac, MMF and steroids.
If not, what are the other options?
paired kidney transplantation would be a good alternative to the patient
What is the impact of the primary disease on graft survival in the indexed case?
FSGS is one of the leading glomerular causes of kidney failure in adults.
When no secondary cause (genetic, viral, drug-associated, or adaptive can be identified and the patient presents with a clinical history of nephrotic syndrome, FSGS is termed primary or idiopathic.
The accurate distinction between idiopathic and secondary causes, however, remains challenging, particularly if ultrastructural evaluation of the kidney biopsy or genetic testing are missing.
Distinguishing between idiopathic and secondary FSGS is especially important in patients being considered for kidney transplantation because idiopathic forms frequently recur in the graft with a substantial rate of subsequent graft loss. Reported rates of recurrence are wide, ranging from 17% to 55% (4–23) in smaller studies and from 9% to 15% (24–27) in registry-based studies.
Multivariable analysis revealed older age at primary disease onset, native kidney nephrectomies, white race, and lower BMI at transplant and recurrence in previous graft to be associated with a higher risk for recurrence.
Recurrent FSGS was most often treated with plasmapheresis with or without rituximab, and this regimen resulted in partial or complete remission in 57% of patients.
Reference
Rubin Zhang.Donor-Specific Antibodies in Kidney Transplant Recipients.Clin J Am Soc Nephrol. 2018 Jan 6; 13(1): 182–192.
Audrey Uffing, Maria José Pérez-Sáez.Recurrence of FSGS after Kidney Transplantation in Adults.Clin J Am Soc Nephrol. 2020 Feb 7; 15(2): 247–256
-This couple are ABO compitable
-All historical and current cross matches are negative.
-No DSA
-HLA mismatch broad 110 (as Dr 15 and 16 are split of Dr 2 ) and 111 split
-When HLA antigens were first identified in 1970 ,only 27 antigens were named (broad antigens ) and with further improvement in tissue typing other antigens were discovered and some of the broad antigens were divided or splitted into more antigens , as split antigens have more refined and specific cell surface reaction compared to broadantigen.
In kidney transplantation ,matching at the level of split antigens yield better results than matching at broad level regarding graft function and survival and lower incidence of rejection .Matching at split level is more significant for HLA A and B while Dr is more significant in case of retransplantation .
-Yes , I will
– As this is a low immunological risk recipient ( first transplant , no DSA) , I would consider
Induction with Basiliximab and maintenance with (steroid , MMF and Tac )and early steroid withdrawlcould be considered in this patient..
If No , other options would be
1- Hemodialysis and continue on waiting list for more suitable donor : but this is not te best option as death rate is higher among patients on dialysis and being on waiting list for long time compared with transplanted patients
2- Paired kidney donation.
Impact of primary kidney disease on graft survival;
1ry FSGS is a leading cause for ESRD among adults and its common to reoccur after transplantation in one third of cases (between 17-55%) with increasing the risk of graft loss . Risk factors for recurrence include young ager at diagnosis , rabid progress to ESRD, collapsing variant and failure to achieve complete response to treatment.
Ref
1. Opelz, Gerhard .IMPORTANCE OF HLA ANTIGEN SPLITS FOR KIDNEY TRANSPLANT MATCHING .The Lancet, Volume 332, Issue 8602, 61 – 64.
2. Opelz G, Scherer S, Mytilineos J. Analysis of HLA-DR split-specificity matching in cadaver kidney transplantation: a report of the Collaborative Transplant Study. Transplantation. 1997 Jan 15;63(1):57-9.
3-Uffing A, Pérez-Sáez MJ, Mazzali M, Manfro RC, Bauer AC, de Sottomaior Drumond F, O’Shaughnessy MM, Cheng XS, Chin KK, Ventura CG, Agena F, David-Neto E, Mansur JB, Kirsztajn GM, Tedesco-Silva H Jr, Neto GMV, Arias-Cabrales C, Buxeda A, Bugnazet M, Jouve T, Malvezzi P, Akalin E, Alani O, Agrawal N, La Manna G, Comai G, Bini C, Muhsin SA, Riella MC, Hokazono SR, Farouk SS, Haverly M, Mothi SS, Berger SP, Cravedi P, Riella LV. Recurrence of FSGS after Kidney Transplantation in Adults. Clin J Am Soc Nephrol. 2020 Feb 7;15(2):247-256.
ABO compatible.
Broad antigen is 110 and split antigen 111 mismatch.
Historic FCM is negative for T and B cells.
DSA was negative.
Split antigens have more refine or specific cell surface reaction relative to broad antigen and leads to less rejection in the future.
Serological methods have high error to split HLA-DR(1)
In second transplants, two-year graft survival was significantly better in the patients with equal broad HLA-mismatches, but more split HLA-DR mismatches (1)
Performed DSA results in sensitization of patients leading to hyper-acute, accelerated or acute rejection early after transplantation.
High DSA showed probability of worse outcome for living and deceased donor transplants (2) zi
yes, I will proceed.
Induction with basiliximab and methylprednisolone and then triple therapy with CNIs, MMF and prednisone.
The recurrence rate of FSGS after transplantation is about 30-60 percent.
In one study of 172 idiopathic fsgs, 32% (57) cases had the recurrence of the disease. (Tango study) (3)
Recurrences were more prevalent in re-transplants, lower BMI and history of native nephrectomy.
The risk of recurrence is increased in HLA DR-7, DR-53 and HLA-DQ 2(and lower in DQ-7)
Genetic tests are recommended to predict the rate of recurrence.
Five-year graft survival was significantly lower in the recurrence group comparing with the other patient but if FSGS does not recur, graft survival is compatible with others.
References:
1. Opelz G. Importance of HLA antigen splits for kidney transplant matching. Lancet. 1988 Jul 9; 2(8602):61-4.
2. Ziemann M, Altermann W, Angert K, Arns W, Bachmann A, Bakchoul T, Banas B, von Borstel A, Budde K, Ditt V, Einecke G. Preformed donor-specific HLA antibodies in living and deceased donor transplantation: a multicenter study. Clinical Journal of the American Society of Nephrology. 2019 Jul 5; 14(7):1056-66.
3. Uffing A, Pérez-Sáez MJ, Mazzali M, Manfro RC, Bauer AC, de Sottomaior Drumond F, O’Shaughnessy MM, Cheng XS, Chin KK, Ventura CG, Agena F, David-Neto E, Mansur JB, Kirsztajn GM, Tedesco-Silva H Jr, Neto GMV, Arias-Cabrales C, Buxeda A, Bugnazet M, Jouve T, Malvezzi P, Akalin E, Alani O, Agrawal N, La Manna G, Comai G, Bini C, Muhsin SA, Riella MC, Hokazono SR, Farouk SS, Haverly M, Mothi SS, Berger SP, Cravedi P, Riella LV. Recurrence of FSGS after Kidney Transplantation in Adults. Clin J Am Soc Nephrol. 2020 Feb 7; 15(2):247-256.
-ABO compatible.
broad antigen is 110 and split antigen 111( DRB1 is broad antigen split into 15,16).
FCM is negative for T and B cells.
NO DSA .
– Difference between broad and split antigens:
Broad antigens serologically poor or broad to other specificities and defined by 2 or more split antigens.
Split antigen :(molecular testing)
having more refined or specific cell surface reaction relative to broad antigen.
– Impact of split mismatch on graft survival:
It was shown that difference within three years for graft survival with 0 or 6 mismatches for HLA-A, B, DR was 31% for split antigens with 6% for broad antigens.
-Influence of DSA on graft survival:
Pre-transplant DNA have the risk of increased ABMR with related graft failure due to subsequent severe vasculitis and thrombosis leading to graft loss.
-Yes, to proceed for transplantation
– Immunosuppression protocol:
Induction: basiliximab; low immunological risk
Maintenance therapy: steroid, MMF& tacrolimus.
-Focal segment glomerulosclerosis has risk of recurrence 20-40 %;with predisposing factors of young age, heavy proteinuria, collapsing variants and mesangial hypertrophy.
· Comment on the report.
Thirty-one years -old patient with ESRD due to FSGS is planned to receive kidney from 29 year-old living person. This is a compatible transplant for ABO. Rh is incompatible but, has no effect on kidney transplant. They are 110 broad and 111 split mismatch. The patient has been on waiting list since 2017. Both the T cell and B cell flow cytometric cross-match are negative. Luminex–SAB showed no DSA. FSGS could be recurred after transplantation which should be considered and followed.
· Comment on the difference between the broad and the split mismatch.
Broad antigen mismatch is less specific than split antigen mismatch. So, matching by split antigens is more precise and leads to less rejection in the future. For example, HLA-DR2 was split to HLA –DR15 and HLA-DR16.
· What is the impact of split mismatch on graft survival?
Opelz and colleagues studied 30000 deceased donors with the first kidney transplants for survival rate in terms of the broad or split HLA antigen matching in 1988[1]. The results showed that zero to four split mismatches for HLA-A and HLA-B had 18% and all HLA antigens split mismatches had 31%difference in 3 years survival rate comparing 6% for broad antigens.
Opelz and colleagues researched the consequence of split HLA-DR mismatches in 1997[2]. At that time broad HLA-DR was used for matching deceased donor transplants. Serological methods have high error to split HLA-DR. So, Opelz by using DNA-probes for splitting HLA-DR, studied more than eight thousands of the deceased donor transplants in the term of graft survival rate. For first transplants, there was no difference in the outcome, but in second transplants, two-year graft survival was significantly better in the patients with equal broad HLA-mismatches, but more split HLA-DR mismatches. By DNA sequencing methods more sub-split HLA-DR mismatches were known and again the outcome of 177 transplants with more sub-split mismatches was not significantly as good as the outcome of 343 transplants without mismatches.
· Explain how the presence of DSA influences graft survival would.
· The donor specific antibody (DSA) could be in two forms: performed or de novo DSA. DSA are known to cause antibody mediated rejection (AMR) but depends on their specificities such as IgG classes, C1q binding ability and their MFI. Performed DSA are produced due to blood transfusion, previous transplantation and pregnancy and results in sensitization of patients leading to hyper-acute, accelerated or acute rejection early after transplantation. On the other hand de novo DSAs are related to chronic or late acute AMRs [3]. Ziemann evaluated the outcome of transplantation in patients with different types of DSA during 2012 to 2015 showed probability of worse outcome 2.53 and 1.59 times for living and deceased donor transplants, respectively. DSAs with lower MFI (below three thousands) were accompanied with lower survival for transplant especially in living transplants [4].
· In contrast, Kamburova in the Netherlands performed a research on 4724 kidney transplants without desensitization and showed worse outcome in deceased donors comparing living Donors and there was no association between MFI and the outcome [5].
· Orandi studied the effects of DSA after desensitization in three groups of incompatible patients from 22 centers and compared with 9669 compatible patients. The outcome of the PLNF group was similar to the compatible group, but the PFNC and the PCC group had worse outcome respectively [6].
· Gosset studied a linkage between DSA and presence of IF/TA in the allograft biopsies after one year. After other causes excluding, DSA remained the most prevalent factor. They concluded that DSA are linked with allograft fibrosis even without obvious AMR [7].
· Will you proceed with the transplantation?
Yes, I will proceed.
· If yes, what is your immunosuppression protocol?
Induction with basiliximab and methylprednisolone and then triple therapy with CNIs, MMF and prednisone.
· If not, what are the other options?
Other options are: Living related donor with low mismatch or through kidney paired donation.
· What is the impact of the primary disease on graft survival in the indexed case?
The recurrence rate of FSGS after transplantation is about 30-60 percent.
Unfortunately, the graft will be lost in resistant cases (50%) in spite of treatment [8].
In TANGO study, among 176 cases with FSGS who underwent transplantation, fifty-seven cases had the recurrence of the disease. Recurrences were more prevalent in re-transplants, lower BMI and history of native nephrectomy. Twenty-two (39%) of patients lost their transplants due to FSGS recurrence with a hazard ratio of 4.8 [9].
There is no strong evidence to recommend prophylactic measures to prevent the recurrence of FSGS. Genetic tests are recommended to predict the rate of recurrence. Close monitoring for proteinuria after transplantation, especially in the first few days after transplantation is necessary. The time of recurrence after transplantation is about 10 to 14 days in children to 45 days in adults, but it can happen after months or years [10].
In Francis study based on Australia and New Zealand Dialysis and Transplant Registry, 736 cases of primary FSGS were transplanted and recurrence occurred in 10.3% of patients. Five-year graft survival was significantly lower in the recurrence group comparing with the other patient (52% vs 83%, respectively). [11]
Another study by Hickson [12] showed that among eight death-censored graft losses, seven (50%) were in the FSGS recurrence group comparing the only one in the other group.
Altogether, abovementioned studies agree in low graft survival in patients with FSGS recurrence after transplantation, but if FSGS does not recur, graft survival is compatible with others.
References:
1. Opelz G. Importance of HLA antigen splits for kidney transplant matching. Lancet. 1988 Jul 9; 2(8602):61-4.
2. Opelz G, Scherer S, Mytilineos J. Analysis of HLA-DR split-specificity matching in cadaver kidney transplantation: a report of the Collaborative Transplant Study. Transplantation. 1997 Jan 15; 63(1):57-9.
3. Zhang R. Donor-Specific Antibodies in Kidney Transplant Recipients. Clin J Am Soc Nephrol. 2018 Jan 6; 13(1):182-192. doi: 10.2215/CJN.00700117. Epub 2017 Apr 26. PMID: 28446536; PMCID: PMC5753302.
4. Ziemann M, Altermann W, Angert K, Arns W, Bachmann A, Bakchoul T, Banas B, von Borstel A, Budde K, Ditt V, Einecke G. Preformed donor-specific HLA antibodies in living and deceased donor transplantation: a multicenter study. Clinical Journal of the American Society of Nephrology. 2019 Jul 5; 14(7):1056-66.
5. Kamburova EG, Wisse BW, Joosten I, Allebes WA, van der Meer A, Hilbrands LB, Baas MC, Spierings E, Hack CE, van Reekum FE, van Zuilen AD, Verhaar MC, Bots ML, Drop ACAD, Plaisier L, Seelen MAJ, Sanders JSF, Hepkema BG, Lambeck AJA, Bungener LB, Roozendaal C, Tilanus MGJ, Voorter CE, Wieten L, van Duijnhoven EM, Gelens M, Christiaans MHL, van Ittersum FJ, Nurmohamed SA, Lardy NM, Swelsen W, van der Pant KA, van der Weerd NC, Ten Berge IJM, Bemelman FJ, Hoitsma A, van der Boog PJM, de Fijter JW, Betjes MGH, Heidt S, Roelen DL, Claas FH, Otten HG. Differential effects of donor-specific HLA antibodies in living versus deceased donor transplant. Am J Transplant. 2018 Sep; 18(9):2274-2284.
6. Orandi BJ, Garonzik-Wang JM, Massie AB, Zachary AA, Montgomery JR, Van Arendonk KJ, Stegall MD, Jordan SC, Oberholzer J, Dunn TB, Ratner LE, Kapur S, Pelletier RP, Roberts JP, Melcher ML, Singh P, Sudan DL, Posner MP, El-Amm JM, Shapiro R, Cooper M, Lipkowitz GS, Rees MA, Marsh CL, Sankari BR, Gerber DA, Nelson PW, Wellen J, Bozorgzadeh A, Gaber AO, Montgomery RA, Segev DL. Quantifying the risk of incompatible kidney transplantation: a multicenter study. Am J Transplant. 2014 Jul;14(7):1573-80.
7. Gosset C, Viglietti D, Rabant M, Vérine J, Aubert O, Glotz D, Legendre C, Taupin JL, Van-Huyen JP, Loupy A, Lefaucheur C. Circulating donor-specific anti-HLA antibodies are a major factor in premature and accelerated allograft fibrosis. Kidney international. 2017 Sep 1; 92(3):729-42.
8. Uffing A, Hullekes F, Riella LV, Hogan JJ. Recurrent Glomerular Disease after Kidney Transplantation: Diagnostic and Management Dilemmas. Clin J Am Soc Nephrol. 2021 Nov; 16(11):1730-1742.
9. Uffing A, Pérez-Sáez MJ, Mazzali M, Manfro RC, Bauer AC, de Sottomaior Drumond F, O’Shaughnessy MM, Cheng XS, Chin KK, Ventura CG, Agena F, David-Neto E, Mansur JB, Kirsztajn GM, Tedesco-Silva H Jr, Neto GMV, Arias-Cabrales C, Buxeda A, Bugnazet M, Jouve T, Malvezzi P, Akalin E, Alani O, Agrawal N, La Manna G, Comai G, Bini C, Muhsin SA, Riella MC, Hokazono SR, Farouk SS, Haverly M, Mothi SS, Berger SP, Cravedi P, Riella LV. Recurrence of FSGS after Kidney Transplantation in Adults. Clin J Am Soc Nephrol. 2020 Feb 7; 15(2):247-256.
· Comment on the report.
Both potential recipient and deceased donor are in approximate age group and have compatible ABO group (the recipient is B positive and the donor is O negative).
The HLA mismatch is 1-1-0 in broad antigen matching and 1-1-1 in split antigen matching. The cross match for B and T cell is negative 5 times over 3years with no detectable DSA.
· Comment on the difference between the broad and the split mismatch.
Split antigens are antigens which were discovered with the development of molecular technology resulting from split of previously undistinguishable broad antigens which was detected with serological methods . split antigens has a more refined or specific cell surface reaction relative to a broad antigen .(Example: HLA-B51 and HLA-B52 are split antigens of HLA-B (broad antigen ) , HLA A23 and A24 are split antigens of A9 which is the broad antigen. And HLA DR15 and DR16 split antigens are split of DR2 broad antigen .(1)
· What is the impact of split mismatch on graft survival?
HLA mismatch as general have great impact in decreasing graft function and graft survival but split mismatch which is more specific can’t be ignored in kidney transplant as many studies showed great association with poor graft function and survival in comparison with broad antigens mismatch one of these studies investigate 30000 first cadaveric kidney transplant At three years, they found 18% difference between the survival rates of grafts with 0 or 4 mismatches among transplants typed for HLA-A and B antigen splits whereas the difference in transplants typed for broad antigens was only 2%. .Another study mention consideration of further “subsplit” specificities that resulted in clinically relevant mismatches but only among re transplant .(2)(3)
Explain how the presence of DSA influences graft survival would
Presence of DSA in pretransplant patients have deleterious impact on graft function and graft survival with increase risk of ABMR . De novo donor-specific antibodies are associated with late acute antibody-mediated rejection, chronic antibody-mediated rejection, and transplant glomerulopathy. (4)
Will you proceed with the transplantation?
yes
If yes, what is your immunosuppression protocol?
Induction with basiliximab and methylprednisolone
Maintenance : tacrolimus ,MMF,prednisolone.
If not, what are the other options?
Waiting for another matched deceased donor while continuing in dialysis if he is already on ,or searching for a suitable living donor .
·What is the impact of the primary disease on graft survival in the indexed case?
The impact of FSGS after kidney transplantation depend on whether primary or secondary FSGS as the primary one has high recurrence rate after kidney transplant in about one third of cases and is associated with a five-fold higher risk of graft loss.
A sudy done among 11,742 kidney transplant recipients who were screened for FSGS, they found that 176 had a diagnosis of idiopathic FSGS and were included.
57 patients has recurrence of FSGS ( which represent 32% of patients who were diagnosed previously with idiopathic FSGS ) 39% of them lost their graft over a median of 5 years. Multivariable Cox regression revealed a higher risk for recurrence with older age at native kidney disease onset. Other predictors were white race , body mass index at transplant (HR, 0.89 per kg/m2; 95% CI, 0.83 to 0.95), and native kidney nephrectomies . Plasmapheresis and rituximab were the most frequent treatments (81%). Partial or complete remission occurred in 57% of patients and was associated with better graft survival. ( 5)
Referrence:
1. Hung Do Nguyen, Rebecca Lucy Williams, Germaine Wong and Wai Hon Lim
Submitted: April 13th, 2012 Published: February 13th, 2013
2. Lancet 1988 Jul 9;2(8602):61-4.doi: 10.1016/s0140-6736(88)90001-3..
3. Transplantation. 1997 Jan 15;63(1):57-9. doi: 10.1097/00007890-199701150-00011
4. Clin J Am Soc Nephrol. 2018 Jan 6; 13(1): 182–192. Published online 2017 Apr 26. doi:
10.2215/CJN.00700117. PMCID: PMC5753302PMID: 28446536
5. Clin J Am Soc Nephrol. 2020 Feb 7; 15(2): 247–256.
Published online 2020 Jan 23. doi: 10.2215/CJN.08970719
PMCID: PMC7015092
PMID: 31974287
Well done.
As many of my colleagues noted, We have a match of HLA 02/02 only
DR 15/16 are both splits of DR2 : https://hla.alleles.org/antigens/broads_splits.html
matching according to split antigens is more important in terms of risk for rejection.
Matching according to split antigens, as expected, will have better outcomes in terms of rejection.
This patient has no donor-specific antigen; This patient can be transplanted with Basiliximab with close monitoring. If unavailable, low-dose ATG can be used. Standard maintenance is Tacrolimus7MMF/steroid.
Close monitoring for proteinuria is essential. usually, in patients whose soluble factor (suPAR) is the cause, massif proteinuria will is expected; Consecutive Plasmapheresis sessions usually help
This patient has ESRD due to FSGS, which means it was aggressive and resistant. Most probably primary but could be familial (as the patient is young).
Patients with secondary causes, usually present later than 3rd month. In this case renal biopsy will help differentiate.
Match is 110 broad, 111 split
please check the explanation of broad and split in my comment for your college Mohamad Zeid.
1-Comment on the report.
universal donor blood type
NO DSA
FCXM NEGATIVE
HLA TYPING
HLA typing of donors for kidney transplantation focused on HLA-A, HLA-B, HLA-DR and HLA-DQ loci.
a six antigen mismatch indicates that two A, two B, and two DR antigens in the donor’s phenotype are different from those of the recipient. In addition to the antigens listed for transplant candidates, HLA-DQA and -DPB typing for deceased donors is submitted to the organ procurement organization (OPO) to determine whether antibodies in the transplant candidate’s serum are directed against any antigens of the donor.
2-Comment on the difference between the broad and the split mismatch.
resolution of HLA TYPING METHODS
SPLIT HLA SPECIFICITY MATCHING METHOD SEROLOGY AND LOW RESOLUTION -(GENERIC)- DNA TYPING
BROAD HLA SPECIFICITY MATCHING METHOD SEROLOGY AND LOW RESOLUTION-(GENERIC-) DNA TYPING
3-What is the impact of split mismatch on graft survival?
MAINLY DEPEND ON CDC-FC
IN COMPARSION EFFECT OF DSA
4-Explain how the presence of DSA influences graft survival would.
IF PRA MORE THAN 85% RISK OF GRAFT LOSS WITH IN 5 YEARS WILL BE PRESENT ‘
BUT RISK OF HAR IS LOW WITH ADEQUATE Immunosuppressive drugs
5-Will you proceed with the transplantation? NO
ASSESSMENT OF IMMUNOLOGIC RISK
Risk factors for acute rejection include the following
One or more human leukocyte antigen (HLA) mismatches
Younger recipient and older donor age
Calculated panel reactive antibody (cPRA) greater than 20 percent
Presence of a donor-specific antibody (DSA)
Blood group incompatibility
Delayed onset of graft function
Cold ischemia time greater than 24 hours
Patients with one or more of the above risk factors are considered to be at high immunologic risk for acute rejection. Those who have none of the above risk factors are considered to be at low immunologic risk
6-If yes, what is your immunosuppression protocol?
Patients at high risk of rejection — For patients at high immunologic risk of acute rejection (see ‘Assessment of immunologic risk’ above), we recommend induction therapy with rATG-Thymoglobulin rather than an interleukin (IL) 2 receptor antagonist (basiliximab)
CYCLOSPORINE -STEROIDS -MMF
PLASMA EXCHANGE THERAPY IN CASE OF RECURRENT FSGS IN FIRST 3 MONTHS
rituximab_+PLASMA EXCHANGE THERAPY IN CASE OF RECURRENT FSGS AFTER 3 MONTHS
7-If not, what are the other options?
LIVE UNRELATED DONOR
8-What is the impact of the primary disease on graft survival in the indexed case?
RISK OF RECURRENCE 30-50% AND GRAFT LOSS MORE THAN 90%
The match is 110 broad
111 split
Comment on the report
ABO is compatible
110 mismatch (split mismatch is 111)
Negative crossmatch and noDSA
Comment on the difference between the broad and the split mismatch
Split antigen is an antigen that has a more refined or specific cell surface reaction relative to a broad antigen. They were given number designations that again give no indication as to the supertype to which they belong. Eg: Molecular B*15:12 is equivalent of HLA- B76
What is the impact of split mismatch on graft survival?
Whether matching for HLA antigen “splits” results in better transplant outcome than matching for broad HLA antigens was investigated in 30,000 first cadaver kidney transplants. At three years, there was an 18% difference between the survival rates of grafts with 0 or 4 mismatches among transplants typed for HLA-A and B antigen splits whereas the difference in transplants typed for broad antigens was only 2%. Analysis of HLA-A, B antigens together with HLA-DR antigens showed an even greater advantage of matching for antigen splits
Explain how the presence of DSA influences graft survival would
Preformed DSA are associated with an increased risk for graft loss in kidney transplantation, which was greater in living than in deceased donation. Even weak DSA <3000 MFI are associated with worse graft survival. This association was stronger in living than deceased donation.
Will you proceed with the transplantation?
Yes, I will proceed
If yes, what is your immunosuppression protocol?
The patient is low immunological risk. Basiliximab and methyprednisolone are for induction therapy. Standard maintenance therapy (Tacrolimus, MMF and prednisolone)
If not, what are the other options?
Kidney paired exchange or other donor
What is the impact of the primary disease on graft survival in the indexed case?
The risk of recurrence of FSGS is high post kidney transplantation (30-80%) and is associated with poor graft survival (50%). The risk of recurrence is increased in HLA DR-7, DR-53 and HLA-DQ 2(and lower in DQ-7). Recurrence may occur immediately post-transplantation or recurs lately. A protocol for early detection of FSGR recurrence (frequent protein/creatinine ratio in spot urine) is better to follow. Patients with proteinuria >2 g/day should be treated immediately with an intensive course of plasmapheresis.
References
1. Ziemann, Malte et al. Preformed Donor-Specific HLA Antibodies in Living and Deceased Donor Transplantation: A Multicenter Study. CJASN 14(7):p 1056-1066, July 2019. | DOI: 10.2215/CJN.13401118
2. 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.
3. Abbas F, El Kossi M, Jin JK, Sharma A, Halawa A. Recurrence of primary glomerulonephritis: Review of the current evidence. World J Transplant. 2017 Dec 24;7(6):301-316. doi: 10.5500/wjt.v7.i6.301. PMID: 29312859; PMCID: PMC5743867.
4. Claudio Ponticelli, Recurrence of focal segmental glomerular sclerosis (FSGS) after renal transplantation, Nephrology Dialysis Transplantation, Volume 25, Issue 1, January 2010, Pages 25–31
Thankyou but please revise the paragraph on the effects of DSAs.
thank you Prof.
Exposure to “non-self” HLA molecules, as after blood transfusion, pregnancy or sensitization events, can lead to the development of preformed anti-HLA antibodies. Pre-existing sensitization to HLA-DSA may be a contraindication to transplantation due to the increased risk of acute rejection, delayed graft function, and decreased graft survival. Pre-transplant DSA significantly increased the risk for AMR and kidney allograft failure by 76%, despite a negative flow cytometry crossmatch result.
Comment on the report.
The patient’s blood group is B +ve and the donor’s is O-ve. the blood group are compatible despite this donation deplete the O pool. HLA mismatch is 2-1-0 broad and 2-1-1 split. DR2 Broad (Splits DR15 and DR16. The cross match was negative over 3 years with no detectable DSA.
Comment on the difference between the broad and the split mismatch.
Broad mismatch is obtained through serological methods while split is through molecular method (DNA methods) which make it more accurate(1)
What is the impact of split mismatch on graft survival?
30,000 first cadaver kidney transplants survival rates of grafts were followed for three years. There was an 18% difference between those with 0 or 4 mismatches for HLA-A and B antigen splits whereas the difference in transplants typed for broad antigens was only 2%. Analysis of HLA-A, B antigens together with HLA-DR antigens showed an even greater advantage of matching for antigen splits: the difference in survival at three years between grafts with 0 or 6 mismatches for HLA-A, B, DR was 31% when antigen splits were analysed, in contrast to a 6% difference with broad antigens. (2)
At the HLA-DR locus , the analysis of matching for “broad” or “split” specificitin among first cadaver transplants, was not different broad or split specificities. However, among retransplants, split specificity mismatches had a strong impact on graft outcome. Transplants that changed from a 0 broad to a 1split mismatch had a significantly lower graft survival than transplants with no mismatch by both the broad and split definition.(1)
HLA-DR “split” specificities in 8000 cadaver kidney transplants affected graft survival in re-transplantion. The survival was significantly decreased if a split mismatch was defined, in patients with no broad mismatch (P=0.04) and also in grafts with 2 split mismatches, and 1 broad mismatch (P=0.03). Further “subsplit” specificities resulted in clinically relevant mismatches only among retransplants. (3)
The difference in 3-year graft survival rates between best and worst matched cases was 17% for first grafts and 18% for retransplants. This HLA matching effect persists despite recent improvements in graft outcome. HLA matching is especially important for recipients over age 60 and Black recipients.(4)
The rate of graft survival at one year in recipients of HLA-matched first transplants was 88 percent, as compared with 79 percent in the recipients of mismatched grafts (P<0.001). The estimated half-life of the kidney after the first year was 17.3 years for matched grafts, as compared with 7.8 years for mismatched grafts (P = 0.003). Among paired kidneys from 470 donors, one-year graft survival was 87 percent in the recipients of matched first grafts, as compared with 80 percent in the recipients of the contralateral kidneys, who did not have HLA matches with the donors. In donors and recipients matched for the more highly defined split Class I and Class II HLA antigens, the rate of graft survival after one year was as high as 90 percent.(5)
Explain how the presence of DSA influences graft survival.
the frequency and patient outcomes of pretransplant DSA following renal transplantation were studied in a randomized trial. Transplants were performed against a complement-dependent T- and B-negative crossmatch. Pre- and posttransplant sera were available from 94 of the 118 patients . 16 patients had pretransplant DSA and 3 of these patients developed AMR and 2 of them had early graft losses. Excluding these 2 losses, 6 of 14 patients exhibited DSA at the final follow-up exam, whereas 8 of these patients exhibited complete clearance of the DSA. 5 other patients developed “de novo” posttransplant DSA. Death-censored graft survival was similar in patients with pretransplant donor-specific and non-donor-specific antibodies after a mean follow-up period of 70 months.(6). An observational study in 402 consecutive deceased-donor kidney transplant recipients with a negative lympho-cytotoxic cross-match test on the day of transplantation. The 8-year graft survival was significantly worse (61%) among patients with preexisting HLA-DSA compared with both sensitized patients without HLA-DSA (93%) and non-sensitized patients (84%). Peak HLA-DSA Luminex mean fluorescence intensity (MFI) predicted AMR better than current HLA-DSA MFI (P = 0.028). As MFI of the highest ranked HLA-DSA detected on peak serum increased, graft survival decreased and the relative risk for AMR increased: Patients with MFI>6000 had>100-fold higher risk for AMR than patients with MFI<465 (relative risk 113; 95% confidence interval 31 to 414). The presence of HLA-DSA did not associate with patient survival. (7) Donor-specific antibodies require preactivated immune system to harm renal transplant.The impact of pretransplant DSA and immune activation marker soluble CD30 on 3-year graft survival was analyzed in 385 presensitized kidney transplant recipients. A deleterious influence of pretransplant DSA on graft survival was evident only in patients who were positive for the immune activation marker sCD30. Pretransplant DSA have a significantly deleterious impact on graft survival only in the presence of high pretransplant levels of the activation marker sCD30. (8)
Will you proceed with the transplantation? If yes, what is your immunosuppression protocol?
Induction with basilixmab, single dose rituximab and one apheresis pretransplant and 3 per week on the first 2 weeks if early recurrence occurred. Maintenance with tacrolimus and MMF(9)
If not, what are the other options?
Paired kidney donation or deceased donation.
What is the impact of the primary disease on graft survival in the indexed case
the rate of recurrence of primary FSGS on a renal graft was 20 to 40% for a first graft, but reached 80 to 100% recurrence on subsequent grafts if there was recurrence on the first graft (10)
Compared to transplant for other causes, patients with FSGS have a significantly inferior graft survival with a 5-year graft survival of 81% in FSGS recipients vs. 88% in non-FSGS recipients. In pediatric patients, the difference in the transplant outcome is even more pronounced with 68% 5-year graft survival in FSGS recipients compared to 93% in non-FSGS recipients. Most commonly, recurrence occurs in the first 2 years following kidney transplantation. For patients with FSGS, disease recurrence is a strong predictor for graft outcome. The 5-year graft survival in patients with FSGS recurrence is 52% compared to 83% in patients without FSGS recurrence. Recurrence leads to graft loss in half of the patients within 5 years. patients with FSGS recurrence experience significantly more biopsy-proven acute rejections than patients without recurrence
(NAPRTCS) data revealed that the expected graft survival advantage of a live donor kidney transplant in patients with primary FSGS was lost due to the increased risk for FSGS recurrence. UNOS registry found that the donor type in pediatric patients was not independently associated with disease recurrence. ANZDATA registry demonstrated a significant association between donor type and FSGS recurrence with a higher recurrence rate in recipients of a live donor transplant. Live donor kidney transplantation for FSGS resulted in significantly improved graft survival with a median graft survival of 14.8 years in recipients of a live donor transplant compared to 12.1 years for recipients of a deceased donor transplant. Importantly, a survival advantage was also observed in the pediatric population. A 5-year allograft survival of 80% after living donor kidney transplantation compares favorably to 46% in deceased donor organ recipients. Based on these data, kidney transplantation for truly idiopathic FSGS should not preclude the use of a suitable living donor.(11)
In 176 kidney transplant recipients with idiopathic FSGS, idiopathic FSGS recurs post-transplant in one third of cases and is associated with a five-fold higher risk of graft loss. Response to treatment is associated with significantly better outcomes but is achieved in only half of the cases.(12)
Ref:
1-CTS Collaborative Transplant Study Gerhard Opelz
2-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.
3-Opelz G, Scherer S, Mytilineos J. Analysis of HLA-DR split-specificity matching in cadaver kidney transplantation: a report of the Collaborative Transplant Study. Transplantation. 1997 Jan 15;63(1):57-9. doi: 10.1097/00007890-199701150-00011. PMID: 9000661.
4- Hata Y, Ozawa M, Takemoto SK, Cecka JM. HLA matching. Clin Transpl. 1996:381-96. PMID: 9286584
5-Steve Takemoto, Paul I. Terasaki, J. Michael Cecka, Yong W. Cho, David W. Gjertson, Survival of Nationally Shared, HLA-Matched Kidney Transplants from Cadaveric Donors,N Engl J Med 1992; 327:834-839
6-David-Neto E, Souza PS, Panajotopoulos N, Rodrigues H, Ventura CG, David DS, Lemos FB, Agena F, Nahas WC, Kalil JE, Castro MC. The impact of pretransplant donor-specific antibodies on graft outcome in renal transplantation: a six-year follow-up study. Clinics (Sao Paulo). 2012;67(4):355-61. doi: 10.6061/clinics/2012(04)09. PMID: 22522761; PMCID: PMC3317258.
7-Lefaucheur C, Loupy A, Hill GS, Andrade J, Nochy D, Antoine C, Gautreau C, Charron D, Glotz D, Suberbielle-Boissel C ,Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation, J Am Soc Nephrol. 2010;21(8):1398.
8-Caner Süsal a, Bernd Döhler a , Andrea Ruhenstroth a , Christian Morath b , Antonij Slavcev c , Thomas Fehr d , Eric Wagner e,q , Bernd Krüger f , Margaret Rees g , Sanja Balen h , Stela Živčić-Ćosić h , Douglas J. Norman i , Dirk Kuypers j , Marie-Paule Emonds k , Przemyslaw Pisarski l , Claudia Bösmüller m, Rolf Weimer n , Joannis Mytilineos o , Sabine Scherer a , Thuong H. Tran a , Petra Gombos a , Peter Schemmer p , Martin Zeier b , Gerhard Opelz a , A Collaborative Transplant Study Report:C. Süsal et al. / EBioMedicine 9 (2016) 366–371
9- Naciri Bennani H, Elimby L, Terrec F, Malvezzi P, Noble J, Jouve T, Rostaing L. Kidney Transplantation for Focal Segmental Glomerulosclerosis: Can We Prevent Its Recurrence? Personal Experience and Literature Review. J Clin Med. 2021 Dec 24;11(1):93. doi: 10.3390/jcm11010093. PMID: 35011834; PMCID: PMC8745094.
CopyDownload .nbib
10-Naciri Bennani H, Elimby L, Terrec F, Malvezzi P, Noble J, Jouve T, Rostaing L. Kidney Transplantation for Focal Segmental Glomerulosclerosis: Can We Prevent Its Recurrence? Personal Experience and Literature Review. J Clin Med. 2021 Dec 24;11(1):93. doi: 10.3390/jcm11010093. PMID: 35011834; PMCID: PMC8745094.
11-Kienzl-Wagner,Katrin,A Waldegger,Siegfried,A Schneeberger,Stefan, Disease Recurrence—The Sword of Damocles in Kidney Transplantation for Primary Focal Segmental Glomerulosclerosis, Front. Immunol., 17 July 2019 Sec.
12-Uffing A, Pérez-Sáez MJ, Mazzali M, Manfro RC, Bauer AC, de Sottomaior Drumond F, O’Shaughnessy MM, Cheng XS, Chin KK, Ventura CG, Agena F, David-Neto E, Mansur JB, Kirsztajn GM, Tedesco-Silva H Jr, Neto GMV, Arias-Cabrales C, Buxeda A, Bugnazet M, Jouve T, Malvezzi P, Akalin E, Alani O, Agrawal N, La Manna G, Comai G, Bini C, Muhsin SA, Riella MC, Hokazono SR, Farouk SS, Haverly M, Mothi SS, Berger SP, Cravedi P, Riella LV. Recurrence of FSGS after Kidney Transplantation in Adults. Clin J Am Soc Nephrol. 2020 Feb 7;15(2):247-256. doi: 10.2215/CJN.08970719. Epub 2020 Jan 23. PMID: 31974287; PMCID: PMC7015092.
I agree with my colleague, We have match of HLA 02/02
Want to add: DR 15/16 are both splits of DR2 : https://hla.alleles.org/antigens/broads_splits.html
Thank you Hinda:
the match is 110 broad
111 split.
your review of broad and split ,DSAs is impressive.
BUT ! There are no DSAs in this case so this odd induction is to remove what?
This is a moderate risk match with no DSAs to struggle against.
Your choice of Basilixmab will be fine.
· Comment on the report.
The given interim crossmatch report provides details of Human Leukocyte Antigen (HLA) typing, cross-match and DSA screening of the donor-recipient duo:
a) The recipient-donor pair is blood-group compatible.
b) The HLA typing of the pair in HLA A B and DR reveals a 110 mismatch (not 210 as mentioned) on broad antigen typing and a 111 mismatch (not 211 as mentioned) on split antigen typing. They also show 1 mismatch in HLA-C and HAL-DQB1 and 2 mismatches in HLA-DQA1.
c) Flowcytometry cross match (FCXM) with five historical sera of the patient are negative. The latest FCXM is missing in the report as the last FCXM was dated 03/09/20.
d) The donor specific antibody (DSA) screen does not reveal any DSA.
· Comment on the difference between the broad and the split mismatch.
An HLA molecule with poor specificity is a broad antigen. It can be divided into 2 or more split antigens having a more refined or specific cell surface reaction.
The difference in broad and split mismatch in the index case is due to the broad antigen DR2, which is the common source for split antigen DR15 and DR16, present in the patient and the donor respectively (1).
· What is the impact of split mismatch on graft survival?
As split antigens are more specific than a broad antigen, 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 (2).
· Explain how the presence of DSA influences graft survival.
Presence of DSA is associated with increased risk of antibody mediated rejection, graft loss, accelerated GFR fall and ultimately poorer graft outcomes (3,4).
· Will you proceed with the transplantation?
Yes, if the latest cross match is negative. As the donor-recipient duo has a 111 mismatch and no DSA.
· If yes, what is your immunosuppression protocol?
Induction: Basiliximab
Maintenance immunosuppression: Tacrolimus, MMF and steroids
· If not, what are the other options?
In case the available donor is not accepted, other options include either look for a living donor, enrolment in a living donor kidney-exchange program (if a living incompatible donor is available), or wait for another better matched deceased donor.
· What is the impact of the primary disease on graft survival in the indexed case?
The rates of FSGS recurrence post-transplant range from 10% to 47% (average 30%), with graft loss rates ranging from 30-50% (5-8). The relative risk of graft loss has been reported as 2.03 with respect to other glomerular diseases (9). In the TANGO study, graft loss at 5 year increased from 15% in patients without recurrence to 39% in patients with recurrence of FSGS (8). Recurrence of FSGS has been seen more with a young recipient, a living donor, white ethnicity, rapid worsening of renal function, heavy proteinuria, lower body mass index, presence of mesangial hypercellularity on kidney biopsy and prior recurrence of FSGS (10,11).
References:
1) Deshpande A. The human leukocyte antigen system… Simplified. Glob J Transfus Med [serial online] 2017 [cited 2023 Jan 17];2:77-88. Available from https://www.gjtmonline.com/text.asp?2017/2/2/77/214287
2) 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.
3) Frischknecht L, Deng Y, Wehmeier C, de Rougemont O, Villard J, Ferrari-Lacraz S, Golshayan D, Gannagé M, Binet I, Wirthmueller U, Sidler D, Schachtner T, Schaub S, Nilsson J; Swiss Transplant Cohort Study. The impact of pre-transplant donor specific antibodies on the outcome of kidney transplantation – Data from the Swiss transplant cohort study. Front Immunol. 2022 Sep 21;13:1005790. doi: 10.3389/fimmu.2022.1005790. PMID: 36211367; PMCID: PMC9532952.
4) Zhang R. Donor-Specific Antibodies in Kidney Transplant Recipients. Clin J Am Soc Nephrol. 2018 Jan 6;13(1):182-192. doi: 10.2215/CJN.00700117. Epub 2017 Apr 26. PMID: 28446536; PMCID: PMC5753302.
5) Chadban SJ, Ahn C, Axelrod DA, Foster BJ, Kasiske BL, Kher V, et al. KDIGO Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation. Transplantation. 2020 Apr;104(4S1 Suppl 1):S11-S103. doi: 10.1097/TP.0000000000003136. PMID: 32301874.
6) Cosio FG, Cattran DC. Recent advances in our understanding of recurrent primary glomerulonephritis after kidney transplantation. Kidney Int. 2017 Feb;91(2):304-314. doi: 10.1016/j.kint.2016.08.030. Epub 2016 Nov 10. PMID: 27837947.
7) Hickson LJ, Gera M, Amer H, Iqbal CW, Moore TB, Milliner DS, et al. Kidney transplantation for primary focal segmental glomerulosclerosis: outcomes and response to therapy for recurrence. Transplantation. 2009 Apr 27;87(8):1232-9. doi: 10.1097/TP.0b013e31819f12be. PMID: 19384172.
8) Uffing A, Pérez-Sáez MJ, Mazzali M, Manfro RC, Bauer AC, de Sottomaior Drumond F, et al. Recurrence of FSGS after Kidney Transplantation in Adults. Clin J Am Soc Nephrol. 2020 Feb 7;15(2):247-256. doi: 10.2215/CJN.08970719. Epub 2020 Jan 23. PMID: 31974287; PMCID: PMC7015092.
9) Briganti EM, Russ GR, McNeil JJ, Atkins RC, Chadban SJ. Risk of renal allograft loss from recurrent glomerulonephritis. N Engl J Med. 2002 Jul 11;347(2):103-9. doi: 10.1056/NEJMoa013036. PMID: 12110738.
10) Kang HG, Ha IS, Cheong HI. Recurrence and Treatment after Renal Transplantation in Children with FSGS. Biomed Res Int. 2016;2016:6832971. doi: 10.1155/2016/6832971. Epub 2016 Apr 24. PMID: 27213154; PMCID: PMC4860214.
11) Rudnicki M. FSGS Recurrence in Adults after Renal Transplantation. Biomed Res Int. 2016;2016:3295618. doi: 10.1155/2016/3295618. Epub 2016 Apr 10. PMID: 27144163; PMCID: PMC4842050.
Exellent.
1- Comment on report:
ABO compatible.
broad antigen is 110 and split antigen 111
as DRB1 is broad antigen split into 15,16.
FLOWCYTOMETRY is negative for T and B cells.
NO DSA .
2- Different between broad and split mismatch:
Broad antigen which is serologically poor or broad to other specificities and defined by 2 or more split antigen.
Split antigen :
antigen which more refined or specific cell surface reaction which is relative to broad antigen.
3- What is the impact of split mismatch on graft survival?
Studies showed that there were difference within three years for graft survival with 0 or 6 mismatches for HLA-A, B, DR was 31% for split antigen with 6% for broad antigen in opposite side.
4-Explain how the presence of DSA influences graft survival would?
pre-transplant DNA carry the risk of increasing ABMR with related graft failure.
after transplant leads to subsequent sever vascutitis and thrombosis -which leads to graft loss.this is especially in case of deceased kidney donor.
5-Will you proceed with the transplantation?
Yes.
6-If yes, what is your immunosuppression protocol?
Induction with basiliximab
Maintenance therapy: steroid, MMF and tacrolimus.
7-What is the impact of the primary disease on graft survival in the indexed case?
Focal segment glomerulosclerosis carry risk of recurrence 20-40 %.
Which is more among young age with heart proteinuria, collapsing varients or those with mesengial hypertrophy on initial biopsy.
Well done.
Heart proteinuria??!
Sorry I meant heavy proteinuria
Comment on the report.
Recipient B, Donor O, ABO compatible as Group O considered a universal donor.
HLA mismatch was 110 for broad and 111 for split antigens,
No history of FCXM for positive T and B cell over the past 3 years.
No DSA was detected.
Comment on the difference between the broad and the split mismatch.
Broad antigens can occasionally be divided into two or more subtype antigens, known as “split” antigens. The A9 broad antigen, for instance, was divided further into the A23 and A24 split antigens, The B5 Broad antigen divided to B51 and B52 split, whereas the DR2 broad antigen was divided into the DR15 and DR16 split antigens (1)
What is the impact of split mismatch on graft survival?
Split antigen is associated with better outcomes and graft survival as it’s more specific in yielding further matches among the subtypes. If a mismatch was identified, taking split specificities in patients with no mismatch according to the “broad” criteria into account, transplant survival was drastically reduced. Therefore, primary and regraft recipients exhibit fundamentally distinct detection of HLA-DR split specificity mismatches. (2)
Explain how the presence of DSA influences graft survival would.
The presence of DSA is crucial in graft survival. Nearly 64% of instances that experience graft failure have antibody-mediated rejection as their primary source of graft loss. A tenfold increase in the probability of graft loss is linked to the detection of DSA. (3)
Will you proceed with the transplantation?
As he regarded as low risk (accepted match), we can proceed.
If yes, what is your immunosuppression protocol?
Standard protocol for immunologically low-risk patients
Induction with Basiliximab, and maintenance with Tacrolimus, MMF, and Prednisolone.
If not, what are the other options?
Paired kidney transplantation or keeping him on hemodialysis and waiting for a better-matched donor.
What is the impact of the primary disease on graft survival in the indexed case?
In one-third of cases, idiopathic FSGS occurs after transplantation and is linked to a five-fold increased risk of graft loss. Only half of the patients respond to therapy, despite the fact that this is associated with noticeably improved results. (4)
References:
Well done.
Comment on the report
ABO compatible donor for the recipient.
1 A mismatch, 1 B mismatch, 1 C mismatch, 1 DRB1 mismatch, 0 DRB5 mismatch, 2 DQA1 mismatch, 1 DQB1 mismatch, 0DPB1 mismatch, 0 BW4/6 mismatch.
The patient has a higher split antigen mismatch than the broad antigen.
Cross match between recipient serum and donor cells are negative and no detectable donor specific antibodies.
Comment on difference between split and broad mismatch?
Split mismatch focuses on the HLA antigen when they are “splitted” into narrower specificities as detected by molecular methods while broad mismatch is non-specific, as detected by serology. For example, HLA – A*02:01 and HLA-A*02:05 are split antigens belonging to same serologic group and antigen equivalent on a broad level will be HLA-A2.
Since, not all part of the HLA antigen are immunogenic, splitting the antigen helps to determine the presence of reactive antigens to which the recipient will develop an antibody. Also, it helps to determine antigens that might cross react with other antigens to develop antibodies.
Impact of split mismatch on graft survival?
Multiple studies shows that HLA matching is associated with long term graft survival. 2008 annual report of scientific registry of transplant recipient revealed that graft survival was 75% with zero mismatch compared with 66% with 6 HLA mismatch.
Higher number of split mismatches have a higher risk of developing donor specific antibody post transplantation and a higher risk of graft loss.
Will you proceed with the transplantation?
Yes. HLA mismatches affect graft survival in the long term, he would still benefit from the improved quality of life compared with dialysis. Additionally, because the DSAs are negative now, the risk of acute rejection is much lower. The only drawback is that patient will have to be on intensive immunosuppression.
If yes, immunosuppression protocol?
Due to the high immunological risk, induction with ATG and methylpresnisolone will be preferred. Maintenance with mycophenolate mofetil, tacrolimus and prednisolone.
Other option?
Induction with alemtuzumab
Impact of primary disease on graft survival?
About 30% of primary fsgs will recur post transplantation while secondary fsgs will not recur. Patients who have fsgs recurrence in the first year after transplantation have more than 80% chance of recurrence in subsequent graft.
The type of fsgs needs to be determined in this case to be able to fully predict the outcome. Risk factors for recurrence includes male sex, European ancestry, rapid progression to ESKD, nephrotic range proteinuria etc.
References;
Voora S, Adey DB. Management of Kidney Transplant Recipients by General Nephrologists: Core Curriculum 2019. Am J Kidney Dis. 2019 Jun;73(6):866-879. doi: 10.1053/j.ajkd.2019.01.031. Epub 2019 Apr 11. PMID: 30981567.
Thankyou for mentioning all the HLA screen
are you staging him as a high risk and hence ATG induction?
Comment on the report.
· HLA mismatch: broad 110, split 111.
· Negative FCXM for B &T.
Comment on the difference between the broad and the split mismatch.
15 and 16 are subtype allele of DRB1, they are considered as split antigen.
What is the impact of split mismatch on graft survival?
Analysis of HLA antigens, revealed better outcome and survival when matching for antigen splits(1).
Explain how the presence of DSA influences graft survival would.
Preformed DSA were associated with poor graft survival and graft loss(2). The risk of ABMR tends to double in the setting of significant level of DSA as well as there will be 76% risk of graft failure(3).
Will you proceed with the transplantation?
Yes, I will proceed with this crossmatch for the followings:
· This acceptable mismatch(AM) of 1-1-1,will shorten the stay on dialysis and in the waiting list for KT.
· ABOc.
· No DSA and negative FCXM.
If yes, what is your immunosuppression protocol?
ATG and Methylprednisolone for induction. Considering the primary diagnosis of FSGS, RTX and plasmapheresis will be considered in the setting of positive recent XM.
Maintenance immunosuppression: the triple of CsA(provided the primary FSGS), MMF and prednisolone. I will not consider mTORi in the maintenance therapy as it may exacerbate proteinuria in case of FSGS recurrence.
If not, what are the other options?
· to remain on dialysis therapy while seeking other option.
· To look for altruistic offer.
· To look for kidney paired donation(KPD) or exchange program.
What is the impact of the primary disease on graft survival in the indexed case?
FSGS may recure in the post-transplant period at a rate of 40%-60% with a risk of graft loss in up to 70% at re-transplantation(4). FSGS, should be anticipated in the post-transplant period whenever there’s new onset proteinuria. Genetic testing (for APOL1 and NPHS2) is important for risk assessment and to determine the risk of recurrence.
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. Ziemann M, Altermann W, Angert K, Arns W, Bachmann A, Bakchoul T, Banas B, von Borstel A, Budde K, Ditt V, Einecke G, Eisenberger U, Feldkamp T, Görg S, Guthoff M, Habicht A, Hallensleben M, Heinemann FM, Hessler N, Hugo C, Kaufmann M, Kauke T, Koch M, König IR, Kurschat C, Lehmann C, Marget M, Mühlfeld A, Nitschke M, Pego da Silva L, Quick C, Rahmel A, Rath T, Reinke P, Renders L, Sommer F, Spriewald B, Staeck O, Stippel D, Süsal C, Thiele B, Zecher D, Lachmann N. Preformed Donor-Specific HLA Antibodies in Living and Deceased Donor Transplantation: A Multicenter Study. Clin J Am Soc Nephrol. 2019 Jul 5;14(7):1056-1066. doi: 10.2215/CJN.13401118. Epub 2019 Jun 18. PMID: 31213508; PMCID: PMC6625630.
3. Mohan, Sumit; Palanisamy, Amudha; Tsapepas, Demetra; Tanriover, Bekir; Crew, R. John; Dube, Geoffrey; Ratner, Lloyd E.; Cohen, David J.; Radhakrishnan, Jai. Donor-Specific Antibodies Adversely Affect Kidney Allograft Outcomes. Journal of the American Society of Nephrology 23(12):p 2061-2071, December 2012. | DOI: 10.1681/ASN.2012070664
4. Disease Recurrence-The Sword of Damocles in Kidney Transplantation for Primary Focal Segmental Glomerulosclerosis
Katrin Kienzl-Wagner, Siegfried Waldegger and Stefan Schneeberger.
Thank you Dr ssafi Ibrahim Annour Mohammed
I refer to
ATG and Methylprednisolone as part of immunosuppression?
Reason of ATG and when you can use Basiliximab?
You referred to Genetic testing (for APOL1 and NPHS2) is important for risk assessment and to determine the risk of recurrence.
If these genes were positive what would be the FSGS risk of recurrence?
Do you think you need to differentiate between primary or secondary FSGS?
·Comment on the report
· Patient: 31 yr, ABO & Rh: B+ve
· Donor (deceased): 29 yr, ABO & Rh: O-ve
· HLA Typing:
· -Broad:110
· -Split:111
Crossmatch (FCXM), done several times, 4 to 9 months apart, was negative for both T and B cells on all occasions.
=========================================
·Comment on the difference between the broad and the split mismatch.
· Split matching is a more specific and important marker for a good outcome and a long-term successful survival rate when compared to broad split matching.
· A split mismatch carries a poor outcome for graft survival.
· A split mismatch poses a higher immunological risk to the graft.
Split matching is a more specific and important marker for a good outcome and a long-term successful survival rate, whereas split mismatch has a poor graft survival outcome.
=========================================
·What is the impact of split mismatch on graft survival?
·HLA-A, HLA-B, & HLA-DR split antigen matching are now used in the Eurotransplant Kidney Allocation System, a non-profit organization of eight European member nations.
·Compared to grafts with one or more HLA mismatches, transplants without any HLA-A, -B, or -DR mismatches produce better results.
·In the context of organ & stem cell transplantation, the serological subtype of HLA alleles is of considerable importance, particularly when the patients’ sera contain antibodies against a split antigen. Anti-HLA antibodies can be identified in patient samples using current methods for antibody profiling, such as Luminex bead tests (Picascia et al. 2012).
·Identification of the donor’s HLA type at the split level is still essential for a good transplantation outcome because the presence of DSA in the patient blood has been linked to graft failure (Michielsen et al. 2019). Because of this, transplantation facilities are advised by Eurotransplant, a non-profit organization of eight European member nations, to record HLA typing for both organ donors and patients at the level of the serological split antigen in order to achieve the best possible organ allocation (ETRL Newsletter issue 9).
=========================================
·Explain how the presence of DSA would influences graft survival.
·The presence of preformed DSA is strongly associated with increased graft loss in kidney transplants, related to an increased risk of AMR.
·In a cohort of 237 patients, the incidence of AMR in patients with DSA was 9-fold higher than in patients without DSA and led to a significantly worse graft survival.
Pre-transplant DSA with MFI >1000 significantly reduced graft survival, with patients who had cumulative DSA MFI >5000 experiencing the worst results.
·Even DSA in patients with an MFI of 500 to 1000 were linked to a noticeably higher incidence of ABMR than in those without DSA.
=========================================
·Will you proceed with the transplantation?
· Yes
=========================================
·If yes, what is your immunosuppression protocol?
=========================================
·If not, what are the other options?
·Look for a different qualified donor
=========================================
·What is the impact of the primary disease on graft survival in the indexed case?
References
1. Duygu, B., Matern, B.M., Wieten, L. et al. Specific amino acid patterns define split specificities of HLA-B15 antigens enabling conversion from DNA-based typing to serological equivalents. Immunogenetics 72, 339–346 (2020). https://doi.org/10.1007/s00251-020-01172-8
2. Lefaucheur C et al. Clinical relevance of preformed HLA donor-specific antibodies in kidney transplantation. Contrib Nephrol. 2009;162:1-12. doi: 10.1159/000170788. Epub 2008 Oct 31. PMID: 19001809.
3. Frischknecht et al. The impact of pre-transplant donor specific antibodies on the outcome of kidney transplantation – Data from the Swiss transplant cohort study. Front. Immunol. 13:1005790. doi: 10.3389/fimmu.2022.100579
4. H. Jiang, A. L. Kennard and G. D. Walters, Recurrent glomerulonephritis following renal transplantation and impact on graft survival S. BMC Nephrology (2018) 19:344 https://doi.org/10.1186/s12882-018-1135-7
You need to elaborate more on FSGS specidically.
comment on report.
Comment on the difference between the broad and the split mismatch
Broad antigens are more generalized as compared to split antigen therefore split antigen because of more specific in nature gives you greater graft survival in long term.
split antigen is two or more splits of broad antigen for example A9 splits into A23 and A24.
Impact of split mismatch on graft survival
Increase number of HLA mismatches gives you poor long-term survival with increase in episodes of rejections and graft failure. Therefor split HLA mismatching has been introduced to reduce this risk of even minor mismatching and worst outcome in future.
DSA influencing graft survival.
Both De-novo and pre-formed DSA can lead to complement mediated endothelial injury in the graft of recipient. The effect of DSA is proportionate to the specificity and strength against the particular donar
DSA will lead to ABMR and these reduces graft survival irrespective of this de-novo or pre-formed DSAs.
Proceeding with transplantation
yes it is feasible
Immunosupressive protochol
induction with IL2 ( Basiliximab)
Steroids. MMF, CNIs (tacrolimus)
Impact of graft survival in the indexed case
FSGS can recure in post-transplant period very rapidly and aggressively. We have to monitor the proteinuria immediately post-transplant period and 5 years graft survival is between 50-55% in these cases who has recurrence FSGS as compared to non-recurrence with survival of more than 85%.
PLEX in pre and immediate post transplant period to reduce this recurrence has not shown consistent rtesults.
Pretransplant PX in FSGS is questionable.
Comment on the report
Comment on the difference between the broad and the split mismatch
Broad categories are indistinguishable antigens, while split categories detect differences in antigens.
In this case, is DR2 split into DR15 and DR16. Thus, the split mismatch is more specific compared with broad mismatches.
What is the impact of split mismatch on graft survival?
Since this is more specific antigen detection and identification, this will be leading to better graft survival.
Explain how the presence of DSA influences graft survival would
Preformed HLA-DSA associated with hyperacute rejection, acute accelerated rejection and ABMR. Therefore, risk stratification is very important and those with negative FlowXM, but in the setting of HLA-DSA, the transplant physician may need to proceed with desensitization before transplantation or subject the patient to kidney-paired exchange in the setting of living kidney donation.
Will you proceed with the transplantation?
Yes
If yes, what is your immunosuppression protocol?
What is the impact of the primary disease on graft survival in the indexed case?
Recurrence of primary FSGS post-transplantation is reported to be around 17% to 55%. The recurrence is associated with a higher risk of graft loss. However, early identification and treatment lead to better responses.
It is 110 broad 111 split to be more specific.
You need to elaborate more on FSGS.
Comment on the report.
Comment on the difference between the broad and the split mismatch, what is the impact of split mismatch on graft survival?
Explain how the presence of DSA influences graft survival would.
General speaking detection of DSA is associated with an increase in the risk of graft loss because of ABMR which is either acute or chronic and this is related to multiple factors like:
1. DSA type: (denovo vs preexisting): De novo DSA usually formed after rejection and 8 years of graft survival 34% when compared to pre-existing DSA associated around 65% (2).
2. Complement fixation: IGg 1,3 are Complement fixing and can cause acute or hyperacute rejection, on the other hand, IGg 2,4 are non-complement fixing and more common to cause chronic ABMR (3).
3. DSA sub-class: IgG3 dominant DSA is more associated with acute rejection, complement fixation, C4d capillary deposition, and graft failure. On the other hand, IgG4 dominant DSA was associated with chronic rejection and transplant glomerulopathy (4).
Will you proceed with the transplantation? If yes, what is your immunosuppression protocol? If not, what are the other options?
Labs done in 2017 so it will need to be updated if still the same I will proceed directly for transplantation I will consider the case as low immunological risk and I will proceed with steroids induction with triple maintenance immunosuppression including tac, MMF, and steroids (tacrolimus to be started 3-5 days pretransplant unless long ischemia time and ATN is expected)
If the donor is not suitable other options will be:
What is the impact of the primary disease on graft survival in the indexed case?
FSGS is classified into primary, secondary, or familial.
Primary FSGS is associated with a high risk of recurrence (40-70%) and there is multiple factors related to graft survival like the type of primary FSGS (collapsing associated with worthiest prognosis), time of recurrence, and duration until graft loss after recurrence
REFERENCES
1. Hata Y, Cecka JM, Takemoto S, Ozawa M, Cho YW, Terasaki PI. Effects of changes in the criteria for nationally shared kidney transplants for HLA-matched patients. Transplantation 1998; 65 (2): 208.
2. Haas M, Mirocha J, Reinsmoen NL, et al. Differences in pathologic features and graft outcomes in antibody-mediated rejection of renal allografts due to persistent/recurrent versus de novo donor-specific antibodies. Kidney Int 2017; 91:729
3. Loupy A, Lefaucheur C, Vernerey D, et al. Complement-binding anti-HLA antibodies and kidney-allograft survival. N Engl J Med 2013; 369:1215.
4. Lefaucheur C, Viglietti D, Bentlejewski C, et al. IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury. J Am Soc Nephrol 2016; 27:293.
10- Aubert O, Bories MC, Suberbielle C, et al. Risk of antibody-mediated rejection in kidney transplant recipients with anti-HLA-C donor-specific antibodies. Am J Transplant 2014; 14:1439
11- Jolly EC, Key T, Rasheed H, et al. Preformed donor HLA-DP-specific antibodies mediate acute and chronic antibody-mediated rejection following renal transplantation. Am J Transplant 2012; 12:2845.
5. Abbott KC, Sawyers ES, Oliver JD 3rd, et al. Graft loss due to recurrent focal segmental glomerulosclerosis in renal transplant recipients in the United States. Am J Kidney Dis 2001; 37:366.
Thankyou Ramy but pleare note:
there is a typing mistake in the report A mismatch is 1
For broad and split please revise my explanation with Weam El Nazer as it is 110 broad, 111 split.
Comment on the report
Recipient is 31 year old blood group B positive while the donor is 29 year old blood group O negative. HLA match is 3/6 match with negative T cell cross match and no DSA detected. So they are a compatible pair for transplant.
Broad and split mismatch
Split antigen are more specific in comparison to broad antigens that are generalised. Eg HLA B5 is a broad antigen that splits to B51 and B52.
Thus since the split antigens are more specific than broad antigens matching for the split antigens is associated with greater graft survival in comparison to broad antigens.
DSA and graft survival
Donor specific antibodies are antibodies formed against the donor HLA antigens, they can be preformed due to prior sensitisation episodes or can occur post-transplant. Presence of preformed DSA is associated with increased risk of antibody mediated rejection, delayed graft function and graft loss.
Will you proceed with the transplant?
Yes, they are a compatible pair in blood grouping, HLA match of 3/6 and negative T cell cross match and DSA.
Immunosuppression protocol
Induction with basiliximab two doses on day 1 and 4 and methylprednisolone for 3 days
Maintenance therapy with triple CNI- tacrolimus + steroids + mycophenolate mofetil.
Other options
Living related kidney donation
Impact of the primary disease
Primary FSGS is associated with high risk of recurrence in the first year post-transplantation.
Thankyou but a more clear description of the mismatch is better for broad and splits.
Same for FSGS.
Thankyou prof.
The broad antigens splits to split antigens which the split antigens more specific. Thus matching for split antigens is associated with better graft survival
This patient has 110broad antigens and 111 split antigens, the difference can be explained by DR2 splitting to DR15 and 16.
Primary FSGS has a high risk of recurrence mostly occurs within 2 years post-transplant though it can also occur in the immediate post-transplant period. Plasma exchange can be done prior to reduce this risk
Comment on the report.
Both recipient and donor ABO are compatible. The patient is blood group B while the donor is blood group O who is considered as a universal donor.
T and B lymphocytes flow cytometry cross matches ( FCXM) were negative and no DSA were detected..
This patient has 110 mismatches on broad antigens matching while his mismatch is 111 on split antigens matching.
Comment on the difference between the broad and the split mismatch.
The split antigen is split of broad antigens into two or more, eg, A9 split into A23 and A24 which has more specific or refined cell surface reaction relative to the broad antigen.In this case ,the difference between the broad antigens (110) and the split antigen(111) mismatches is due to DR 2 antigen which splits into DR15 and DR16 antigens and is detected in the split mismatch.
What is the impact of split mismatch on graft survival?
HLA mismatches associate with a 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. Split HLA antigens matching is precise and has a better graft survival and transplant outcome than a broad HLA antigen matching (1).
Explain how the presence of DSA influences graft survival would.
DSA can be pre-formed or de novo DSA . It can lead to endothelial injury via complement-dependent, and independent mechanisms, and up-regulation of the complement regulatory protein (2).The effect of DSA depends on its strength and specificity (3). Different studies showed recipients with DSA have decreased graft survival at 3 and 5 years after transplant (4). Recipients with DSA can develop AMR , and AMR episodes lead to decrease kidney allograft survival , regardless of whether antibodies were pre-formed or de novo DSA, (49%- 83% survival with HLA antibodies and without HLA antibodies, respectively ) ( 5).
Will you proceed with the transplantation?
Yes.
If yes, what is your immunosuppression protocol?
Induction with basilixmab ,and maintenance immunosuppression for this patient from day one: tacrolimus 0.15mg/kg /day in a divide dose /12 hours ,mycophenolate mofetil (MMF)1g/BD. Pulse steroid intra-operatively 1g followed by prednisolone 20mg orally for first 4 weeks tapering to 5-10 at 3month (6).
If not, what are the other options?
Wait for another suitable donor.
What is the impact of the primary disease on graft survival in the indexed case?
FSCS recurrence may present immediately post-transplant with oliguria and graft dysfunction from acute tubular injury. Proteinuria may develop within days – weeks post-transplantation. Recurrence occurs commonly within two-year after transplant . The 5-year graft survival is 81% -88%in FSGS recipients and non-FSGS recipients, respectively. The 5-year graft survival is 52% -83% in recipients with FSGS recurrence and recipients without FSGS recurrence, respectively. Graft losses commonly occur within two -years after disease recurrence (7).
The plasma exchange before transplantation and in the early post-transplantation period is used to reduce the risk of recurrence, but its effectiveness has been difficult to prove ( 6 ).
References:
1. Opelz G: Importance of HLA antigen splits for kidney transplant matching. Lancet 8602:61–64, 1988
2. Zhang X, Reed EF. Effect of antibodies on endothelium. Am J Transplant 2009;9(11): 2459–65.
3. Jindra PT, Zhang X, Mulder A, et al. Anti-HLA antibodies can induce endothelial cell survival or proliferation depending on their concentration. Transplantation 2006; 82(1 Suppl.):S33–5.
4. Hourmant M, Cesbron-Gautier A, Terasaki PI, Mizutani K, Moreau A, Meurette A, et al. Frequency and clinical implications of development of donor-specific and non-donor-specific HLA antibodies after kidney transplantation. J Am Soc Nephrol. 2005; 16:2804–2812. [PubMed: 16014742]
5.. Lachmann N, Terasaki PI, Schonemann C. Donor-specific HLA antibodies in chronic renal allograft rejection: a prospective trial with a four-year follow-up. Clin Transpl. 2006:171–199. [PubMed: 18365377] .
6. Danovitch G.M .Handbook of kidney transplantation. sixth edition. Wolters Kluwer .Press:2017.
7. Hickson LJ, Gera M, Amer H, Iqbal CW, Moore TB, Milliner DS, et al. Kidney transplantation for primary focal segmental glomerulosclerosis: outcomes and response to therapy for recurrence. Transplantation. (2009) 87:1232–9. doi: 40.1097/TP.0b013e31819f12be
Well done
References:
Dear colleagues,
Many of you have mentioned paired donation when your patient has been offered cadaveric kidney donation. I would clarify that paired or pooled donation is applicable ONLY in living donor operation, not in cadaveric organ donation.
Ajay
· Comment on the report.
compatible ABO as the donor is blood group o -ve which is considered as universal donor
HLA mismatch for broad Ag is (110)
HLA mismatch for split Ag is (111)
No DSA
Negative FCXM for both T & B cells but still we need to do a new cross match because the last one done at 2020
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.
split antigen is an antigen that has a specific cell surface reaction relative to a broad antigen. (Example: HLA-B51 and HLA-B52 are split antigens of HLA-B5)
HLA typing methods have evolved from serologic to molecular platforms. Consequently, the number of recognized HLA antigens has increased, and many of which are now named as serologic split equivalents of previously identified broader antigens. For example, DR15 and DR16 are now recognized as unique antigens but may previously have been typed as the broader antigen DR2.
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. split antigen 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.
matching for HLA antigen splits results in better transplant outcome than matching for broad HLA antigens
So ,Split antigen compatibility is more important and it gives good graft survival and good graft outcomes
· DSA
After HLA typing, the recipient is tested for donor-specific antibodies (DSA). These are antibodies (Ab) against the HLA antigens of the prospective donor. DSA can be occure after pregnancy, blood transfusion, previous transplant and infections. If kidney transplantation is done with presence of DSA so hyper- acute graft rejection may occur. Although HLA-C, HLA-DP and HLA-DQ matching is not routinely done, DSA against these antigens can be associated with poorer kidney graft outcomes
Clinical importance of anti-HLA donor-specific antibodies
DSA can be present before transplantation and taken into consideration as preformed antibodies or occur after transplantation and referred to as Denovo
Both kinds are taken into consideration as poor prognostic biomarkers for transplant effects carrying the excessive hazard of antibody-mediated rejection, graft dysfunction, and inferior graft survival
Preformed antibodies generally arise because of preceding organ transplant, being pregnant, or blood transfusion
The presence of high levels of pre-transplant class I (HLA-A and B) ± II (HLA-DR) donor-specific antibodies related to poorer graft outcomes, including the development of acute AMR, chronic AMR, transplant glomerulopathy, and late graft loss
The risk factors for de novo DSA include the following:
(1) high HLA mismatches (particularly DQ mismatches)
(2) insufficient immunosuppression and nonadherence
(3) graft inflammation, which includes viral infection, cell rejection, or ischemia injury
De novo DSAs have directed to donor HLA class 2 mismatches and usually occur during the first year of a kidney transplant, however they could arise at any time, even years after transplantation
The binding of DSA to an antigen expressed on allograft endothelial cells lead to activation of the classical complement pathway which leads to graft damage but even in absence of complement activation DSAs can cause graft damage by antibody-dependent cellular cytotoxicity
Class 1 de novo DSAs are detected soon after transplant and more likely IgG1 and IgG3 subclasses and result in acute antibody-mediated rejection and early graft loss
Class 2 de novo DSAs appear later and are commonly non complement binding IgG2 or IgG4 subclass. These antibodies are persistent and associated with chronic antibody-mediated rejection and transplant glomerulopathy
Yes I will accept this donor
this patient is considered as low immunological risk
(No DSA, negative cross match ) so induction can be done by
-basiliximab given in 2 doses
– methyl prednisolone for 3 days
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:
If we decide to refuse this donor we either do paired kidney transplantation
Or watch for any other greater well-suited donor
Focal Segmental Glomerulosclerosis
FSGS is the most common cause of steroid-resistant nephrotic syndrome leading to ESRD and is the most common acquired cause of ESRD in children.
FSGS is a pathologic analysis and represents the final results of more than one disease, which can also additionally have an immunologic, genetic, or some other basis. The FSGS recurrence is related to negative graft survival
Risk factors for recurrence include the following factors
1-early onset of nephrotic syndrome
2- rapid progression to ESRD (<3 years)
3- mesangial hyperplasia mentioned on histopathology
4-white and Asian recipient race
5- recurrence in a previous transplant
African-American recipients appear to be at lower risk for recurrence
Choice of a living donor or deceased donor has not been associated with disease recurrence
Several genetic form offers have been described and involve genes encoding proteins necessary for normal glomerular basement membrane structure and/or podocyte function
FSGS due to genetic causes like mutations of NPHS1 (nephrin), NPHS2 (podocin), TRPC6, alpha-actinin-4, and WT-1, may account for a significant proportion of patients with steroid-resistant disease
Though the risk of recurrence disease in genetic or familial FSGS is considered to be low, this may depend on the specific mutation.
patients with FSGS have a significantly lower graft survival.the 5-year graft survival of 81% in FSGS recipients vs. 88% in non-FSGS recipients.
In pediatric patients, the difference in the transplant outcome is even more pronounced with 68% 5-year graft survival in FSGS recipients compared to 93% in non-FSGS recipients.
FSGS recurrence can be fulminant with nephrotic-range proteinuria performing hours to days after transplantation. Most commonly, recurrence takes place with in the first 2 years after kidney transplantation
For patients with FSGS, disease recurrence is a strong predictor of graft outcome.
The 5-year graft survival in patients with FSGS recurrence is 52% compared to 83% in patients without FSGS recurrence. Recurrence leads to graft loss in half of the patients within 5 years and the majority of graft losses occur during the first 2 years after disease recurrence
The incidence of delayed graft function is also higher in FSGS patients with disease recurrence if compared to patients without recurrence and patients with FSGS recurrence experience significantly more biopsy-proven acute rejections than patients without recurrence
Reference
1–Gabriel M. Danovitch, MD. Handbook of Kidney Transplantation. SIXTH EDITION.
2-Hung Do Nguyen, Rebecca Lucy Williams, Germaine Wong and Wai Hon Lim. The Evolution of HLA-Matching in Kidney Transplantation. http://dx.doi.org/10.5772/54747.
3-Rubin Zhang. Donor-Specific Antibodies in Kidney Transplant Recipients. Clin J Am Soc Nephrol 13: 182–192, 2018. doi: https://doi.org/10.2215/CJN.00700117
4–Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9 Suppl 3:S1.
5- Katrin Kienzl-Wagner1, Siegfried Waldegger2 and Stefan Schneeberger1*.Disease Recurrence—The Sword of Damocles in Kidney Transplantation for Primary Focal Segmental Glomerulosclerosis.
published: 17 July 2019 doi: 10.3389/fimmu.2019.01669.
That is a wonderful reply. It is very well structured. I like that you have supported your arguments by uploading scientific evidence.
Ajay
Thank you Prof.
This report is a HLA typing report of a young recipient and a deceased donor with ABO compatible (recipient B while donor is universal with negative blood group) kidney donation,
The report showed locus
HLA A split mismatch 1, B. 1, C.1 broad mismatch,
HLA DRB1. 1, DQA1 broad mismatch, DQB1.
So overall split mismatch111, while broad 110.
The crossmatch is negative for donor specific antigen. On the basis of HLA report this would be a good donation and on risk stratification its standard.
Split antigen mean those antigen present on cell surface and has more refined or specific reaction related to broad. Every HLA loci has 2 Antigens and any split mismatch may worsen the prognosis of allograft function. The split antigen is more specific than broad Ag, and may activate de novo antibodies against donor.
What is the impact of split mismatch on graft survival.
Its more advanced technique to study HLA typing, split antigen mean those antigen present on cell surface and has more refined or specific reaction related to broad.
A article published in PUBMED showed greater advantage for split match, in this article the difference between graft having 0 mismatch was 31% when antigen splits were analyzed while, it was 6% with broad antigens. on the bases of evidence and literature split antigen is more specific and has better approach in real life solid organ transplantation, associated with more risk of developing antibodies against graft.
Donor specific antigen is DE NOVO or preexisting both has adverse effect on allograft survival, because DSA is the basic test before proceeding to transplantation, depends the presence of DSA mild, moderate or sever.
Accordingly to the level will be needing desensitization.
A positive DSA level will impact the prognosis of allograft and ABMR formation. If preexisting hyper-acute and acute, if de novo chronic ABMR.
Yes,
Patient primary disease was FSGS which has around 20% to 60% recurrence post transplantation. there is increased risk of recurrence if associated APOLI, HLA DR53, hypertension, I would suggest for plasmapheresis and rituximab then will proceed for transplantation.
ABO compatible,
Good match with broad 110, and split 111,
DSA negative,
Yes I will proceed for transplantation with standard immunosuppression protocol and induction with beciliximab.
Currently the best immunosuppression protocol being followed by BTS and KDOQI guidelines is, depends on risk stratification, while in this patient this has standard risk so according to guidelines induction with two doses of BECILIXIMAB 20MG on day 0 and day 4, Methylprednisolone 250 to 500mg OD for three days then, maitianence immunosuppression is with tacrolimus 0.1mg/kg, mycophenolate mofetil 30mg/kg or 1gram twice a day. prednisolone on day third initially 60mg split dose then taper to 5 mg.
Wait for another suitable match.
There is high risk of recurrence rate with 60% of graft loss. There is increased risk of graft dysfunction with second and third transplantation, overall the prognosis of primary FSGS post transplantation is not good.
That is a wonderful reply. It is very well structured. However, I wish you could have supported your arguments by uploading scientific evidence.
Ajay
Thank you Habid,a very good start but
An allternative option will be PKE rather than wait for a better match.
Pretransplant PX and Retuximab is not a standard procedure.
Comment on the report:
Age is suitable between donor and recipient.
Donor has blood group O can give the recipient
HLA mismatch fr broad Ag is 110 while for split Ag is 111 with no DSA and negative flow cytometry cross match.
Comment on the difference between the broad and the split mismatch:
Abroad antigens is less specific and can be divided into 2 or more split antigen which are more specific.
HLA B5 can be divided into HLA B 51 and B52
What is the impact of split mismatch on graft survival?
Split antigen mismatch associated with poor graft function leading to graft failure, while matching of split antigens is associated with better graft survival and outcomes.
Explain how the presence of DSA influences graft survival would.
DSA are antibodies which are directed to the HLA antigens of the donor, and can be preformed occurring before transplantation due to previous transplant, pregnancy or blood transfusion and can be denote which occur post transplant due to increased HLA mismatch, non adherence to immunosuppressants or inadequate immunosuppressant or graft inflammation due infection or ischemia
Presence of DSA is considered to be poor prognostic markers as the graft is susceptible to acute antibody mediated rejection , graft dysfunction
Will you proceed with the transplantation?
Yes, I will proceed
Immunosuppressive medication:
It is considered low immunological risk ( no DSA and negative cross match )
Induction: basiliximab
Maintenance :
Triple therapy with tac based
If no?
Wait for another more suitable donor
Impact of FSGS on the graft survival?
FSGS can reoccur post transplant either early or late and associated with poor graft survival
Risk factors for recurrence:
-Rapid progression to ESRD
-Recurrence in the previous transplant
-white recipient
-steroid resistant type
FSGS has high incidence of DGF
Also survival of patient with FSGS is lower than individuals without FSGS .
In case of recurrence, 5 years survival is about 51% compared to non recurrence which is 83%
Comment on the report.
ABO compatible, mismatch is 110, but if we consider split antigen then its 111 mismatch. Crossmatch is negative and there are no DSA.
Comment on the difference between the broad and the split mismatch.
Split antigen is specific cell surface reaction compared to a broad antigen.
What is the impact of split mismatch on graft survival?
Split antigen mismatch results in poor graft outcome.
Explain how the presence of DSA influences graft survival?
Presence of DSA increases the risk of acute rejection.
Will you proceed with the transplantation?
Yes
If yes, what is your immunosuppression protocol?
As this patient is low immunological risk so basiliximab and methyl prednisolone for induction. and then TAC,MMF and prednisolone.
If not, what are the other options?
Paired kidney donation
Another donor
What is the impact of the primary disease on graft survival in the indexed case?
As the risk of FSGS recurrence is 40-80% so monitoring is mandatory.
Short and precise reply. I wish you could have supported your arguments by uploading scientific evidence.Paired or pooled donation is applicable ONLY in living donor operation, not in cadaveric organ donation.
Ajay
ABO compatible, 110 mismatch, negative crossmatch, no DSA
Split mismatch have negative impact on graft survival.
Presence of DSA is associated with associated with acute rejection and de novo DSA is associated with chronic antibody mediated rejection.
Yes, I will proceed for transplantation.
Immunosupressive protocol:
Baciliximab and methyle prednisolon induction
Tacrolimus, prednisolon, MMF
Other options
Paired kidney donation
Primary FSGS can recur in transplant recipient, so need to monitor.
Short and precise reply. I wish you could have supported your arguments by uploading scientific evidence.Paired or pooled donation is applicable ONLY in living donor operation, not in cadaveric organ donation.
Ajay
Comments on the reports
ABO-compatible donor group O+ while the recipient is group B+
HLA mismatch is 110 with negative cross-match and no DSAs
What is the difference between split and broad mismatch?
The Spilt mismatch is associated with a high risk of developing rejection, it is a more advanced technique to study HLA typing. In this case, the broad HLA is 110, while the split is 111 in DRB1.
The split matching is associated with good graft function.
As we all know that the presence of Positive DSA is associated with a high acute rejection rate. on the other hand,it is not mean that if you have DSA, inevitably, you will have a rejection
in this case, DSA is negative and negative cross-match as well .
Yes, i will proceed with transplantation as he has good matching and negative cross-match as well
i will deal with this patient as low immunological risk and will do induction with basiliximab and methyl predinsolon
then after that will keep him on triple immunosuppression medications (Tac,MMF,Predinsolon)
FSGN is very agressive disease specially the primary type ,this is her second transplant so FSGN recurrence rate is 80% so will need close monitering for disease recurrence .
She may need further managmnet if it is Primary FSGN.
That is a wonderful reply. It is very well structured. However, I wish you could have supported your arguments by uploading scientific evidence.
Ajay
This is an ABO compatible kidney donation from young deceased donor.
HLA 110 MM for split and 111 MM for broad, Flowcytometry crossmatch and DSAs are negative.
The difference between the broad and the split mismatch:
HLA antigen classification has varied throughout time as test improvement has enabled the discovery of previously undetectable antigen variations (split -broad ). Split antigens are more specific than broad antigens.
Impact of split mismatch on graft survival
Multiple studies have demonstrated that mismatched HLA antigens have a negative effect on graft outcome, resulting in higher rates of rejection (ABMR) and graft loss. Furthermore, transplant recipients who were typed on splits for class I had better outcomes with zero mismatches compared to those who were typed with broad.Studies from multiple transplant centers demonstrate the potential advantages of split antigen typing over broad.
How the presence of DSA influences graft survival
It is widely established that the presence of preexisting DSAs will result in acute rejection and that the presence of De novo DSAs with ABMR will result in poor graft survival. It is also crucial to note that not all DSAs inevitably result in rejection, as this would depend on whether the DSAs are De novo or preexisting, as well as the DSAs’ strength, complement fixation capacity, and subclass of antibodies.
Will you proceed with the transplantation?
This is a low risk transplantation having the following findings:
Immunosuppression protocol:
· Induction : Basiliximab and Pulse Methylprednisolone
· Maintenance :Tacrolimus/MMF/Prednisolone
Risk of primary disease recurrence
Primary FSGS is more aggressive and has a higher probability of recurrence than secondary disease.
Up to 40%, 80%, and 90% FSGS recurrence has been documented in the first, second, and third transplants, respectively.
HLA DR7, DR53, and DQ2 are related with an increased risk of FSGS recurrence, but HLA DQ7 is associated with a decreased risk of recurrence.
Among the risk factors for FSGS recurrence are obesity, black race, and living donor. Repeated occurrence
That is a wonderful reply. It is very well structured. However, I wish you could have supported your arguments by uploading scientific evidence.
Ajay
The HLA typing showed 2 HLA A antigens with one mismatch 02, 31 vs 02,03, HLA B one mismatch 40, 40 vs 07,40 with one mismatch. and DR antigen is DRB1, DRB5 vs DRB 1 and DRB5 therefore result of mismatching is 110. However, when Split antigen is recognized situation will be different as on split antigens level it will be DRB1 04, 15 vs 04, 16 and DRB5 01,03 vs 01, 03 which is representing one split antigen mismatch, therefore HLA typing with consideration of split antigen would reflect 111 mismatches. B and T lymphocytes Flow cytometry cross match was negative from 2017 until 2020 on 5 testing. And testing for Donor specific antibodies was negative.
Split HLA antigen mismatch:
Was associated with adverse allograft outcome as it might trigger robust production of de novo donor specific antibodies DSA.
DSA impact on allograft survival:
Development of de novo DSAs is related to adverse allograft outcome as its provoked by the level of HLA mismatch particularly HLA DR mismatch. Similarly, complement fixing DSAs are inherently related to worse allograft than the non-complement fixing DSAs. DSAs against MHA type 1 are related to higher incidence of acute rejection events, on the other hand, DSAs against type 2 MHA is linked to Chronic deterioration of allograft function with Chronic changes of antibody mediated rejection. IgG 1 and IgG 3 are associated with higher incidence of acute ABMR than IgG2 and Ig4 who associated with chronic ABMR.
Nonadherence to anti-rejection therapy is a prominent risk factor for development of DSAs.
Selection of Donor:
I would proceed with this donor as FCXM is negative, with no DSAs and 111 HLA mismatch. however, I would advocate induction with ATG, and anti-rejection protocol based on Tacrolimus mycophenolate and prednisolon , I would maintain Tac trough level around 8-10 for the first 3 month with monitoring of emergence of DSAs.
FSGS:
There is high risk of recurrence of FSGS post transplantation. Close observation for proteinuria, A prophylactic plasmapheresis protocol might be implemented along with Rituximab.
Reference:
Lucture of Prof. Halawa in Module 2
Thank you Wael your report for DSAs is very good. you will need a recent CM to be sure as the ones in the report is historical.
ABO compatible, the donor group o negative and recipient group b positive
broad mismatch 110 and split mismatch 111
FCXM negative for both Band T lymphocytes and last one on 2020
DSA is not detected.
Split antigens is a specific cell reactions on the surface of broad antigens for example HLA-B5 split in B52 and B51.
split mismatch results in more risk of graft rejection and split matching has better graft survival.
Yes
induction by i.v basiliximab 20mg and methylprednisolone
Triple-maintenance immunosuppression includes TAC, MMF and prednisolone
FSGS has incidence of recurence from 12 to 25%and lead to 60%graft loss
Referenc
Ingulli E, Tejani A (1991) Incidence, treatment and outcome of recurrent focal segmental glomerulosclerosis post-transplantation in 42 allografts in children. A single-center experience. Transplantation 51: 401–405
Thank you Manal more details for FSGS.
1_ The provided report shows ABO compatible couples ( as donor blood group O is a universal donor, while RH blood group is not usually considered in renal transplantation) in addition to 110 mismatch on the level of braoad HLA antigens. Negative cross match and negative DSA.
2. The difference between broad antigens and split antigens depends on the presence of main surface antigens detected by low resolution HLA typing while subtypes detected by high resolution typing.
In our case the broad antigens mismatch is 110, while it is 111 on the level of split antigens as HLA DR B 15 and 16 represents the split antigens of HLA DR 2.
3. Evidence suggests that split antigens may have mild to moderate effect on graft survival and so epitope and eplet matching may provide better outcome but it is costy and not avialble in all labs and health care facilities.
4_ the presence of DSA prior to transplantation (preformed DSA) means previous sensitization of the recipient against the index donor which carries a high risk of hyperacute and early acute ABMR rejection with eventual early graft loss.
It may be related to previous sensitizing agent as blood transfusion.
Presence of DSA requires desensitization prior to transplantation by PEX and rituximab.
However, presence or detection of DSA after transplantation is called Denovo DSA and is related to chronic ABMR
5_ I will proceed to transplantation without need to desensitization.
6_ I will use induction therapy with ATG and then use tacrolimus based tripple maintenance immunosupressives with steroids and MMF.
-use of ATG strong induction is preferred in case of FSGS as it is suggested to decrease the risk of recurrence post transplant although our patient has low immunological risk.
– the evidence is not strong about preemptive PEX to decrease the risk of recurrent FSGS post transplant.
7_ I think it is suitable option and has better prognosis than staying on HD.
Waiting for better matched donor or living donor through paired kidney donation may be another option.
8- The original kidney disease of FSGS causing renal failure at the age excluding genetic form of FSGS.
Mostly it is acquired and if related to circulating permeability factors that carries high risk of recurrence post transplantation.
_ Close monitoring of recurrence by regular ACR for early detection together with allograft biopsy with EM examination for effacement of foot processes .
_early treatment of recurrence with PEX , rituximab can save the graft in 50% of cases.
_ Risk factors for recurrence includes late onset of the disease , cases presented with full blown picture if nephrotic syndrome , rapid progression to ESKD, collapsing variant of FSGS in native kidney biopsy, previous recurrence in transplantation and recurrence is higher among living donor than in deceased donor.
_ risk of recurrence and graft loss in retransplantation accounts for more than 90%.
_About native nephrectomy, it is indicated in case of persistent heavy protinuria prior to transplantation to correct hypoalbuminemia that can lead to graft vessel thrombosis, hypovolemia and graft hypoperfusion in addition to help to judge recurrence of protinuria after transplantation.
Thank you Mai
can you explain the relation between Tcell ablation and FSGS!
Otherwise well done.
Thanks dear professor
_ we usually use ATG in case of FSGS but after reviewing literature and UpTo date I did not actually find any evidence suggests this and even preemptive plasmapheresis did not decrease the risk of recurrence, however it is effective in treatment of recurrence either alone or with rituximab.
Comment on the report.
Donor O negative, recipient B positive, so ABO compatible
HLA mismatch present, Broad mismatch 210 and Split mismatch 211
DSA negative
Negative cross match for B and T cells
Comment on the difference between the broad and the split mismatch.
A split antigen is more specific in terms of reaction than broad antigen.
What is the impact of split mismatch on graft survival?
Split is more specific and sensitive. Split antigens are important for HLA A and B in comparison to HLA DR.
Split antigen mismatch gives rise to poor graft outcome with more risk of rejection.
Explain how the presence of DSA influences graft survival would.
The presence of antibodies either preformed or de novo increase the risk of antibody mediated rejection. Pre formed DSA is associated with hyper acute or acute ABMR. De novo DSA is usually associated with chronic ABMR.
Will you proceed with the transplantation?
Yes, with caution.
If yes, what is your immunosuppression protocol?
Induction with ATG and maintenance with triple immunosuppression TAC+MMF+Prednisone
If not, what are the other options?
Kidney Paired Donation or Maintenance hemodialysis or CAPD
What is the impact of the primary disease on graft survival in the indexed case?
There is risk of recurrent disease in the graft. Which needs proper counseling and focus on poor prognostic factors.
Thank you Eusha but the correct report is 110 broad,111 split so it is low to moderate risk with no DSAs and negative cross match.
more information is needed for FSGS
1-Comment on the report.
———————————————-
ABO compatible
HLA mismatches are 1 1 0 at broad level and 1 1 1 at split level .
No DSA
Negative FCXM and auto FCXM .
This patient carries low immunological risk, but there is risk of primary disease recurrence .
2-Comment on the difference between the broad and the split mismatch.
——————————————————————————————
split antigen is an antigen that has a more refined or specific cell surface reaction relative to a broad antigen.
3-What is the impact of split mismatch on graft survival?
—————————————————————————–
Worse graft outcome had been found in a recipient with HLA-DR split mismatches . Decreased allograft survival is found in re –transplanted recipients with HLA-DR split mismatches . Also in cadaveric kidney transplantation split mismatches are found to be associated with decreased graft survival .
4-Explain how the presence of DSA influences graft survival would.
———————————————————————————————–
Preformed donor-specific antibodies in sensitized patients can trigger hyperacute rejection, accelerated acute rejection, and early acute antibody-mediated rejection. De novo donor-specific antibodies are associated with late acute antibody-mediated rejection, chronic antibody-mediated rejection, and transplant glomerulopathy.
5-Will you proceed with the transplantation?
———————————————————————————-
Yes
6-If yes, what is your immunosuppression protocol?
———————————————————————————–
Basilixmab as an induction therapy and maintenance triple TAC
7-If not, what are the other options?
————————————————————————
Paired kidney donation
8-What is the impact of the primary disease on graft survival in the indexed case?
—————————————————————————————————-
The reported recurrence rate of FSGS after kidney transplant is 10-56% . Genetic testing should be performed in a young kidney transplant candidate and those with steroid resistant .
REFERENCE;
1-Analysis of HLA-DR split-specificity matching in cadaver kidney transplantation ;a report of the collaborative transplant study ,G Oplelz et al ,Transplantation,1997.
2- Dantal J, Baatard R, Hourmant M, et al. Recurrent nephrotic syndrome following renal transplantation in patients with focal glomerulosclerosis. A one-center study of plasma exchange effects. Transplantation. 1991; 52: 827-831.
3-https://www.ncbi.nlm.nih.gov › articles R Zhang · 2018 Presence of preformed DSAs directly affects the transplant decision making. Kidney transplant should not
Thankyou , but you need to clarify:
Difference in recurrence between Primary and Genetic types of FSGS as they are diff. types.
If it is proved to be a genetic type what is the precaution against a related donation.
Comment on the report
Young age DD with blood group o -ve which is universal donor so compatible ABO Rh
HLA broad antigen 110 mismatch
HLA split antigen 111 mismatch
Old date at 2020 FCXM which is negative for both T & B cells
DSA negative
>>> acceptable such DD
Comment on the difference between the broad and the split mismatch
Split antigen more refined and /or specific cell surface reaction relative to a broad antigen
What is the impact of split mismatch on graft survival?
Split antigen considered as better transplant outcome than matching for broad HLA antigens, typing for HLA antigen splits is important in renal transplantation, that the potential benefit of HLA matching in renal transplantation is greater than currently accepted, and that HLA typing and kidney allocation routines must be refined in order to exploit this potential.
Explain how the presence of DSA influences graft survival would
Donor-specific anti-HLA antibodies (DSAs) detected by cell-based cytotoxicity assays are considered an absolute contraindication to transplantation because of their propensity to cause hyperacute rejection ,antibody-mediated rejection (ABMR) and reduced graft survival.
Will you proceed with the transplantation?
Yes , I will .
If yes, what is your immunosuppression protocol?
We will consider induction immunosuppressive medication such as IV basiliximab 20 mg intraoperatively in combination with IV methylprednisolone (7 mg/kg), and 20 mg on postoperative day 4.
Then with maintenance immunosuppressive therapy of tacrolimus,steroids and and mycophenolate mofetil.
If not, what are the other options?
paired kidney donation program.
What is the impact of the primary disease on graft survival in the indexed case?
Recipients known to have primary FSGS have a high incidence of recurrence after transplantation, reported between 20% and 40%.
The odds of recurrence are increased in patients who are younger,those with a history of heavy proteinuria and clinical nephrotic syndrome, those who had a rapid progression to ESKD, those with the collapsing variant, and those whose showed mesangial hypertrophy in initial biopsy .
The strongest predictor of recurrence is a history of recurrence in a previous transplant.
Patients should be forewarned of the possibility of recurrence.
If a living donor is being considered, both the transplant candidate and the potential donor should be aware of the risk for graft loss from recurrent FSGS.
Plasma exchange before transplantation and in the early posttransplantation period has been suggested to reduce the risk for recurrent disease, but its effectiveness has been difficult to prove. Rituximab, abatacept, and Belatacept have been used as part of immunosuppression to prevent or treat FSGS but their results are less than satisfactory.
Some patients with FSGS continue to have heavy proteinuria (more than 10 g daily) while on dialysis. In these cases, native kidney nephrectomy may be indicated both for nutritional consideration and because persistent massive native kidney proteinuria makes the evaluation of post-transplant proteinuria very difficult.
Reference
Importance of HLA antigen splits for kidney transplant matching
G Opelz 1
Affiliations expand
Uptodate Kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing
Uptodate Kidney transplantation in adults: Induction immunosuppressive therapy
SIXTH EDITION Handbook of Kidney Transplantation
Well done Hoda.
1. A 31-year-old CKD 5 patient due to FSGS received a kidney offer from a deceased 29-year-old donor.
· Comment on the report
ABO compatible – the donor is blood group O hence a universal donor, Rhesus status does not matter in kidney transplantation
HLA match – 111 (A, B, DR)
Flow cytometry crossmatch – negative T cell and negative B cell
DSA – not detected
· Comment on the difference between the broad and the split mismatch.
A split antigen has a more specific cell surface reaction compared to a broad antigen.
· What is the impact of split mismatch on graft survival?
The difference between graft survival among transplants typed for split antigens is greater compared to transplants typed for broad antigens i.e., there is a greater advantage of matching for antigen splits in terms of graft survival. This indicates that typing for HLA antigen splits is important in kidney transplantation. (1)
· Explain how the presence of DSA influences graft survival.
Presence of DSA is strongly associated with increased graft loss due to an increased risk of antibody mediated rejection and an accelerated decline in kidney function. (2, 3)
· Will you proceed with the transplantation?
Yes, I would – ABO compatible, acceptable HLA match, negative FCXM, negative DSA.
· If yes, what is your immunosuppression protocol?
From the information provided, the potential kidney transplant recipient seems to have a low immunologic risk. The preferred immunosuppression protocol would entail: –
o Induction immunosuppression with IL-2R antagonist (Basiliximab) and
o Maintenance immunosuppression with a CNI (preferably Tacrolimus), an antiproliferative agent with or without corticosteroids. (4)
· If not, what are the other options?
Kidney paired exchange donation program or source for a living donor.
· What is the impact of the primary disease on graft survival in the indexed case?
Risk of disease recurrence is a major stumbling block in kidney transplantation among patients with primary FSGS. It is associated with poor graft outcomes and a five-fold increased risk of graft loss. Recurrent FSGS affects almost two-thirds of first kidney grafts and almost 80% of patients who lost their first graft because of recurrent FSGS. Regrettably, patients with FSGS have an inferior graft survival compared to their non-FSGS counterparts – with a 5year graft survival of 81% among FSGS recipients against 88% in the non-FSGS patients. Older age at onset of primary FSGS, white race, lower BMI at transplant and native kidney nephrectomy have been associated with an increased risk of recurrence. Such patients require close monitoring of proteinuria, immediate and aggressive treatment for recurrence. Treatment with plasmapheresis ± rituximab results in partial or complete remission in 57% of patients with recurrent FSGS. (5, 6)
References
1. Opelz G. IMPORTANCE OF HLA ANTIGEN SPLITS FOR KIDNEY TRANSPLANT MATCHING. The Lancet. 1988 1988/07/09/;332(8602):61-4.
2. Lefaucheur C, Suberbielle-Boissel C, Hill GS, Nochy D, Andrade J, Antoine C, et al. Clinical relevance of preformed HLA donor-specific antibodies in kidney transplantation. Contributions to nephrology. 2009;162:1-12. PubMed PMID: 19001809. Epub 2008/11/13. eng.
3. Frischknecht L, Deng Y, Wehmeier C, de Rougemont O, Villard J, Ferrari-Lacraz S, et al. The impact of pre-transplant donor specific antibodies on the outcome of kidney transplantation – Data from the Swiss transplant cohort study. Frontiers in immunology. 2022;13:1005790. PubMed PMID: 36211367. Pubmed Central PMCID: PMC9532952. Epub 2022/10/11. eng.
4. KDIGO clinical practice guideline for the care of kidney transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009 Nov;9 Suppl 3:S1-155. PubMed PMID: 19845597. Epub 2009/10/23. eng.
5. Kienzl-Wagner K, Waldegger S, Schneeberger S. Disease Recurrence-The Sword of Damocles in Kidney Transplantation for Primary Focal Segmental Glomerulosclerosis. Frontiers in immunology. 2019;10:1669. PubMed PMID: 31379860. Pubmed Central PMCID: PMC6652209. Epub 2019/08/06. eng.
6. Uffing A, Pérez-Sáez MJ, Mazzali M, Manfro RC, Bauer AC, de Sottomaior Drumond F, et al. Recurrence of FSGS after Kidney Transplantation in Adults. Clinical journal of the American Society of Nephrology : CJASN. 2020 Feb 7;15(2):247-56. PubMed PMID: 31974287. Pubmed Central PMCID: PMC7015092. Epub 2020/01/25. eng.
Once FSGS recurs in allograft, it is much more likely to happen in subsequent transplants with increasing probability.
We had third transplant patient many years ago. After a very good urine output for 3 days, the recurrence of FSGS was so dramatic that we were contemplating vascular cause of allograft dysfunction.
1- Young age 29 years old deceased donor for 31 patient with FSGS as original disease, with compatible ABO, the donor was O negative, with good HLA match (111 mismatch), negative FCXM from 2017 to 2020, and no DSA was present.
2- Difference between split and broad mismatch:
Split HLA antigens is the detailed analysis of the broad antigens, we can depends on the split antigens more than broad one in determining HLA mismatch for better graft survival and outcome.
3- Graft survival and outcome is better with split antigen analysis than broad one.
4- Presence of DSA negatively affect graft outcome as it increased risk of antibody mediated rejection, in presence or absence of anti-HLA antibody, also it causes graft loss, but not affecting patient survival itself.
5- Yes I will proceed for transplantation
6- The protocol; it is low immunological risk, induction by basiliximab and maintained on tacrolimus, MMF, and prednisolone.
7- If not, will proceed for paired kidney donation program.
8- It is poor outcome than other causes of end stage renal disease, because of high risk of recurrence of FSGS in the graft reach 15-40% in pediatric patients and can reach 60% in the adult.
references:
1- G Opelz. Importance of HLA antigen splits for kidney transplant matching. Lancet. 1988 Jul 9;2(8602):61-4.
2- Lukas Frischknecht , Yun Deng , Caroline Wehmeier, Olivier de Rougemont, Jean Villard, Sylvie Ferrari-Lacraz , et al. The impact of pre-transplant donor specific antibodies on the outcome of kidney transplantation – Data from the Swiss transplant cohort study. Front. Immunol., 21 September 2022 Sec. Alloimmunity and Transplantation. Volume 13 – 2022.
3-Anna Francis, Peter Trnka, Steven J. McTaggart. Long-Term Outcome of Kidney Transplantation in Recipients with Focal Segmental Glomerulosclerosis. Clin J Am Soc Nephrol. 2016 Nov 7; 11(11): 2041–2046.
Thankyou Riham but it is 110 for broad,youa are right for splits.
Need more information about DSAs
Risk factors for FSGS recurrence.
A 31-year-old CKD 5 patient due to FSGS received a kidney offer from a deceased 29-year-old donor
Report of the patient
Ø Comptable blood group donor o –ve and recipient Bpositive
Ø HlA :111(A,B,DR)
Ø Negative final cross match
Ø No DSA.
The difference between the broad and the split mismatch:
HLA antigen classification have evolved over time as assay development has allowed the detection of differences in antigens (split category) that were previously un distinguishable (broad category ).
Split is more specific relative to a broad antigen
The impact of split mismatch on graft survival:
Split specificity mismatch had astrong impact on graft out come transplants that changes from 0 to a 1 mismatch had a significantly lower graft survival than transplant with no mismatch by both the broad and split definition
The presence of DSA influences graft survival would
Donor-Specific Antibodies
The presence of donor-specific antibody ([DSA], is known to be associated with poorer allograft survival. The incidence of de novo DSA in the first year after transplant is reported to be around 2%, but increases to 10% at 5 years and approximately 20% at 10 years. Its development has prognostic significance, especially if it is associated with graft dysfunction or proteinuria. Although many patients with DSA will suffer from AMR, not all DSA is considered ―equal‖ and some patients with DSA do not have graft dysfunction or signs of antibody-mediated injury on biopsy Patients who have complement-binding DSA, as detected by a C1q-binding assay, are more likely to have lesions of AMR on protocol biopsy. DSA IgG subclass may discriminate between those who have an acute or subclinical AMR with the presence of IgG3 and IgG4 DSA subclasses having a positive predictive value of 100% to identify antibody-mediated injury
Will you proceed with the transplantation:
Yes
Immunosuppression protocol:
Induction :
ATG and Pulse Methyl Predisilone
Mantenace :
Tacrolimus
MMF predisolone
What is the impact of the primary disease on graft survival in the indexed case?
Ø The incidence of recurrent about 20 to 40%
Ø Secondary type not recurrent ,but it common in primary type .
Ø Risk factors :
Ø History of heavy proteinuria
Ø Clinical nephrotic syndrome,
Ø Rapid progression to ESKD
Ø Collapsing variant, and those whose initial biopsy showed mesangial hypertrophy.
Ø History of recurrence in a previous transplant
Refernces :
1-Formica R. Allocating deceased donor kidneys to sensitized candidates. Clin J Am Soc Nephrol 2016;11:377–378.
2-Gebel H, Kasiske B, Gustafson S, et al. Allocating deceased donor kidneys to candidates with high panel reactive antibodies. Clin J Am Soc Nephrol 2016;11:505–511
.
3-Hall E, Massie A, Wang J, et al. Effect of eliminating priority points for HLA-B matching on racial disparities in kidney transplant rates. Am J Kidney Dis 2011;58:813–816
.
4-Leichtman A. Improving the allocation system for deceased-donor kidneys. N Engl J Med 2011;364:1287–1289.
5-Massie A, Luo X, Lonze B, et al. Early changes in kidney distribution under the new allocation system. J Am Soc Nephrol 2016;27(8):2495–2501.
6-Stewart D, Kucheryavaya A, Klassen D, et al. Changes in deceased donor kidney transplantation one year after KAS implementation. Am J Transplant 2016;16(6):1834–1847.
7-Stewart D, Garcia V, Rosendale J, et al. Diagnosing the decades-long rise in the deceased donor kidney discard rate in the US [published online ahead of print October 19, 2016]. Transplantation. doi:10.1097/TP.0000000000001539
Dear All
Anyone has a question on this area or shall we move to another case?
1- Comment on the report.
Since donor is O negative and recipient is B positive, so this is blood grouping is acceptable.
HLA broad mismatch 110 and split 111
Negative T and B cell FXCM indicate lack of DSA against HLA class I and II
No DSA
2– Comment on the difference between the broad and the split mismatch
Broad serologic typing evolution to more specific typing which is split typing lead to recognition of new MHC molecules that split the existing antigens, because the immune system recognizes MHC molecules in an overlapping manner ,thereby Ab against a specific HLA antigen can recognize other MHC molecules with same sequence motifs (public epitopes) and producing Ab against it . Cross-reactive group (CREG) with same antigens contain shared amino acids. Multiple antigens have more than a single public determinant and belong to more than a CREG(1).
Matching for broad antigens increases the probability of detecting HLA-matched recipients for a donor .
Split HLA matching results in better transplant outcome than matching for Broad HLA antigens .
Split antigen matching seems to be more clinically significant for HLA-A and-B antigens than for HLA-DR antigens.
For the current case The broad match of HLADR 2 is split HLADR15 and HLA DR 16. (2).
3- What is the impact of split mismatch on graft survival?
Split mismatches for HLA-A and HLA-B locus (matching for HLA class I antigens) improved graft survival also in spite that HLA-DR split crossmatching does not have and important effect on first transplants, they have an important effect on retransplant survival (3).
4- Explain how the presence of DSA influences graft survival would.
Pretransplant DSA is associated with AMR, leading to graft loss in low-risk renal patients transplanted with a negative CDC crossmatch specially if their level remained high after transplantation (4).
5- Will you proceed with the transplantation
yes
6- If yes, what is your immunosuppression protocol?
Current case has low immunological risk so Induction with Basilimab , maintenance MMF ,Tacrolimus and, prednisolone can be the protocol.
7- If not, what are the other options?
Kidney paired program
Await more compatible donor
8- What is the impact of the primary disease on graft survival in the indexed case?
FSGS has worse transplant outcomes than other ESRD causes , due to disease recurrence in the transplanted kidney occurring early post transplant with cases having heavy proteinuria
Idiopathic FSGS recurs post-transplant in one third of cases and is associated with a five-fold higher risk of graft loss.
FSGS recurrence risk factors include race higher in white race and less in black , steroid responsiveness, and donor age over 40 which is not present in our case ,BMI (5).
Graft survival for cases with primary FSGS was significantly better for Living Donors versus Deceased donors’ grafts (6).
Reference
1- Gao Y, Twigg AR, Hirose R, et al. Association of HLA Antigen Mismatch With Risk of Developing Skin Cancer After Solid-Organ Transplant. JAMA Dermatol. 2019;155(3):307–314
2-Nguyen, Hung et al. “The Evolution of HLA-Matching in Kidney Transplantation” In Current Issues and Future Direction in Kidney Transplantation, edited by Thomas Rath. London: Intech Open, 2013. 10.5772/54747
3-Opelz, Gerhard1; Scherer, Sabine; Mytilineos, Joannis. ANALYSIS OF HLA-DR SPLIT- SPECIFICITY MATCHING IN CADAVER KIDNEY TRANSPLANTATION: A Report of the Collaborative Transplant Study. Transplantation 63(1):p 57-59, January 15, 1997.
4- David-Neto E, Souza PS, Panajotopoulos N, Rodrigues H, Ventura CG, David DSR, et al. The impact of pretransplant donor-specific antibodies on graft outcome in renal transplantation: a six-year follow-up study. Clinics. 2012;67(4):355-361.
5- Uffing A, Pérez-Sáez MJ, Mazzali M, et al. Recurrence of FSGS after Kidney Transplantation in Adults. Clin J Am Soc Nephrol. 2020;15(2):247-256.
6-Francis A, Trnka P, McTaggart SJ. Long-Term Outcome of Kidney Transplantation in Recipients with Focal Segmental Glomerulosclerosis. Clin J Am Soc Nephrol. 2016;11(11):2041-2046.
Thank you Dr Doaa Elwasly
Some reports look conflicting with others for instance ref 5 suggest recurrence risk is higher in white race whilst ref 6 suggests the opposite. Graft survival for cases with primary FSGS was significantly better for Living Donors versus Deceased donors’ graft. You did not highlight the fact that recurrence risk was higher in live donor cases compared to deceased.
Overall the most important predictor is previous recurrence in a transplanted kidney which is the most strong predictor for second recurrence.
Yes previous recurrence is an important risk factor
1.COMMENT ON THE REPORT;
-The pair is ABO compatible ; Donor is O neg with recipient Being B pos.
-HLA is 110 mismatch for Broad and 111 mismatch for split.(DR15 and DR16 are split antigens of DR2 in our scenario}
-No DSA.
-Serial FCM XM is negative for both T and B cells.
2.COMMENT ON THE DIFFERENCE BETWEEN BROAD AND SPLIT MISMATCH.
-A split antigen has more specificity in terms of reaction relative to a broad antigen(DR15 and DR16 are split antigens of DR2 in our scenario}.
3.WHAT IS THE IMPACT OF SPLIT MISMATCH ON GRAFT SURVIVAL?
-Split antigens are vital for HLA A and B in comparison to HLA DR and would greatly improve outcome if done in re-transplanted cases.
-Split antigens mismatches have poor graft outcomes with more risk of rejection.[1}
4.HOW DOES DSA INFLUENCE GRAFT SURVIVAL?
-Pre formed DSA increase the risk of rejection through humoral mechanism.{2}Pre formed DSA is associated with hype acute, accelerated acute and early acute ABMR. De novo DSA is linked to late acute ABMR, Chronic ABMR and transplant glomerulopathy.
-Risk factors to preformed DSA ; Pregnancy, Prior blood transfusion or transplantation etc
5.WILL YOU PROCEED WITH TRANPLANT?
-Yes, Factors to in favor of transplantation; ABO compatibility, No DSA,FCXM negative for B and T cells.
6.IMMUNOSUPPRESION PROTOCOL.
-Low immunological risk, Induce with Basiliximab ,Maintain with triple regimen ; TAC/MMF/PDL
7.OTHER OPTIONS;
-Maintain RRT – HD/PD
-Paired exchange Program.
8.IMPACT OF PRIMARY DISEASE ON GRAFT SURVIVAL.
-Primary FSGS has more risk of recurrence compared to secondary and is more aggressive.
-FSGS recurrence has been reported up to 40 % ,80% and 90% in 1st, 2nd and 3rd transplant respectively.{3}
-HLA DR7,DR53 and DQ2 increase risk of FSGS recurrence while HLA DQ7 has been associated with less risk of recurrence.
-Some of the risk factors for recurrence of FSGS include;
a. Obesity and prior native nephrectomy are associated with upto x5 risk of recurrence.
b. Blacks .> Whites.{4}
c. Living > Deceased donor.
d. Previous recurrence > No recurrence.
-Follow up UPCR is frequently done to monitor recurrence post transplant.
REFERENCES;
1.Opelz,Gerhard1 et al ; Analysis of HLA DR split specificity matching in cadaver kidney transplantation.63(1);P 57-59,1997
2.Michael G.H,Betjes et al; Pre transplant Donor Specific Anti HLA antibodies and risk for rejection related graft failure of kidney allografts, Journal of transplantation ,Vol 2020
3.Uffing A,Leonardo V et al ; Recurrence of FSGS after kidney transplantation in adults;CJASN.2020 Feb 7;15(2);247-256
4.Abott KC,Oliver JD et al;Graft loss due to recurrent FSGS in renal transplantation recipients in United states.AMJ Kidney Dis 2001;37;366
well done, very good start.
Thank you Prof.
Comment on the report.
Donor O negative, recipient B positive – ABO compatible
HLA mismatch present (Broad 210 / Split 211)
There is no antibody against the donor (DSA negative)
Negative crossmatches for B and T cells
Comment on the difference between the broad and the split mismatch.
The split antigens are more specific, being able to differentiate the B1*15 and 16 antigens as a mismatch DR, and not B
What is the impact of split mismatch on graft survival?
Split is more specific and sensitive, being able to correlate risk factors. Mismatch DR is more related to B lymphocytes, activated T lymphocytes and antigen-presenting cells. HLA DR mismatch is a poor prognostic sign and increases the risk of osteoporosis, hospitalization for infections, and late post-transplantation complications.
Explain how the presence of DSA influences graft survival would.
The presence of antibodies increases the risk of antibody rejection, with specific interventions for its prevention (patient desensitization) or for treatment (acute or late antibody-mediated rejection).
Will you proceed with the transplantation?
Yes
If yes, what is your immunosuppression protocol?
rATG induction and triple immunosuppression TAC+MMF+Prednisone
If not, what are the other options?
Kidney Paired Donation
What is the impact of the primary disease on graft survival in the indexed case?
FSGS can evolve with rapid progression, especially in young people, when there is the recurrence of a previous event, and usually evolves with a collapsing variant and hyperplasia/hypertrophy of epithelial cells.
Both the donor and the recipient must be informed of the risk of the disease recurring and the increased chance of graft loss.
Thankyou Philip,
The correct match is BROAD 110
SPLIT111
probably print mistake.
mismatch relation to osteoporosis???
This is a moderate risk, no DSAs, negative crossmatch though historic and needs to be updated,so Basiliximab is a good choice.
Thank you, Professor
We do not have Basiliximab in Brazil, which is why I did not comment about it.
▪︎Comment on the report.
-The recipient is Blood group B and the donor is BG O, so they are ABO compatible. – HLA mismatches at ABRD is 1.1.0 at the level of the broad ( RDB1*15 and 16 which have the the same broad which is DR2), & 1.1.1 at the level of the split antigens.
-There is no DSA
– FCM XM is negative for both B and T cells
▪︎Comment on the difference between the broad and the split mismatch.
– The split antigen is an Ag that has a more or specific cell surface reaction relative to a broad Ag (In our case DRB1*15 & 16 are splits from their broad DR2).
▪︎ What is the impact of split mismatch on graft survival?
– Matching for split HLA antigens results in better outcome when compared to matching for broad antigens.
▪︎ Explain how the presence of DSA influences graft survival
– Preformed DSAs can cause instant hyperacute rejection and graft necrosis, whereas memory B and plasma cell response may trigger an accelerated acute rejection within hours or days of kidney transplant. Preformed DSAs are also responsible for early acute antibody-mediated rejection after transplant [1].
▪︎Will you proceed with the transplantation? Yes
▪︎If yes, what is your immunosuppression protocol?
Induction with Basiliximab and maintenance with prednisolone tacrolimus & MMF.
▪︎If not, what are the other options? Paired exchange donation
▪︎ What is the impact of the primary disease on graft survival in the indexed case?
FSGS has been reported as having poorer transplant outcomes than most other causes of ESRD , largely because of disease recurrence in the transplanted kidney [2].
—-‐————-
Ref:
[1] Rubin Zhang. Donor-Specific Antibodies in Kidney Transplant Recipients [2] Long-Term Outcome of Kidney Transplantation in Recipients with Focal Segmental Glomerulosclerosis.
[2] Anna Francis, Peter Trnka, and Steven J. McTaggart Long-Term Outcome of Kidney Transplantation in Recipients with Focal Segmental Glomerulosclerosis Anna Francis, Peter Trnka, and Steven J. McTaggart https://doi.org/10.2215/CJN.03060316
Thankyou but can you explain more details for DSAs,subtypes,Intensity, time of appearance.
Types of FSGS ,risk factors for recurrevne.
ABO compatible
HLA matching is negative
Broad 011 and Split 111
Negative T and B cell
No DSA detected
Split matching is more specific and important marker for good outcome and carry long term successful survival rate but split mismatch carry poor outcome of graft survival. Also split mismatch has more immunological risk on graft.
It’s poor with long term graft survival
It’s carrying high risk of acute antibodies mediated rejection and graft dysfunction and low survival rate.
Yes because transplant better than patients become on dialysis also no DSA detected with ABO compatible
Induction with Basiliximab and maintenance with steroid therapy and tacrolimus and MMF
Transplant allocation system and Paired donor exchange
Recurrence of FSGS is 5 fold post transplant and carry risk of graft loss and common risk of ESRD and manifested by nephrotic range proteinuria.
Serial renal biopsy protocol is important to detect and treat primary recurrence early by rituximab and plasma exchange.
Counselling recipient regarding recurrence.
Thank Dr Sahar Kharraz
Are you sure that broad HLA match is 011 ?
Sorry he is broad match 110
Thank you
Well done
I could not understand 5 fold of what/compared to whom?
Thank you Dr Zahran
Well done
Do you think there is any difference between cPRA and DSA in terms of the rejection risk post transplant?
Why familial cases of FSGS carry small risk of recurrence?
Dear Dr Mohsen,
First, I want to thank Dr Zahran for his outstanding contribution.
Do you think there is any difference between cPRA and DSA in terms of the rejection risk post-transplant?
The cPRA represents the likelihood of positive crossmatch in the national population. It is calculated by comparing the anti-HLA antibodies in the potential recipient serum diagnosed by the single-antigen bead (SAB) assay against the HLA typing of about 10,000 potential donors of the local population. So the cPRA is the likelihood of the patient getting a suitable allograft in a specific population rather than matching with a specified donor.
On the other hand, donor-specific anti-HLA antibody (DSA) represents preformed antibodies against the HLA antigens of a particular donor. The presence of DSA is associated with lower allograft survival compared to recipients without DSA (1).
The outcome of sensitized recipients (with non-DSA alloantibody) remains controversial, as some studies showed negative outcomes (2). In contrast, other studies showed no impact of having non-DSA on graft outcome (1).
Why familial cases of FSGS carry small risk of recurrence?
The mechanisms underlying posttransplant recurrence of genetic FSGS are not well defined (3). However, a possible explanation is that the transplanted kidney has a normal glomerular structure, unlike the original kidney, which had abnormal podocyte or slit diaphragm proteins. In general, the genes involved encode for proteins that are the components of the glomerular filtration barrier (podocytes, glomerular basement membrane [GBM], and the fenestrated capillary endothelium) (3).
References:
1) Caro-Oleas JL, González-Escribano MF, et al. Clinical relevance of HLA donor-specific antibodies detected by single antigen assay in kidney transplantation. Nephrol Dial Transplant. 2012;27(3):1231.
2) Richter R, Süsal C, Köhler S, et al. Pretransplant human leukocyte antigen antibodies detected by single-antigen bead assay are a risk factor for long-term kidney graft loss even in the absence of donor-specific antibodies. Transpl Int. 2016;29(9):988.
3) Fernando C Fervenza, Sanjeev Sethi, Rasheed A Gbadegesin. Focal segmental glomerulosclerosis: Genetic causes. © 2023 UpToDate (accessed on 18 January 2023).
Great Dr AHMED AREF
Do you think there is any difference between pre transplant DSA and de novo post transplant DSA in terms of rejection risk and graft survival?
Dear Dr Mohsen,
Sorry for the late reply,
The denovo DSA has a worse prognosis for transplantation compared to pre-formed DSA in sensitized patients.
References:
1) Wiebe C, Gibson IW, Blydt-Hansen TD, 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.
2) Aubert O, Loupy A, Hidalgo L, et al. Antibody-Mediated Rejection Due to Preexisting versus De Novo Donor-Specific Antibodies in Kidney Allograft Recipients. J Am Soc Nephrol. 2017;28(6):1912.
also, Although idiopathic steroid-resistant NS (SRNS) with familial FSGS pathology is believed to be caused by some circulating factors and is therefore prone to recur after kidney transplantation, most familial FSGS have defective components of the kidneys, particularly podocytes, and therefore their risk of recurrence is low if not zero
Thank you Dr Mohamed Zahran
Familial FSGS less likely to recur because the podocyopathy is caused by genetic mutation in the native kidneys which is corrected by transplanting a kidney with the correct gene.
This explains the recommendation for cases of FSGS in young patients to screen for any genetic defect for a number of reasons:
1- They will not respond to any immunosuppression because the treatment is to correct the genetic defect
2- Less likely for disease recurrence after transplantation because the genetic defect is no longer present in the new transplanted kidney
3- To screen other family members for early disease detection and to avoid donors with the same problem
ABO compatible
FCMXM negative for T and B cell (but old and need to be updated)
HLA mismatch :1:1:0 broad, split:1:1:1
No DSA
Split antigen test a more refined or specific cell surface reaction relative to a broad antigen.(Example: HLA-B51 and HLA-B52 are split antigens of HLA-B5)
higher split HLA matching is associated with better graft survival than those with less split match. this is more profound for HLA-A, B and C. In HLA-DR, it is more significant for re-transplant (Opelz et al,1997)
pre-transplant:
presence of DSA indicates immunological memory to these antigens.
If sufficient DSA are present at the time of transplantation then hyper-acute rejection
(HAR) may occur. More likely is the rapid development of a memory B-cell immune
response → early, severe AMR.
In addition, there will also be a memory T-cell immune response → ↑risk TCMR
post-transplant:
Retrospective and prospectivestudies demonstrate:
• About 20% develop HLA antibodies following transplantation
• The risk of graft loss is ↑3-fold following the development of HLA antibodies.
Oddly, outcomes were similarly poor whether or not the HLA Ab were donor-specific. Only DSA seem to be associated with chronic AMR and transplant glomerulopathy.
low risk: basiliximab induction and maintain on Tacrolimus+MMF+ steroid
maintain on dialysis for better match donor, or paired donation
The recurrence of FSGS following renal transplantation is a significant problem. It is estimated to recur in 20 to 50% of cases.
Primary FSGS, characterised by the nephrotic syndrome, is associated with a high risk of disease recurrence in the transplant, particularly if there is:
end stage renal failure at a young age, particularly during adolescence
rapid progression to end stage renal failure
recurrent disease in a previous transplant
In these situations the rate of graft loss secondary to recurrent disease may be significantly above 50%.
FSGS is not a single entity disease which explains the different reported recurrence rate:
-It could start early < 3 months or late post-transplantation, usually for those with primary or idiopathic disease.
· Consider preventive strategies to reduce the risk of recurrence; plasmapheresis, rituximab.
· Monitoring the recurrence by urine CPR starting immediately on the first day postoperatively. If the proteinuria is significant, allograft biopsy is necessary to confirm FSGS recurrence or other pathology.
Thankyou for mentioning the possible role of the memory lymphocytes.
You can ellaborate more on the subtypes of of DSAs.
Still the issue of pretransplant PX.Rituximab is questionable.
Comment on the report.
Both donor and recipient are ABO compatible as Blood group O is universal donor.
No DSA
FCM XM negative for B and T cells
HLA mismatches- Split antigens- 110 Broad antigens 111
( HLA DR 2 has two splits DR 15 and DR 16)
Comment on the difference between the broad and the split mismatch.
Historically broad antigens were identified , but with advancements in immunology split antigens were identified. Broad antigens can bind with multiple antibodies while split bind only one antibody. For example DR 2 is split into DR 15 and DR 16.
What is the impact of split mismatch on graft survival?
Matching at HLA split level has better outcomes and compared to matching HLA Broad. Split HLA matching is more important for HLA A &B , while less important for HLA DR. It should be considered in those having retransplant
Explain how the presence of DSA influences graft survival would.
Pretransplant DSA can lead to graft loss. The is high incidence of ABMR.
Will you proceed with the transplantation?
Yes as it is low immunological risk. I will use standard immune suppression.
If yes, what is your immunosuppression protocol?
Induction with Basiliximab and triple immune with Tacrolimus, MMF and steroids.
If not, what are the other options?
Paired kidney donation
Long term dialysis
What is the impact of the primary disease on graft survival in the indexed case?
FSGS recurrence after kidney transplant can lead to graft loss. Primary FSGS can recur in graft leading to graft loss. Recurrence rates vary between 20-80 %. Graft survival in FSGS recurrence is 81% at 5 year while it is 88% in Non FSGS recipients. Early recurrence can happen within two weeks with fulminate proteinuria or can occur within two years. Late recurrences are associated with less fatal outcomes. Recipient should be regularly assessed for proteinuria.
Kang HG, Ha IS, Cheong HI. Recurrence and Treatment after Renal Transplantation in Children with FSGS. Biomed Res Int. 2016;2016:6832971.
Thankyou but
BROAD is 110
SPLIT is 111
You need to elaborate more on Ig subtypes of DSAs.
Good START.
Thank you Prof Dawlat. Yes it is 110 Broad and 111 Split. Unfortunately a typo
Comment on the report.
· ABO- compatible as the potential DD is O-ve (universal donor) and the potential recipient is B +ve.
· Rh(D)-incompatibility are not considered for organ matching in solid organ transplantation as it does not exist in non-erythroid cells.
· HLA 110 broad MM and 111 for split MM.
· No DAS.
· Historic FCXM for both B and T cell were negative last was in 2020 need to repeat current FCXM with DSA level.
Comment on the difference between the broad and the split mismatch.
What is the impact of split mismatch on graft survival?
• HLA matching has traditionally been performed at the broad antigen level which may increase the probability of identifying more compatible kidneys for ethnic minorities and highly sensitized transplant candidates.
· Broad Antigen: testing of cell surface antigens, a serological specificity that is poor or broad relative to other specificities and can be defined as 2 or more split antigens.
· Split Antigen: has a more refined or specific cell surface reaction.
· (Example: HLA-B51 and HLA-B52 are split antigens of the HLA-B5 broad antigen).
· Split HLA antigens matching results in better outcome when compared to broad antigens, ad it is more clinically significant for HLA- A and HLA-B when compared to HLA-DR.
· HLA-DR split specificities do not exert a significant influence in first transplants, they have a significant impact on re-transplant survival.
· One study showed; transplants with zero mismatches, as defined both by the broad and split definitions (B=0, S=0), had a graft survival rate of 80±2% at 2 years. When split typing revealed an HLA-DR mismatch (B=0, S=1), the 2-year success rate was 9% lower: 71±4% (log rank, P=0.04)
Explain how the presence of DSA influences graft survival would.
· DSAs have become an established biomarker predicting ABMR.
– ABMR is the leading cause of graft loss after kidney transplant.
· Pre-transplant DSA were associated with a significantly increased risk of ABMR, graft loss, and accelerated eGFR decline.
· Certain characteristics of DSAs have been associated with poor outcomes among patients with ABMR.
· DSA type: (preexisting or de novo), ABMR in patients with a de novo DSA, which is thought to be mostly related to medication non-adherence or inadequate immunosuppression, has been associated with poorer outcomes compared with ABMR in patients with preexisting DSA.
· Complement-binding capacity; at high risk for kidney allograft loss
· Class of DSA: directed at Class I and Class II HLA antigens were strongly associated with increased risk of ABMR, but only DSA directed at Class II associated with graft loss.
· The Ig subclass of DSA; DSAs detected in the first year post-transplant, IgG4 was associated with later allograft injury, increased allograft glomerulopathy, and IFTA. By contrast, IgG3 was associated with a shorter time to rejection, increased microvascular injury, C4d capillary deposition, and graft failure. These findings suggest that IgG subclasses may identify distinct phenotypes of kidney allograft antibody-mediated injury.
· DSA strength MFI
Will you proceed with the transplantation?
Repeat cross match and DSA level before deciding.
Yes, will proceed with Transplantation as:
– The donor and recipient are age matched.
– ABO compatible
– Acceptable HLA match, 0 DR MM
– Cross match is negative and no DSA though need to be repeated.
If yes, what is your immunosuppression protocol?
Basiliximab for induction and triple maintenance therapy (steroid +tacrolimus +MMF).
If not, what are the other options?
Look for better HLA matching living donor or paired exchange.
What is the impact of the primary disease on graft survival in the indexed case?
· FSGS recurrence rate is variable from 17 % up to 60%, the best data obtained from TANGO cohort study, which reported a 32% risk of recurrence.
· It could start early < 3 months or late> 3 months post-transplantation, usually for those with primary or idiopathic disease.
· Consider preventive strategies to reduce the risk of recurrence; plasmapheresis, rituximab.
· Monitoring the recurrence by urine PCR starting immediately on the first day postoperatively. If the proteinuria is significant, allograft biopsy is necessary to confirm FSGS recurrence or other pathology.
References:
– Opelz, Gerhard1; Scherer, Sabine; Mytilineos, Joannis. ANALYSIS OF HLA-DR SPLIT-SPECIFICITY MATCHING IN CADAVER KIDNEY TRANSPLANTATION: A Report of the Collaborative Transplant Study. Transplantation 63(1):p 57-59, January 15, 1997.
– Nguyen, H. D. , Williams, R. L. , Wong, G. , Lim, W. H. . The Evolution of HLA-Matching in Kidney Transplantation. In: Rath, T. , editor. Current Issues and Future Direction in Kidney Transplantation [Internet]. London: IntechOpen; 2013 [cited 2023 Jan 16]. Available from: https://www.intechopen.com/chapters/42879 doi: 10.5772/54747.
– Hata, Yoshinobu2; Cecka, J. Michael3; Takemoto, Steven; Ozawa, Miyuki; Cho, Yong W.; Terasaki, Paul I.. EFFECTS OF CHANGES IN THE CRITERIA FOR NATIONALLY SHARED KIDNEY TRANSPLANTS FOR HLA-MATCHED PATIENTS1. Transplantation 65(2):p 208-212, January 27, 1998.
– Zhang R. Donor-Specific Antibodies in Kidney Transplant Recipients. Clin J Am Soc Nephrol. 2018 Jan 6;13(1):182-192. doi: 10.2215/CJN.00700117. Epub 2017 Apr 26. PMID: 28446536; PMCID: PMC5753302.
– Uffing A, Pérez-Sáez MJ, Mazzali M, Manfro RC, Bauer AC, de Sottomaior Drumond F, O’Shaughnessy MM, Cheng XS, Chin KK, Ventura CG, Agena F, David-Neto E, Mansur JB, Kirsztajn GM, Tedesco-Silva H Jr, Neto GMV, Arias-Cabrales C, Buxeda A, Bugnazet M, Jouve T, Malvezzi P, Akalin E, Alani O, Agrawal N, La Manna G, Comai G, Bini C, Muhsin SA, Riella MC, Hokazono SR, Farouk SS, Haverly M, Mothi SS, Berger SP, Cravedi P, Riella LV. Recurrence of FSGS after Kidney Transplantation in Adults. Clin J Am Soc Nephrol. 2020 Feb 7;15(2):247-256. doi: 10.2215/CJN.08970719. Epub 2020 Jan 23. PMID: 31974287; PMCID: PMC7015092.
Thankyou Hadeel this is a well organised exellent answer.But the issue of preventive pretransplant PE is highly questionable.
Well done.
Comment on the report.؟ABO compatible.
Rh incompatible.
Negative crossmatch.
No DSA .
1-1-0 mismatch by Broad .
1-1-1 mismatch by splits .
Comment on the difference between the broad and the split mismatch.
Split HLA is a subtype or subgroup of broad HLA.
The listing of broad specificities in paracentesis after a narrow specificity .eg. HLA-A23(9) is optional .
What is the impact of split mismatch on graft survival?Gerhard Opelz study published in lancet showed that :
The difference in survival at three years between graft with 0 or 6 mismatches for HLA-A ,B,DR was 31% when antigen splits were analysed,in contrast to a 6% difference with broad antigen .
Example of Broad and Split HLA:
A9(A23,A24),A10(A25,A26,A34,A66),A19(A29,A30,A31,A32,A74),B5(B51,B52),B12(B44,B45),B15(B62,B63,B75,B76,B77)
B16(B38,B39),B21(B49-B50)B40(B60,B61)
DR2(DR15,DR16),DR3(DR17,DR18),DR5(DR12,DR11) and DR6(DR13,DR14).
In UK Split match are used more than Broad match since ten years.
Explain how the presence of DSA influences graft survival wouldDSAs, are a well established biomarker predicting antibody-mediated rejection and graft loss.
There are tow types of antibodies:
1-Preformed .
2-De novo .
Preformed DSAs can cause instant hyperacute rejection and graft necrosis, whereas memory B and plasma cell response may trigger an accelerated acute rejection within hours or days of kidney transplant.
It is also responsible for early acute antibody-mediated rejection after transplant.
De novo DSAs in previously nonsensitized patients is associated with late acute antibody-mediated rejection, chronic antibody-mediated rejection, and transplant glomerulopathy.
The complement play a major role in some bathways.
IgG subclasses have various abilities to activate complement and recruit effector cells through the Fc receptor.
C1q binding IgG3 DSA is associated with acute antibody-mediated rejection, more severe graft injury, and early graft loss.
C1q nonbinding IgG4 DSA is more related with subclinical or chronic antibody-mediated rejection and transplant glomerulopathy, which suggests complement-independent pathways as the underline pathogeneses.
Complement binding DSA and IgG subclass assays are not generally performed.
De novo DSAs are frequently detected, in stable transplant recipients .
C1q and IgG subclass can predict those with high risk of AMR ,and serial monitoring maybe indicated.
Our knowledge of DSA characteristics can stratify the patient’s immunologic risk, distinguish harmful DSAs from benign DSAs, and predict the phenotypes of antibody-mediated rejection, and hopefully, they will guide our clinical practice to improve the transplant outcomes.
Will you proceed with the transplantation?I have to repeat the crossmatch ,because last one is done since tow years .
If the crossmatch com negative i will proceed with transplantation.
If yes, what is your immunosuppression protocol?Induction therapy with basiliximab and steroids.
Maintenance therapy (CNI-MFM-steroids).
If not, what are the other options?Paird kidney donation to get the best matched donor.
What is the impact of the primary disease on graft survival in the indexed case?FSGS recurs in 32 percent of patients and cause graft loss.
Risk factors for recurrence FSGS are:
1- Old age.
2- Whit race.
3- Increase BMI.
4- Native kidney nephrectomy.
5- Previous graft loss due to FSGS.
6- Recurrence of FSGS less than five years after transplantation.
Studies observe that the histology of FSGS classification in recurrent FSGS after kidney transplant is most commonly the as that observed prior transplantation.
And the histologic type is also important in prognosis and relevance.
Although antibodies for focal segmental glomeruli- sclerosis may give us same clues as biopsy.
The most important antibodies are:
• Anti Su-par.
• Cardiotrophin like cytokine.
• Micro RNA .
• Anti tnf a.
Pretransplant anti cd40 has the highest accuracy in predicting recurrence of FSGS.
Urine creatine/albumin ratio and kidney biopsy are the cornerstone in diagnosis FSGS.
Many studies were done to know the best way for preventing FSGS recurrence post-transplant.
The most effective treatment is a combination of plasmapheresis with RITUXIMAB cycles for five to
Six months.
Refference:
1-GerhardOpelz.IMPORTANCE OF HLA ANTIGEN SPLITS FOR KIDNEY TRANSPLANT.
2-Dr Ahmed Halawa online lectures.
3-Donor-Specific Antibodies in Kidney Transplant Recipients.
4_Senggutuvan P, Cameron JS, Hartley RB, Rigden S, Chantler C, Haycock G, Williams DG, Ogg C, Koffman G: Recurrence of focal segmental glomerulosclerosis in transplanted kidneys: Analysis of incidence and risk factors in 59 allografts. Pediatr Nephrol 4: 21–28, 1990 [PubMed] [Google Scholar] [Ref list]
Thank you Dr Abdullah Hindawy
Well done.
Few points to make the answer clinically relevant:
1- Rh incompatible. what is the impact of this on transplant decision?
2-IgG3 and C1q are complement fixing and associated with aggressive ABMR but they are not routinely done as you mentioned and only for research purposes so far
3-Risk factors for recurrence FSGS are:
1- Old age.
2- Whit race.
3- Increase BMI.
4- Native kidney nephrectomy.
5- Previous graft loss due to FSGS.
6- Recurrence of FSGS less than five years after transplantation.
Most important predictor of recurrence is recurrence in a previous transplant but other less important such as live donor transplant and rapid native kidney loss other factors that predict early recurrence with possible graft loss
Interesting that you did not refer to familial cases of FSGS with more culprit genes are identified. Risk of recurrence in these cases is very minimal depending on the identified gene the genotype of the recipient
When you quote a reference please refer to the year of publication (Gerhard Opelz study published in lancet)
Thank you Dr Weam El Nazer
CDC cross match could turn positive with low level DSA? What you need to do if this happened?
At MFI levels of about 10,000, the beads may become full and no longer be able to bind any more antibodies that might be in the serum.
In these kinds of situations, the antibody load could be underestimated.
Supersaturation of the beads by antibodies could leave a low level of serum DSA.
In situations like this, titration tests (dilution) may be carried out to offer a more accurate measurement of the amount of antibody present.
False negatives DSA can also happen when a low-level antibody attacks a public or shared epitope. since the binding of the antibody is dispersed across more than one bead. This can be found by looking at SAB histogram reports for alloantibodies that bind to CREGs.
There could be non-HLA antibodies or immunoglobulin M (IgM) HLA in the body, which could lead to false-positive CDC results. If the patient’s serum was treated with DTT first, this would be less likely to happen. Non-HLA requires specific beads to be detected.
Vajdic CM, van Leeuwen MT. Cancer incidence and risk factors after solid organ transplantation. International Journal of Cancer. 2009;125(8):1747–54.
Well done this means that positive cross match could happen with low level DSA but these are exceptional cases.
DEAR ALL
The correct report is:
as DR15 ,DR16 belong to the (mother) antigenDR2 so it is a0 mismatch at the broad level.
But when the splits are considered separate enteties it will be a 1 mismatch
So broad 110
split 111
Something to consider : if this report was a recent one the last FCXM was in 2020!!
We know there are no DSAs in this case but when can we get a negative cdc, fcxm and still have DSAs?
If the level of DSA is low, that is not sufficient to cause a positive cross-match. Usually, FXM is negative if the DSA < 3000 MFI
HLA type 111 broad 011 split.
Negative cross match.
No DSA antibodies.
· What is the impact of split mismatch on graft survival?
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 (1).
Explain how the presence of DSA influences graft survival would
DSA increase the risk of antibody-mediated rejection and have a deleterious effect on
kidney graft survival, even in the presence of a negative CDC) and/or flow cytometry
cross match Patients with DSA and TCMR have increased chronic renal allograft
damage at 1 year.
· Will you proceed with the transplantation?
Yes.
· If yes, what is your immunosuppression protocoL?
Induction with IL2 , basiliximab
Maintenance:
CNI plus MMF and corticosteroid.
· If not, what are the other options?
Wait for suitable donor.
Paired kidney donation.
· What is the impact of the primary disease on graft survival in the indexed
case?
Recurrent glomerulonephritis occurs in 12-25 percent of a patient with glomerular
disease, cause 60 percent of graft loss (2).
References:
1-GerhardOpelz.IMPORTANCE OF HLA ANTIGEN SPLITS FOR KIDNEY TRANSPLANT
MATCHING. The Lancet: Volume, 9 July 1988, Pages 61-64.
2-An JN, Lee JP, Oh YJ, et al. Incidence of post-transplant glomerulonephritis and its
impact on graft outcome. Kidney Res Clin Pract. 2012;31(4):219-226.
doi:10.1016/j.krcp.2012.09.004
Thankyou but the correct answer is :
broad 110
split 111
you need more information on DSAs
Good you mentioned a negative CDC and FCXM in the presence of DSAs can you explain .
Your FSGS needs more information.
DSA either performed or de novo which associated with early rejection and graft
loss with performed and late AMR and chronic AMR and transplant
glomerulopathy with de novo DSA.
low level of of DSA can give negative CDC XM and flow-XM. also the prozone
phenomenon i.e. when diluted serum gives a higher MFI than the undiluted
serum and false negative results at high HLA antibody concentration, which can
be negated by pre-heating the test serum, adding ethylene-diamine-tetra-acetic
acid (EDTA) or dithiothreitol (DTT)(1).
Focal segmental glomerulonephritis is common post transplantation with high
incidences with primarily FSGS, less with secondary and none or rare with
genetic one .It’s associated with Poor graft survival around of 55% in five
years, but the risk of recurrence in primary focal segmental glomerulonephritis
is less in familial type. In addition to increase the risk of graft dysfunction , the
graft loss is common after the recurrence of FSGS, with a worse prognosis
compared to other cases of post-transplant loss, especially in-patient who failed
to response to the treatment or those with partial response compared to the
patient with complete response, which occur with the meantime of 8 months.
The previous allograft loss due to FSGS is associated with an increased risk of
recurrence of about 85% in subsequent transplantation.
The presence of SUPAR in a high level is associated with the highest risk of
recurrence as do other antibodies like CD40, PTPRO, CGB5, FAS, P2RY11,
SNRPB2, and APOL2 (2).
References:
1-Mohanka R El Kosi , Jin JK2, Sharma and Halawa .Careful Interpretation of
HLA Typing and Cross Match Tests in Kidney Transplant .Joj Nephrology and
Urology. Review Article Volume 3 Issue 5 – August 2017 .
2-Fujisawa M, Iijima K, Ishimura T, et al. Long-term outcome of focal segmental
glomerulosclerosis after Japanese pediatric renal transplantation. Pediatr
Nephrol. 2002;17(3):165-168. doi:10.1007/s00467-001-0759-0
· Comment on the report.
ABO compatible (Donor O which is universal donor to blood group B)
HLA typing :shown matching 1:1:1 as split and M1:1:0 as abroad.
Flow cytometry cross matches & Auto cross matches: Negative.
No DSA.
It is considered low immunological risk with good matching.
· Comment on the difference between the broad and the split mismatch.
Split antigen is an antigen that has a more refined or specific cell surface reaction relative to a broad antigen such as
-A9 Broad (Splits A23 and A24)
-A10 Broad (Splits A25, A26, A34, and A66)
-A19 Broad (Splits A29, A30, A31, A32, A33, and A74)
· What is the impact of split mismatch on graft survival?
The difference in survival at three years between grafts with 0 or 6 mismatches for HLA-A, B, DR was 31% when antigen splits were analyzed, in contrast to a 6% difference with broad antigens, so it has a better graft survival than broad mismatching (1).
· Explain how the presence of DSA influences graft survival would.
Pretransplant DSAs are a risk factor for early graft loss and increase the incidence for humoral rejection and graft loss (2).
· Will you proceed with the transplantation?
Yes, it is considered low immunological risk , no DSA and will be inducted with standard immunosuppression and will have long term graft survival.
· If yes, what is your immunosuppression protocol?
Basiliximab as induction D0+D4 with tacrolimus based triple therapy (steroid +tac +MMF).
· If not, what are the other options?
Paired Kidney Donation.
· What is the impact of the primary disease on graft survival in the indexed case?
Recurrence of primary FSGS is around 30-50 % mainly on the first 3month post kidney transplant (3).
We should obtain a random or spot urine protein-to-creatinine ratio on the first postoperative day, the day of scheduled hospital discharge, weekly for four weeks, and then monthly for one year after transplantation (4).
References:
1-Gerhard Opelz FOR THE COLLABORATIVE TRANSPLANT STUDY (Lancet 1988).
2- Michiel G. H. Betjes, Kasia S. Sablik, Henny G. Otten, Dave L. Roelen, Frans H. Claas, Annelies de Weerd, “Pretransplant Donor-Specific Anti-HLA Antibodies and the Risk for Rejection-Related Graft Failure of Kidney Allografts”, Journal of Transplantation, vol. 2020, Article ID 5694670, 10 pages, 2020. https://doi.org/10.1155/2020/5694670.
3- Uffing A, Pérez-Sáez MJ, Mazzali M, et al. Recurrence of FSGS after Kidney Transplantation in Adults. Clin J Am Soc Nephrol. 2020;15(2):247-256. doi:10.2215/CJN.08970719.
4- Vincenti F, Ghiggeri GM. New insights into the pathogenesis and the therapy of recurrent focal glomerulosclerosis. Am J Transplant. 2005;5(6):1179-1185. doi:10.1111/j.1600-6143.2005.00968.x.
Thankyou Mohamad for your answer regarding broad and split antigens.
However the DSA part needs more information:
subtypes,MFI,complement fixing alongside with the time of detection.
If this was a recent report the last FCXM was in 2020!
References;
2.Importance of HLA antigen splits for kidney transplant matching, G Oplez 3.Recurrence of FSGS after Kidney Transplantation in Adults, Audrey Uffing et. al
3.Importance of HLA antigen splits for kidney transplant matchingG Opelz 1
Thankyou Ben just confirming the information it is
broad 110 as DR has DR15, DR16 both inside DR2 so it is considered 0 mismatch.
split will be 111 as you will consider DR15,DR16 as two seperate anttigens.
Abroad antigen will combine with more than one antibody.
A split antigen will combine with only one antibody.
YOU need to elaborate more on DSAs as MFI, subtypes,complement fixing.
Thank you prof.
Here are more information about DSA;
Class I and Class II DSA
References;
☆ Comment on the report
● ABO compatible as recipiant is B+ and donor is O-
● As for HLA matching it is 110 mismatch for broad antigen and 111 mismatch for split antigen ( considering that DR15 and DR16 are split antigens of DR2
● FCM is negative for B and T cell
● No DSA
☆ Comment on the difference between the broad and the split mismatch
● split antigen is more specific cell surface reaction relative to a broad antigen.
● typing for HLA antigen splits is important in renal transplantation, that the potential benefit of HLA matching in renal transplantation is greater than currently accepted, and that HLA typing and kidney allocation routines must be refined in order to exploit this potential.
● Split antigen matching appears to be more important for HLA-A and-B antigens than for HLA-DR and should be considered especially in recipients and donors of kidney retransplants
☆ What is the impact of split mismatch on graft survival?
● Matching for HLA antigen “splits” results in better transplant outcome than matching for “broad” HLA antigens especially for HLA-A and B antigen splits and in retransplants
☆ Explain how the presence of DSA influences graft survival would.
● Presence of DSA, either preformed or de novo, has become a well established biomarker predicting poor transplant outcomes
● The presence of donor-specific antibodies (DSAs) against HLA molecules is a risk factor for humoral rejection after kidney transplantation. The introduction of the complement-dependent cytotoxicity (CDC) test has been a major step forward in excluding high-risk donor-acceptor combinations .
● The CDC recognizes the most harmful DSA, which are able to bind complement and subsequently lyse donor cells carrying HLA on their cell surface.
In kidney transplantation the presence of preexisting (DSA) is associated with an augmented risk of antibody-mediated rejection (AMR) and worst graft survival
● The presence of pretransplant DSA identifies patients which are sensitized to allogeneic HLA, e.g., by pregnancy, blood transfusions, or a previous transplantation. Therefore, pretransplant DSA may identify patients with both an increased risk for antibody-mediated rejection as well as Tcell-mediated rejection .
● The presence of pre-Tx DSA was initially associated with the occurrence of AMR, and this condition may lead to graft loss in low-risk renal patient populations transplanted with a negative CDC crossmatch.
● pre-Tx DSAs are likely only problematic when these concentrations remain positive after transplantation ( de novo DSA ) and above a certain threshold.
☆ Will you proceed with the transplantation?
Yes . I will continue with the transplant because all the findings , whether for the recipient or the donor, suggest good survival of the graft
▪︎ABO compatible
▪︎Good HLA matching
▪︎FCM is negative for B and T cell
▪︎No DSA
☆ If yes, what is your immunosuppression protocol?
Induction therapy with Basiliximab and
Maintenance therapy with
Tac + MMF + pred
☆ If not, what are the other options
Paird kidney donation or living kidney donor
☆ What is the impact of the primary disease on graft survival in the indexed case?
The primary disease is FSGS which has propability of recurrence especially idiopathic fsgs ( rate recurrence 30 – 50 % ) other secondary fsgs types have less rate as genetic fsgs ( recurrence rate only 4 % )
Recurrence of fsgs is usually early at 3 months after transplantation with poor outcome of the graft
Thankyou Hoda ,that was a very good start, you are one of few that has the correct interpretation of the broad and split index report and thier effect on the Tx. outcome.
However one should notice that the last XM was in 2020 but still the DSAs are negative, hopefully that was a recent fact.
Please always mention the references.
It is
broad 110
split 111
Comment on the report:
The donor is 29 years old (cadaver) with blood group O Rh(-) , the recipient blood group B Rh(+). However the Rh incompatibility is not expressed in no erythroid cells, so the donor blood group would be compitable.
The mismatch is 111 (A,B, and DR),
No DSA for both T and B lymphocytes were negative in 5 occasions the last two were 8 months apart.
Comment on the difference between the broad and the split mismatch:
The serologic supertypes are the broad specificities, example HLA B15.
Splits or subtypes are the finer specificities that compromise the supertype, example B62, B63 ,B70, ..etc.
As the split were discovered, they were given number designation that again give no indication as to the supertype to which they belong ex: molecular B*15:12 is eqivelant of HLA-B76.
What is the impact of split mismatch on graft survival?
In a study transplant with zero mismatch broad and split had a 2 years survival of (80±2 %), with split mismatch this was 9 years less, transplants with one HLA-DR mismatch by both the broad and split definitions had a significantly higher success rate (72±2% at 2 years) than transplants for which split typing revealed a second mismatch (60±6%, P=0.03) (1).
Explain how would the presence of DSA influences graft survival?
Pretransplant donor-specific anti-HLA antibody (DSA) do not appear to consistently predict graft outcomes, but higher rates of ABMR and graft loss were seen when pretransplant DSA had MFI values >10,000 but were comparable between all other groups (moderate MFI [5000 to 10,000] versus low MFI [1000 to 5000]). We do not know with this DSA will remain negative or rapidly increasing post renal transplant upon repeated exposure to antigen son we might follow it post transplant specially in sensitized patients(3).
Absence of pretransplant DSA on outcome — Even in the absence of donor-specific anti-HLA antibody (DSA), some studies have shown that sensitized recipients (with non-DSA alloantibody) are at higher risk for graft failure (2). However, this remains controversial, as other studies have shown no impact of having non-DSA on graft outcome (5).These disparate findings may depend upon whether more or less aggressive immunosuppression is used or could also reflect incomplete identification of DSA depending upon whether antibodies against all loci.
Will you proceed with the transplantation?
yes, I’ll proceed with transplantation
If yes, what is your immunosuppression protocol?
I would give and induction with basilixumab, with low immunological risk, and would keep him on prednisolone, MMF, and tacrolimus.
If not, what are the other options?
Paired exchange program.
What is the impact of the primary disease on graft survival in the indexed case?
The FSGS recurrence increased in the following settings: HLA-DR7,DR53, and DQ2. But patients with HLA-DQ7 found to have less recurrence risk. Patients experienced FSGS disease recurrence within 2 years, are at increased risk. Obese patients, and history of prior nephrectomy of native kidneys, have 5 folds’ risk of FSGS recurrence. Some reports indicate 80% risk of FSGS recurrence in the second transplant, and 90% risk after the third one(4).
References:
(1) Opelz G, Scherer S, Mytilineos J. Analysis of HLA-DR split-specificity matching in cadaver kidney transplantation: a report of the Collaborative Transplant Study. Transplantation. 1997 Jan 15;63(1):57-9. doi: 10.1097/00007890-199701150-00011. PMID: 9000661.
(2) Süsal C, Döhler B, Opelz G. Presensitized kidney graft recipients with HLA class I and II antibodies are at increased risk for graft failure: a Collaborative Transplant Study report. Hum Immunol. 2009 Aug;70(8):569-73. doi: 10.1016/j.humimm.2009.04.013. Epub 2009 Apr 16. PMID: 19375472.
(3) UpToDate –kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing.
(4) Uffing A, Pérez-Sáez MJ, Mazzali M, Manfro RC, Bauer AC, de Sottomaior Drumond F, O’Shaughnessy MM, Cheng XS, Chin KK, Ventura CG, Agena F, David-Neto E, Mansur JB, Kirsztajn GM, Tedesco-Silva H Jr, Neto GMV, Arias-Cabrales C, Buxeda A, Bugnazet M, Jouve T, Malvezzi P, Akalin E, Alani O, Agrawal N, La Manna G, Comai G, Bini C, Muhsin SA, Riella MC, Hokazono SR, Farouk SS, Haverly M, Mothi SS, Berger SP, Cravedi P, Riella LV. Recurrence of FSGS after Kidney Transplantation in Adults. Clin J Am Soc Nephrol. 2020 Feb 7;15(2):247-256. doi: 10.2215/CJN.08970719. Epub 2020 Jan 23. PMID: 31974287; PMCID: PMC7015092.
(5) Caro-Oleas JL, González-Escribano MF, González-Roncero FM, Acevedo-Calado MJ, Cabello-Chaves V, Gentil-Govantes MÁ, Núñez-Roldán A. Clinical relevance of HLA donor-specific antibodies detected by single antigen assay in kidney transplantation. Nephrol Dial Transplant. 2012 Mar;27(3):1231-8. doi: 10.1093/ndt/gfr429. Epub 2011 Aug 2. PMID: 21810767.
That is a wonderful reply, dear Dr Hasan. It is very well structured and supported by evidence.
How would you monitor for post-transplant FSGS recurrence?
Ajay
Thank you Prof. Ajay
i would follow the urine protein/creatinine ratio for possible FSGS recurrence
The above recipient report:
ABO compatible
110 MM
No DSA
The split mismatch has a better graft survival, than a broad mismatch
3 years study found that; there was 18% difference between the survival rates of graft with 0 or 4 mismatch among transplant type for HLA-A and B antigen in split mismatch , compared to only 2% in broad antigens.
While the differences was 31% in mismatch of 0 or 6 HLA-a, B, DR, in contrast to a 6% in broad mismatch.
DSA influence on graft survival:
A study done in 160 patient of which 14 of them have DSA, 7 patients with persistant performed DSA, 6 had dnDSA, compare the outcome of transplantation at 7 and 11 yaesr , found that; death censored allogfart survival rates of recipient with DSA vs those without DSA, were 77.9% vs 97.8% and 60.6 vs 89.2% respectively.
The graft survival rate was lower in patients with persistant performed DSA and/or dnDSA, and the persistance of performed and dnDSA at 1 year was a predictor of long term survival.
We can proceed for transplantation for this patient as he had accepted MM 110 and negative cross match with no DSA.
Immunosuppressant protocol:
Induction phase:
Pre-op:
Pre-Op:
Post-Op:
Day 4:
Basiliximab 20 mg IV
Maintenance immunosuppressant;
Risk of FSGS recurrence:
Primary FSGS has a great percent of recurrence even shortly after transplantation, while secondary associated with no recurrence rate.
Recurrence of FSGS should not lead to postponed transplantation, and plasmapheresis and intensive immunosuppressant protocol should be started for treatment
Refferences:
G Opelz
2.Impact of persistent preformed and de novo donor-specific antibodies detected at 1 year after kidney transplantation on long-term graft survival in Japan: a retrospective studyNobuhiro Fujiyama 1, Shigeru Satoh 2, Mitsuru Saito 3, Kazuyuki Numakura 3, Takamitsu Inoue 3, Ryuhei Yamamoto 3, Takuro Saito 3, Sohei Kanda 3, Shintaro Narita 3, Yoko Mitobe 1, Tomonori Habuchi 3
3.A retrospective study of focal segmental glomerulosclerosis: clinical criteria can identify patients at high risk for recurrent disease after first renal transplantationRutger J H Maas 1, Jeroen K J Deegens, Jan A J G van den Brand, Elisabeth A M Cornelissen, Jack F M Wetzels
4.
That is a wonderful reply, dear Dr Kamal.
How would you monitor for post-transplant FSGS recurrence?
Ajay
Sure i will do screening of proteinuria , ACR if significant we can go for 24 hrs collection for real estimation
Comment on the report.
ABO-compatible, the DD donor is a universal donor from Blood group O to A, Rh incompatibility is not a histocompatibility barrier then the major Rh antigen accountable for allosensitization after blood exposure, RhD, is not existing in nonerythroid cells (1).
HLA class1 genes expressed in all nucleated cells accept RBCS, including class-A, B, and C, and are responsible for the control of activation & proliferation of cytotoxic T cells
HLA class II molecules are constitutively expressed by antigen-presenting cells (APC) like the dendritic, macrophage, and monocyte cells and B lymphocytes, but these antigens can be induced on activated T cells and endothelial cells, including the glomerular endothelium, renal tubular cells, and capillaries. Both class1,11 HLA antigens are polymorphic, Limited analyses of HLA allele-level mismatches among kidney transplant recipients suggest an added effect of allele-level HLA mismatches on graft survival rate.
110 mismatches by split antigen and 111 mismatches by broad, split match more specific than broad like in this case DR2 broad split of (15,16).
FXCM including auto crossmatch was repeatedly negative for both T and B cells however no comment on the mean cell shift or MFI and the cutoff value for negative results
No DSA, still we need to repeat the FCXM for both T and B cells with the cut-off value of the MFI level, and DSA levels as there is no recent crossmatch most recent report was back in 2020.
Comment on the difference between the broad and the split mismatch.
HLA matching has had the greatest clinical impact in kidney and bone marrow transplantation, where efforts are made to match at the HLA-A, -B, and -DR loci.
The split mismatch is more specific splitting some HLA antigens into narrower specificities. for example the HLA-A9 was split into HLA-A23 and -A24, and HLA-A10 was split into HLA-A25, -A26, -A34, and -A66
.
What is the impact of split mismatch on graft survival?
The number of HLA mismatches is a potent predictor of transplant outcome, not every HLA mismatch will have an equal effect on graft failure. collecting evidence suggests that some HLA mismatches may transport alloimmunity, whereas others are well-tolerated (4).
the currently used allocation algorithm by Euro transplant is based on HLA typing at serological broad (HLA-A and HLA-B) and split antigen (HLA-DRB1) levels and not at the level of more precise two-field molecular typing (3). With the improvement in molecular genetic testing, the HLA matching at the level of epitopes can improve the transplant outcome(6).
HLA epitope analysis is considered a policy to permit safe immunosuppression minimization to improve patient outcomes through:
(1) improved allocation systems that favor donor-recipient pairs with a low HLA epitope mismatch load (especially at the class II loci)
(2) avoiding specific epitope mismatches.
Explain how the presence of DSA influences graft survival would.
The presence of DSA indicates previous sensitization from previous transplantation or multiple pregnancies in case of female recipients or blood transfusions and usually, the performed DSA can impact the graft survival and transplantation outcome as it’s associated with a higher rate of acute rejection. sensitization was associated with 8% lower graft survival at 5 years and with a higher rate of late graft loss among first cadaver kidney recipients. Sensitization also was associated with an increase in delayed graft function by 36% among multiply retransplanted patients (3).
Will you proceed with the transplantation?
Yes, as he is at low immunological risk by split antigen matching, and if repeated FXCM is negative and no DSA will go ahead with the transplantation.
If yes, what is your immunosuppression protocol?
Induction is a standard immunological risk with basiliximab 20mg D0, D4 (anti-CD 25 monoclonal AB) followed by triple IS including steroids as this patient’s primary disease is FSGS and if primary FSGS there is a risk of recurrence post-transplantation
If not, what are the other options?
Paired kidney donation (PKD ) or exchange program
What is the impact of the primary disease on graft survival in the indexed case?
FSGS is one of the primary glomerular diseases with a reported higher rate of recurrence post-transplantation which depends on many factors like primary ( idiopathic vs secondary or hereditary FSGS ) as primary FSGS associated with a higher rate of recurrence with the first 3 years post-transplantation in addition to older age, rapid and aggressive course, and severe proteinuria and should be discussed with the recipient in details
References
1. Kidney transplantation handbook, 6th edition, Gabriel donavistsh.
2.Sheldon S, Poulton K. HLA typing and its influence on organ transplantation. Methods Mol Biol. 2006; 333:157-74.
3.Cecka JM. The UNOS renal transplant registry. Clin Transpl. 2001:1-18. PMID: 12211771.
4.Unterrainer C, Döhler B, Niemann M, Lachmann N, Süsal C. Can PIRCHE-II Matching Outmatch Traditional HLA Matching? Front Immunol. 2021 Feb 26;12:631246.
5.Claas F. H. J., Dankers M. K., Oudshoorn M., et al. Differential immunogenicity of HLA mismatches in clinical transplantation. Transplant Immunology. 2005;14(3-4):187–191. doi: 10.1016/j.trim.2005.03.007.
6.Wiebe C., Nickerson P. Strategic use of epitope matching to improve outcomes. Transplantation. 2016;100(10):2048–2052.
That is an excellent reply, Dr Saja. It is very well structured and supported by evidence.
How would you monitor for post-transplant FSGS recurrence? I know you have alluded to proteinuria.
Ajay
The current scenario of 31 years old patient with CKD stage V secondary to FSGS (potential recipient) received offer from 29 years old potential deceased donor:
-ABO: compatibility
Donor :O negative
Recipient: B positive
-HLA matching:
110 mismatches at HLA -A,B and DR .split antigens (DR15 and 16 split of broad DR2)
1-1-1-1-2 mismatches at HLA -A,B,C,DR and DQ
-HLA Ab screening: No DSA
-Flowcytometry cross matches: T and B FCXMs were negative
-Auto cross matches: Negative
Comment on the difference between the broad and the split mismatch:
–Split antigen is an antigen that has a more refined or specific cell surface reaction relative to broad antigen. It subgroup (Splits) of broad antigen Examples:
B5 Broad (split B51 and B 52)
B12 Broad (Split B44 and B45)
B15 Broad (Split B62 B63 and B75)
DR2 (split DR15,16)
-Split antigens matching give a better transplant outcome than matching for “broad” HLA antigens that was investigated in 30,000 cadaver kidney transplants. At three years, there was an 18% difference between the survival rates of grafts with 0 or 4 mismatches among transplants typed for HLA-A and B antigen splits whereas the difference in transplants typed for broad antigens was only 2%. These results indicate that typing for HLA antigen splits is important in renal transplantation, the potential benefit of HLA matching in renal transplantation is greater than currently accepted.
Explain how the presence of DSA influences graft survival?
The anti HLA antibodies either preformed DSA or de novo DSA against HLA class I and class II present in the recipient’s immune system have a crucial role in long term graft survival. These antibodies directed against antigens expressed on donor organs, if not treated by desensitization results in an immune attack on the transplanted organ and increases risk of graft loss and rejection. DSA attacks the endothelium of the allograft, resulting in subsequent ABMR. Frequent attacks of ABMR resulting in chronic changes over time that ultimately impact graft function and survival. It has shown that up to 96% of rejected allografts develop some degree of DSA.
De Novo DSA in Post-Transplant Recipients
De novo antibody production may cause subclinical ABMR that is associated with long- term graft dysfunction. Negative outcomes can take several years to occur after de novo antibody production. DSA is Predictive of Lower Graft Survival and risk of Transplant Glomerulopathy development depends on anti-HLA-II levels.
Will you proceed with the transplantation?
Yes,in view of no DSA and negative cross matches,will directly proceed for transplantation.
Immunosuppression protocol:
Since the patient has low immunologic risk for rejection,so induction with Basiliximab (IL-2 receptor antagonists)will be more enough at dose of IV 20 mg within 2 hours prior to transplant surgery, followed by a second 20 mg dose 4 days after transplantation in addition to maintenance triple immunosuppression of CNI, Antimetabolites and steroids in tapering doses with target tacrolimus level of 6-8 ng/ml.
If not, what are the other options?
Other options might be matched living donor or paired kidney exchange program.
What is the impact of the primary disease on graft survival in the indexed case?
Primary FSGS can recur after transplantation and risk factors in the index case are young age at presentation, Rapid decline of renal function and progression to ESRD which is common in aggressive forms of FSGS like collapsing variants.
If there was history of failed renal transplant within 3 years.
That is a wonderful reply, dear Dr Foud. I wish you could support your arguments with evidence.
How would you monitor for post-transplant FSGS recurrence?
Ajay
This is a crossmatch report, which reveals a compatible blood group between the donor and the recipient but is not matched. The Rh factor is incompatible. The patient’s previous flow cytometry cross-match is negative.
HLA typing: broad MM: 1:1:0, split: 1: 1:1
Flow cytometry cross-match has a negative history. in addition to negative DSA.
The split antigen is described as an antigen that elicits more distinct and particular cell surface reactions than a wide antigen when compared to a broad antigen. Separated antigens: The division of a single antigen into subtypes; an antigen that produces a more specific cell surface response than a more general antigen. (For example, the HLA-B5 broad antigen is divided into the HLA-B51 and HLA-B52 subtypes.)
• About 1% to 6% of transplant patients have acute graft-versus-host disease (AMR) right after the transplant. This number can go up to between 21% and 55% in patients who had DSA before the transplant and were given treatment to make them less sensitive to it.
• A low allograft survival rate is linked to DSA that stays the same or comes back after transplantation.
• Low levels of DSA before a transplant have been linked to more subtle types of graft damage, which could cause graft function to be delayed.
• It is well known that damage that happens early on can lead to long-term changes that are caused by antibodies. This is probably because the structure of the endothelium has been damaged and new antigenic epitopes have appeared on the surface of the transplanted tissue.
Yes, it is a low immunological risk (the cross-match has negative historical and recent. in addition to a negative DSA). Additionally, they are matched in age.
As he is low immunologically low risk, we will give induction basiliximab and maintenance on triple immunosuppressant (tacrolimus, MMF, prednisolone).
Keep the tacrolimus within (5-7) and avoid the steroid-free protocol.
Calculate the proteinuria before transplant and keep close track of it post-transplant.
Many glomerulonephrites may recur after transplantation, but only a few are clinically relevant in terms of graft function and survival. The recurrence rate of primary FSGS is 20–50 percent, with a 50 percent graft loss rate.
Early recurrence of FSGS is linked to significant podocyte foot process effacement and lower allograft survival. Older allografts had less explosive proteinuria and varied foot process effacement. No relation exists between recurrence risk and the initial FSGS variety (tip lesion, perihilar, collapsing, etc.), despite the fact that it is often (but not always) the same as the native kidney.
-Risk factors for disease recurrence include young age at disease onset (i.e., pediatric patients), rapid progression to end-stage renal disease, bilateral nephrectomy, white race, and loss of a previous allograft because of FSGS recurrence.
Reference :
-Helman S W.etal, Interpretation of HLA Typing Results for Entry into UNet. Organ Procurement and Transplantation Network,Jan 2003.–
– Francis A, Trnka P, McTaggart SJ. Long-Term Outcome of Kidney Transplantation in Recipients with Focal Segmental Glomerulosclerosis. Clin J Am Soc Nephrol 2016; 11:2041.
Pinto J, Lacerda G, Cameron JS, et al. Recurrence of focal segmental glomerulosclerosis in renal allografts. Transplantation 1981; 32:83.
That is a wonderful reply, dear Dr Nazer. It is very well structured and supported by evidence.
Ajay
The match is 110
Split antigen is more refined and specific to cell surface reaction relative to broad antigen.
Split antigen matching has better outcome than broad antigen as shown in study that 3 years graft survival is 18% in split antigen match with respect to broad antigen that is 2%
Presences of DSA in pretransplant patient, or those who are pre-sensitized like pregnancy, blood transfusion and second transplant where preformed antibody are present, they ae at high risk of developing AMR soon after transplant and subsequent graft loss if specific measure are not used.
With adequate HLA matching, negative cross match and no DSA, it is quite reasonable to go for transplant but with proper work up as the receipt has FSGS here is high risk of reoccurrence and subsequent graft loss.
I want to investigate the patient history biopsy report and treatment response as poor response to treatment there is high chance of reoccurrence, will quantify proteinuria before surgery and if present subsequent for next three month to identify de novo vs reoccurrence.
Before transplantation with intensive workup, I will start with induction therapy with depleting or non-depleting agent (we used to start with ATG in our center). Followed by triple regime including CNIs, antimetabolite and low dose steroid.
If no transplant than ckd management, any indication for dialysis, preparing for dialysis access.
Referene;
Okimoto K, Juji T, Ishiba S, Maruyama H, Tohyama H, Kosaka K. HLA–Bw54 (Bw22-J, J-1) antigen in juvenile onset diabetes mellitus in Japan. Tissue Antigens 1978 11(5):418–22 pmid=694905
Importance of HLA antigen splits for kidney transplant matching, Lancet 1988 Jul 9;2(8602):61-4.doi: 0.1016/s0140-6736(88)90001-3.
T. B. Dunn, H. Noreen, K. Gillingham et al., “Revisiting traditional risk factors for rejection and graft loss after kidney transplantation,” American Journal of Transplantation, vol. 11, no. 10, pp. 2132–2143, 2011.
P. Amico, G. Hönger, M. Mayr, J. Steiger, H. Hopfer, and S. Schaub, “Clinical relevance of pretransplant donor-specific HLA antibodies detected by single-antigen flow-beads,” Transplantation, vol. 87, no. 11, pp. 1681–1688, 2009.
Nephrology and hypertension on board review, Phuong-Chi T. Pham, MD, FASN
Dear Dr Chowdhary,
I like your reply but it is not complete.
Ajay
Comment on the report;
ABO compatible
HLA 110 MM for split and 111 MM for broad, FCM XM and DSAs are negative.
0 mismatch at DR(clinically significant)
Difference between broad and split mismatch;
In context of organ transplant evidence suggests split antigen match has better outcome like graft survival compared to broad antigen match.
Broad antigen can split into further split antigens with potential of forming more antibodies than split antigen which could have single antibody.
Split antigens are clinically significant for class 1(HLA-A,B) than class 2(HLA-DR).
Impact of split mismatch on graft survival;
Multiple studies have shown the impact of mismatched HLA antigens on graft outcome with higher rates of rejection(ABMR) and graft loss, furthermore transplant recipients who were typed on splits for class 1 had better outcomes with zero mismatches compared to the other group whom were typed with broad.
Studies from across transplant centers clearly indicates the potential benefits of split antigen typing compared to broad.
How the presence of DSA influences graft survival;
It well documented that presence of preexisting DSAs would lead to acute rejection and De novo DSAs with ABMR would lead to poor graft survival. it is also important to note that all DSAs are not necessarily leads to rejection and would be interpret in context of whether DSAs are De novo or preexisting and/or strength of DSAs, complement fixation ability and sub class of antibodies.
Will you proceed with the transplantation?
Yes
Immunosuppression protocol;
induction with antithymocye globulins(deceased donor and risk of DGF with potential of delayed initiation of CNIs but cost and adverse events are concerns for ATG).
Maintenance is with triple regimen.
If not, what are the other options?
Wait for next better match but would prefer to go ahead with this transplant owing to best modality of RRT.
in case of living donation KPD.
Impact of the primary disease on graft survival in the indexed case;
Recurrent FSGS(primary)
In case of primary FSGS which is not a kidney disease per se and rather a disease with Su factors affecting native kidneys and would be affecting donor graft as well. It would recur in 30-40% of patients, out of which would 80% would recur in first post transplant year.
Early proteinuira is hallmark of recurrence, in few cases on table massive proteinuira has been described as well. multiple recurrence after remission is common with higher graft loss.
In case of recurrence Pri FSGS protocols including PEX, CYCLO and Rituximab be initiated.
Wait for a better match and leave this young donor? Can you elaborate on this, Dr Ullah?
You mention 1-1-0 for a 2-1-0 broad mismatch offer!
On the report, comment.
Explain the variations between the broad and split mismatches.
What is the impact of split mismatch on graft survival?
Explain how the presence of DSA influences graft survival would.
Will you proceed with the transplantation?
If yes, what is your immunosuppression protocol?
If not, what are the other options?
What is the impact of the primary disease on graft survival in the indexed case?
.
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References
1. Fogo AB. Causes and pathogenesis of focal segmental glomerulosclerosis. Nat Rev Nephrol. (2015) 11:76–87. doi: 10.1038/nrneph.2014.216
2- Maas RJ, Deegens JK, van den Brand JA, Cornelissen EA, Wetzels JF. A retrospective study of focal segmental glomerulosclerosis: clinical criteria can identify patients at high risk for recurrent disease after first renal transplantation. BMC Nephrol. (2013) 14:47. doi: 10.1186/1471-2369-14-47
3- Barisoni L., Schnaper H.W., Kopp J.B. A proposed taxonomy for the podocytopathies: A reassessment of the primary nephrotic diseases. Clin. J. Am. Soc. Nephrol. 2007;2:529–542. doi: 10.2215/CJN.04121206.
4- Rudnicki M. FSGS recurrence in adults after renal transplantation. Biomed Res Int. (2016) 2016:3295618. doi: 10.1155/2016/3295618
5- D’Agati V.D., Kaskel F.J., Falk R.J. Focal segmental glomerulosclerosis. N. Engl. J. Med. 2011;365:2398–2411. doi: 10.1056/NEJMra1106556.
6- Königshausen E., Sellin L. Circulating Permeability Factors in Primary Focal Segmental Glomerulosclerosis: A Review of Proposed Candidates. BioMed Res. Int. 2016;2016:3765608. doi: 10.1155/2016/3765608.
7- Ciurea SO, de Lima M, Cano P, Korbling M, Giralt S, Shpall EJ, et al. High risk of graft failure in patients with anti-HLA antibodies
undergoing haploidentical stem-cell transplantation. Transplantation. 2009;88:1019–24.
8- Ciurea SO, Thall PF, Wang X, Wang SA, Hu Y, Cano P, et al Donor-specific anti-HLA Abs and graft failure in matched unrelated
donor hematopoietic stem cell transplantation. Blood. 2011;118:5957–64.
9- Kosmoliaptsis V, Sharples LD, Chaudhry AN, Halsall DJ, Bradley JA, Taylor CJ: Predicting HLA class II alloantigen immunogenicity from the number and physiochemical properties of amino acid polymorphisms. Transplantation 91: 183–190, 2011
10- Nankivell B, Alexander S. Rejection of the kidney allograft. N Engl J Med 2010; 363 (15): 14
Why consider paired donation in light of this very young cadaveric donor?
Thanks alot Prof.Sharma
May be to reduce mismatches is the goal of paired donation.
Pair or pooled donation is applicable ONLY in living donor operation, not in cadaveric organ donation.
Yes
Thanks alot Prof.Sharma
First; Comment on the immune- histocompatibility report?
-ABO compatible Couple (D-> O to R-> B, ABO => O is a universal donor)
-HLA typing: (6MM )110 mismatch for split antigens, and 111 for broad antigens
-FCM XM negative for both T and B cells
-DSA Not detected
Second; Comment on the difference between the broad and the split mismatch?
•Matching for HLA antigen “splits” results in better transplant outcome than matching for “broad”
•Matching for split HLA antigens results in better outcome when compared to matching for broad antigens
•Matching for split antigens is more clinically significant for HLA- A and HLA-B when compared to HLA-DR (2), Hata Y, 1998
•HLA antigens was investigated in 30,000 first cadaver kidney transplants.
•At three years, there was an 18% difference between the survival rates of grafts with 0 or 4 mismatches among transplants typed for HLA-A and B antigen splits
• whereas the difference in transplants typed for broad antigens was only 2%.
• Analysis of HLA-A, B antigens together with HLA-DR antigens showed an even greater advantage of matching for antigen splits: the difference in survival at three years between grafts with 0 or 6 mismatches for HLA-A, B, DR was 31% when antigen splits were analyzed, in contrast to a 6% difference with broad antigens.
•These results indicate that typing for HLA antigen splits is important in renal transplantation, that the potential benefit of HLA matching in renal transplantation is greater than currently accepted, and that HLA typing, and kidney allocation routines must be refined in order to exploit this potential, (G Opelz, 1988)
Third; What is the impact of split mismatch on graft survival?
•A meta-analysis of 23 cohort studies involving 486,608 recipients=> What is the impact of HLA mis-matching on graft survival and mortality in renal transplantation?
Xinmiao Shi1, Jicheng Lv2,3,4,5, Wenke Han6,7, Xuhui Zhong1, Xinfang Xie2,3,4,5, Baige Su1 and Jie Ding1*
•HLA per mismatch was significant associated with increased risks of overall graft failure (hazard ratio (HR), 1.06; 95% confidence interval (CI), 1.05–1.07), death-censored graft failure (HR: 1.09; 95% CI 1.06–1.12) and all-cause mortality (HR: 1.04; 95% CI: 1.02–1.07).(3)
FOURT; Explain how the presence of DSA influences graft survival would?
•The presence of pre-transplant DSA increases the risk for ABMR and graft loss but is not associated with a changed incidence of TCMR. These findings are important for risk stratification of patients awaiting a donor kidney and the use of desensitization protocols.
•
•Circulating anti-donor-specific HLA antibodies (anti-HLA DSA) were recognized in hyper acute rejection in 1969 .
•However, it took more than 40 years for the transplant community to consider the presence of anti-HLA DSA as the main reason for allograft rejection and long-term failure
•Antibody-mediated rejection is a more important cause of graft loss than cellular rejection
T cells are still important!
Caused by the presence of DSA either at time of transplant or that develop post-transplant(Mao et al, AmerJ Transpl2007;7:864)
FIFTH; Will you proceed with the transplantation?
As ABO compatibile e& 6 HLA MMH & 0 DR mismatch, -VE FCXM & no DSA detected.
SIX; If Yes, What Is Your Immunosuppression Protocol?
•Induction (Center Protocol)=> Ratg 3-5 Mg /Kg Maximum 1 Mg/Kg Daily According To CBC (WBC,ANC,PLT)
•Maintenance => Steroids With Slow Tapering , MMF, Tacrolimus With Level (8-10) Accepted
SEVEN; If Not, What Are The Other Options?
Waiting another Donor , LURD,
•1- If no indication for RRT (fu weekly )=> Continues on same management
•2-RRT (HD, PD) if indicated suitable donor available
EIGHT; What is the impact of the primary disease on graft survival in the indexed case?
FSGS recurs in 30–40% patients
•The majority (80%) recur in the first post-transplant year, often within a few weeks &occasionally within hours of transplantation
•Clinical CCC:
– Heavy Proteinuria
– Normal Creatinine at the start then AKI
– Foot process effacement on biopsy (early sign )
•Early & Aggressive but also late recurrence
•Multiple recurrence also possible
•Higher rate of graft loss
•2ry FSGS should not recur.
Risk factors for recurrent FSGS include:Aggressive 1° disease, with ESRD developing <3 years after presentation
* Recurrent FSGS in previous transplant (>80% recurrence in subsequent grafts)
* Paediatric patients >6 years old
* Histology demonstrating prominent mesangial proliferation
* Non-African-Caribbean races
* Use of induction IS and live donors (see box) may ↑ recurrence risk
Clinical Diagnosis of Recurrence of FSGS After Kidney transplant?
1- AKI & oligo-anuric after recovering
2- increasing ACR FU.
( ACR & Routein blood weekly)
•If 1ry FSGS and transplanted and failing, then plan for 2nd tx. what your plan?
• PLEX 3T/WEEK For at least 1 month for next tx. Because if you think to bring proteinuria to Zero need years
Clinical Pearls :
•10 y risk of recurrence LRD 14.6 vs 6.6 in DD (AZNDATA), (Kennard 2017)
•MM & FSGS Worse > MM & other GN (US SRTR), Cibrik,2003
•Rate of graft loss Hi w Recurrence > 60 % at 10 y
•20-40% recurrence in 1st tx & up to 80% in re-transplant , SAVIN NEJM, 1996
Recommendation in FSGS;
– Advice patient & Donors of risk of recurrence
– Screening for permeability factor not routinely available
– No Recommendation as to immunosuppression
– Monitoring of proteinuria begaining early after Tx .
– EM required for Bx. diagnosis
– PLEX is the Mainstay of Therapy
– Prophylaxis may decrease recurrence rate
-Rituximab
Dear Dr AbdelHamid,
I like your reply but why would you consider donor recurrence in this cadaveric donor.
I would use much lesser typing in bold.
I wish you could support your arguments with evidence.
Ajay
Thanks Dr Ajay
1st all your recommendation noted i will improve that
2nd i know cadaveric better than LRKTx Donor but i think bec. still not excellent match & young recipient age especially if with aggressive 1ry GN ???/
Evidence to support your arguments?
Comment on the report.
The report of this patient shows the following:
Comment on the difference between the broad and the split mismatch, What is the impact of split mismatch on graft survival?
Explain how the presence of DSA influences graft survival would.
ABMR is the commonest cause of graft loss and is responsible for nearly 64% of cases who develop graft failure. Detection of DSA is associated with 10 fold increase in the risk of graft loss. (3) Not all DSAs have bad impact on graft survival ad this depends on the followings:
1- DSA type: (denovo vs preexisting)
2- Strength of DSA (MFI): by luminex
3- Complement fixing ability of DSA :
4- DSA sub class:
5- Specificity of DSA :
Will you proceed with the transplantation? If yes, what is your immunosuppression protocol? If not, what are the other options
I will proceed for transplantation since there is ABO compatibility, excellent HLA matching with 0 DR mismatch, negative cross match and no DSA detected, although the graft survival of deceased is lower than living donor transplantation. (12) but it may be preferred in the setting of FSGS
Immunosuppression protocol will include basiliximab induction and triple maintenance immunsosupression including tacrolimius, MMF and steroids
If the donor is not suitable other options will be:
What is the impact of the primary disease on graft survival in the indexed case?
FSGS is classified into primary, secondary (due to hyperfiltration, toxins, viral infection or previous injury) or genetic: due to gene mutation for nephrin (NPHS1) or podocin (NPHS2)
Recurrence rate in patients with primary FSGS is high (up to 57%) especially in the early post-transplant period (first 3 months) (13), while secondary FSGS and genetic FSGS recur less. In practice it may be difficult to determine the actual risk of recurrence since sometimes it is difficult to differentiate between types of FSGS.
Risk factors for recurrence of primary FSGS
Patients commonly presents in the early post-transplant period (first 3 months) with rapid onset of proteinuria (usually nephrotic range), associated with renal impairment in most of the cases.
Recurrent FSGS is associated with an increased incidence of allograft loss. In one study it was found that graft failure occurred 2 years after recurrence in 48% of recipients who develop recurrent primary FSGS (20)
In summary FSGS recur in half of the patient with primary FSGS and once recur it can cause graft loss in nearly half of the patients 2 years after recurrence.
REFERANCES
1- Terasaki PI. Histocompatibility testing, 1980, 1980.
2- Hata Y, Cecka JM, Takemoto S, Ozawa M, Cho YW, Terasaki PI. Effects of changes in the criteria for nationally shared kidney transplants for HLA-matched patients. Transplantation 1998; 65 (2): 208.
3- C. Wiebe, I. W. Gibson, T. D. Blydt-Hansen et al., “Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant,” American Journal of Transplantation, vol. 12, no. 5, pp. 1157–1167, 2012.
4- Haas M, Mirocha J, Reinsmoen NL, et al. Differences in pathologic features and graft outcomes in antibody-mediated rejection of renal allografts due to persistent/recurrent versus de novo donor-specific antibodies. Kidney Int 2017; 91:729
5- Tait BD, Süsal C, Gebel HM, et al. Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation. Transplantation 2013; 95:19.
6- Parajuli S, Joachim E, Alagusundaramoorthy S, et al. Donor-Specific Antibodies in the Absence of Rejection Are Not a Risk Factor for Allograft Failure. Kidney Int Rep 2019; 4:1057.
7- Haas M, Mirocha J, Reinsmoen NL, et al. Differences in pathologic features and graft outcomes in antibody-mediated rejection of renal allografts due to persistent/recurrent versus de novo donor-specific antibodies. Kidney Int 2017; 91:729.
8- Loupy A, Lefaucheur C, Vernerey D, et al. Complement-binding anti-HLA antibodies and kidney-allograft survival. N Engl J Med 2013; 369:1215.
9- Lefaucheur C, Viglietti D, Bentlejewski C, et al. IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury. J Am Soc Nephrol 2016; 27:293.
10- Aubert O, Bories MC, Suberbielle C, et al. Risk of antibody-mediated rejection in kidney transplant recipients with anti-HLA-C donor-specific antibodies. Am J Transplant 2014; 14:1439
11- Jolly EC, Key T, Rasheed H, et al. Preformed donor HLA-DP-specific antibodies mediate acute and chronic antibody-mediated rejection following renal transplantation. Am J Transplant 2012; 12:2845.
12- 2009 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1999-2008. U.S. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, MD.
13- Uffing A, Pérez-Sáez MJ, Mazzali M, et al. Recurrence of FSGS after Kidney Transplantation in Adults. Clin J Am Soc Nephrol 2020; 15:247.
14- Nehus EJ, Goebel JW, Succop PS, Abraham EC. Focal segmental glomerulosclerosis in children: multivariate analysis indicates that donor type does not alter recurrence risk. Transplantation 2013; 96:550.
15- 3Abbott KC, Sawyers ES, Oliver JD 3rd, et al. Graft loss due to recurrent focal segmental glomerulosclerosis in renal transplant recipients in the United States. Am J Kidney Dis 2001; 37:366.
16- Striegel JE, Sibley RK, Fryd DS, Mauer SM. Recurrence of focal segmental sclerosis in children following renal transplantation. Kidney Int Suppl 1986; 19:S44.
17- Conlon PJ, Lynn K, Winn MP, et al. Spectrum of disease in familial focal and segmental glomerulosclerosis. Kidney Int 1999; 56:1863.
18- Canaud G, Dion D, Zuber J, et al. Recurrence of nephrotic syndrome after transplantation in a mixed population of children and adults: course of glomerular lesions and value of the Columbia classification of histological variants of focal and segmental glomerulosclerosis (FSGS). Nephrol Dial Transplant 2010; 25:1321.
19- Schachter ME, Monahan M, Radhakrishnan J, et al. Recurrent focal segmental glomerulosclerosis in the renal allograft: single center experience in the era of modern immunosuppression. Clin Nephrol 2010; 74:173.
20- Francis A, Trnka P, McTaggart SJ. Long-Term Outcome of Kidney Transplantation in Recipients with Focal Segmental Glomerulosclerosis. Clin J Am Soc Nephrol 2016; 11:2041.
Hi Dr Yusuf,
I like your reply. However, I would not call it excellent mismatch, though it is a good enough match.
Comment on the report.
· a potential recipient of 31 years old, his blood group is B+ve, having a deceased kidney offer from a deceased donor 29 years, his blood group is O-ve
· HLA matching revealed 110 mismatches.
· Wet cross match is -ve by flow cytometry.
· No DSA.
Comment on the difference between the broad and the split mismatch.
· Broad mismatch is defined by the degree of matching at the major antigenic loci, HLA-A, HLA-B & HLA-DR.
· Split mismatch is defined by the degree of matching at the partial antigenic loci as the subdivisions of HLA-DR, i.e DRB1, DRB2, DRB3, DRB4, and so on.
What is the impact of split mismatch on graft survival?
· split mismatch has a modest effect on graft survival but insignificantly affects patient survival
Explain how the presence of DSA would influence graft survival.
· DSA will greatly affect graft survival due to serious acute and chronic antibody-mediated rejection. if the titer of DSA is very high, hyperacute rejection will occur unless pre-transplant removal of these DSA was done.
Will you proceed with the transplantation?
· yes
If yes, what is your immunosuppression protocol?
· induction therapy with Basilixumab
· maintenance therapy with Tacrolimus, MMF, and prednisolone.
If not, what are the other options?
· paired kidney exchange to minimize the degree of mismatching.
What is the impact of the primary disease on graft survival in the indexed case?
· recurrent FSGS can occur with possible graft loss unless plasmapheresis and/or other intensive therapies were done
That is a wonderful reply, dear Dr Omar. I wish you could support your arguments with evidence.
How would you monitor for post-transplant FSGS recurrence?
Why consider paired donation in light of this very young cadaveric donor?
Ajay
thank you, sir,
Paired or pooled donation is applicable ONLY in living donor operation, not in cadaveric organ donation.