Graft survival;
Studies found that, increased HLA mismatches are associated with risk of overall graft failure ,death –censored graft failure and all cause mortality .
Patient survival
Also studies found an increased risk of mortality in recipients with increased HLA mismatches .
Acute rejection rate
Several retrospective studies have demonstrated that HLA matching is associated with a lower risk of acute rejection among kidney transplant recipients Although most of these studies were performed in patients receiving cyclosporine-based immunosuppressant . The number of HLA mismatches was found to be an independent risk factor for acute rejection .
Post-transplant adverse events;
1-Death with a functioning graft:
The number of HLA-A, -B, and -DR mismatches correlated with a higher cumulative incidence of death with a functioning graft, from any cause, during the first three years post-transplant. This association was significant for death due to cardiovascular or infectious causes but not from malignancy.
2-Post-transplant lymphoproliferative disorders:
HLA-DR mismatches are associated with a twofold higher risk of developing post transplant non-Hodgkin lymphoma.
3-Post-transplant bone fractures;
HLA mismatches are associated with an increased risk of post-transplant bone fractures in kidney transplant recipients.
References:
1- Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017.
2. Williams RC, Opelz G, Weil EJ, McGarvey CJ, Chakkera HA. The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts 2: Living Donors, Summary, Guide. Transplant Direct. 2017 Apr 7;3(5):e152.
Akram Abdullah
3 years ago
HLA matching has a number of advantages, including improved graft function, longer graft life, the chance for less immunosuppression and , fewer rejection events. HLA mismatches are associated with more frequent rejection reactions, which necessitate higher immunosuppression, which increases the risk of infection and cancer. Sensitization can occur as a result of HLA mismatches, which might diminish the likelihood of a repeat transplant and lengthen the waiting period.. -Based on the number of HLA- and HLA-DR mismatches in living donor and deceased donor kidney transplants, there is a significant difference in renal graft survival up to 3 years utilizing our current immunosuppressive procedures -Avoiding donor antigens to which a patient has antibodies, reducing antibody strength to an acceptable level, and/or using more intensive immunosuppression may be used as matching methods for sensitized patients.
Abdullah Raoof
3 years ago
Human leukocyte antigen (HLA) mismatches have been shown to adversely affect renal allograft outcomes and remain an important component of the allocation of deceased donor (DD) kidneys. The ongoing importance of HLA mismatches on transplant outcomes in the era of more potent immunosuppression remains debatable. Using Australia and New Zealand Dialysis and Transplant Registry, data for live and DD renal transplant recipients between 1998 and 2009 showed . The association between the number of HLA mismatches and HLA-loci mismatches and outcomes were examined. Of the 8036 renal transplant recipients, 59% had between 2 and 4 HLA mismatches. Compared with 0 HLA mismatch, increasing HLA mismatches were associated with a higher risk of graft failure and patient death in the adjusted models. HLA mismatches were associated with an incremental risk of rejection although the relative risk was higher for live donor kidney transplants. Increasing HLA-AB and HLA-DR mismatches were associated with a greater risk of acute rejection, graft failure, death-censored graft failure, and/or death. There was no consistent association between initial immunosuppressive regimen and outcomes. Our results corroborate and extend the previous registry analyses demonstrating that HLA mismatches are associated with poorer transplant outcomes independent of immunosuppression and transplant era.
Abdullah Raoof
3 years ago
The kidney Graft survival is better with no DSA than with any DSA. DSA is associated with higher incidence of antibody mediated rejection and chronic allograft nephropathy. This correlation is supported by : 1- The presence of complement split product (C4d) is associated with antibody mediated allograft injury. 2- The association of donor anti HLA specific antibody with bad transplant result. In the early post transplant period, the incidence of acute antibody mediated rejection is about 2-5%, but the incidence is increased to about 40% when recipient has a positive donor HLA specific antibody before transplantation or when he receive desensitization therapy. Preexisting (pre transplant ) DSA and de novo DSA ( new emergent one ) is associated with bad allograft result. Even with the presence of low titer DSA ( MFI level less than 3000 ) it may cause subtle graft damage, which may end with chronic allograft nephropathy.
DSA (De Novo)DevelopmentRisk Factors
There are many risk factors for the development of DSA,antibody mediated rejection and graft failure. Although Anti HLA class I antibody may play a role, the more important role is for HLA- class II antibody. Therefore the presence of HLA-DR, HLA- DQ,HLA–DP mismatch carry a higher risk for late onset antibody mediated rejection.
Risk factors are
– 2nd transplantation
– Pre transplant DSA
– Young(18–35 y )
– Deceased donor
– DR, DQ mismatch
– Non compliance-Non adherence
– Inadequate immune suppression
– Inflammatory process(infection)
– Rejection TCMR (Subclinical) In their study, hidalgo et al,demonstrate dnDSA in 37% of recipient after years of transplantation , and the antibodies are mainly of dnDSA type ( 60%) directed against HLA –CLASS II mismatched antigen. Half of grafts was lost at five year of dnDSA detection. Another study by Wiebe et al, showed ten fold higher graft loss and 40% lower ten year graft survival in patient with positive dnDSA than without these antibodies. 24% graft failure, after 3 years of dnDSA detection has been demonstrated by Everly et al. Everly et al, demonstrated a 24% graft failureafter 3 years of dnDSA detection .(10) The complement fixing DSA has worse graft outcome than with non complement fixing. Graft survival at 5 year is 54% with complement fixing DSA which is far less than survival with non complement fixing DSA of 93%.
Ahmed Ziada
3 years ago
HLA mismatch negatively affect long-term graft survival. HLA-DR matching appears the most powerful in this context, but the number of mismatches is important.
Incidence of DGF Increases with HLA mismatch.
incidence of acute rejection Increased too, subsequent usage of immunosuppressive drugs may exposes patient to infection and malignancy which may affect patient survival
Alyaa Ali
3 years ago
higher degree of HLA mismatching is associated with worse transplant outcome
UNOS registry : there was a 13 percent higher risk of graft failure with one HLA mismatch and a 64 percent higher risk with six HLA mismatch
Australian and New Zealand Dialysis and Transplant Registry that included living and deceased donor kidney transplant recipients increasing HLA mismatches were associated with a higher risk of graft failure
Relative importance of specific HLA antigens: several studies have demonstrated that mismatches at individual HLA loci do not have equal weight with regards to transplant outcomes( there is strong association between HLA matching HLA -A, -B and -DR loci)
long term graft survival is better in HLA matching in both deceased and living donors
patient survival of highly sensitized recipients of HLA mismatched kidneys is higher when compared with highly sensitized transplant candidates who remain in the waiting list
HLA matching is associated with a lower risk of acute rejection
HLA matching has been associated with higher risk of death with a functioning kidney allograft
HLA matching is an independent risk factor for development of post transplant non hodgkin lymphoma
UP TO Date
Mahmoud Hamada
3 years ago
cross matching between donor and recipient has been a corner stone in transplantation work up.
possibilities ranges from zero mismatch to 6 mismatches.
several studies proved that the degree of mismatch is proportionally associated with poor transplantation outcome and poor prognosis.
Graft survival
In the transplant registry (1), there was a significant prolonged survival among zero mismatched recipients and those with positive mismatches.
Patient survival
on contrary to graft survival, a large transplantation trial (2) has shown results that recipients of mismatched kidney had better long term survival than those who never got kidney transplantation or those who received transplant from matched deceases donor.
Acute rejection rate
Many trials (4-5) are in concordance that acute rejection rates are significantly less among recipients of matched kidney transplant.
Post-transplant adverse events
HLA mismatch is associated with some post transplantation adverse effect including bone fracture. up to 9% as reported in one large retrospective study.(5).
references:
1 – The Scientific Registry of Transplant Recipients http://www.ustransplant.org (Accessed on February 02, 2010).
2- Orandi BJ, Luo X, Massie AB, Garonzik-Wang JM, Lonze BE, Ahmed R, 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. Survival Benefit with Kidney Transplants from HLA-Incompatible Live Donors. N Engl J Med. 2016 Mar 10;374(10):940-50. doi: 10.1056/NEJMoa1508380. PMID: 26962729; PMCID: PMC4841939.
3- McKenna RM, Lee KR, Gough JC, Jeffery JR, Grimm PC, Rush DN, Nickerson P. Matching for private or public HLA epitopes reduces acute rejection episodes and improves two-year renal allograft function. Transplantation. 1998 Jul 15;66(1):38-43. doi: 10.1097/00007890-199807150-00006. PMID: 9679819.
4- Wissing KM, Fomegné G, Broeders N, Ghisdal L, Hoang AD, Mikhalski D, Donckier V, Vereerstraeten P, Abramowicz D. HLA mismatches remain risk factors for acute kidney allograft rejection in patients receiving quadruple immunosuppression with anti-interleukin-2 receptor antibodies. Transplantation. 2008 Feb 15;85(3):411-6. doi: 10.1097/TP.0b013e31816349b5. PMID: 18322434.
5- Nikkel LE, Hollenbeak CS, Fox EJ, Uemura T, Ghahramani N. Risk of fractures after renal transplantation in the United States. Transplantation. 2009 Jun 27;87(12):1846-51. doi: 10.1097/TP.0b013e3181a6bbda. PMID: 19543063.
Ibrahim Omar
3 years ago
in both living and deceased donor transplantation, HLA mismatch affects the outcome. the intensity of induction and maintenance therapies is directly proportional to the degree of mismatch. consequently, the short and long-term adverse events will be increased.
acute rejection rate and so graft survival will be increased, particularly in the 1st year, with increasing mismatch. however, patient survival is almost the same.
being the graft from living or deceased donor, rather than matching status, will greatly affect the outcome. it is estimated that the outcome of living related transplantation with 000 mismatch equal that of deceased related transplantation with 222 match.
saja Mohammed
3 years ago
What is the effect of HLA mismatch in living and deceased donor transplantation on the following?
Graft survival
Patient survival
Acute rejection rate
Post-transplant adverse events
The HLA match between recipient and donor for HLA A-B-C and DR antigen can affect both graft and patient survival for both living and DD program the higher the mismatch 4 -6mismatch associated with lower graft survival and higher the risk of DGF , acute rejection in first year and subsequent Chronic AMR and post transplant infection , PTLD and cardiovascular death so zero-mismatch refer to absent of an HLA-A-B-C and DR antigen to donor phenotype but with moving to molecular level of HLA-typing may not recognize the HLA antigen at allel level that mean the serologically reported as zero-mismatch dose not rule out allel level mismatch, while six mismatch means that 2A,2B,2 DR antigen in the donor phenotype are different from those of the recipient , with high immunological risk for DGF, rejection and reduced graft survival ,and over all mortality due to increase risk of infection , metabolic complications with cardiovascular events so kidney allocation program based on the number of HLA mismatch considered important predictor for risk of DGF, one year acute ejection rate and 10 years graft survival for both living donor and DD transplant based on different data from varies registers since 1987TILL 2013 by UNOS , revised in 2014 , SRTR ,ANZDATA. based on data from SRTR that found the mismatch for HLA-A, -B, and -DR has been associated with a higher risk of HLA sensitization in both adult and pediatric patients who are relisted for a second kidney transplant. the risk of sensitization increased by 37% for six-mismatch in HLA A-B-, DR antigens as they carry the most polymorphism.
references 1-up to date “Kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing”.) 2-hi, X., Lv, J., Han, W. et al. What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients. BMC Nephrol19, 116 (2018).
Ahmed Omran
3 years ago
Increasing extent of HLA mismatching results in worsening transplant outcomes.in case of deceased donors,13 %increased risk of graft failure was found with HLA mismatch. The risk increases to &64%with six HLA mismatches,1.Studies involving both live and deceased donors revealed that one HLA mismatch was associated with 7 % higher risk of graft failure compared to74%with six HLA mismatches,2.Certain mismatches at HLA loci ;namely HLA -A,B&DR ones ,;as being most polymorphic, have their impact on patient and graft outcomes,3,4.HLA-DR mismatching has more impact than HLA -Bor A,5,6.In addition ,HLA-DR mismatches with rejection episodes are associated with worse long-term survival,7. with increasing HLA mismatching,8.Sensitization occurs in 10% of cases with zero mismatching and is 37%with increasing HLA mismatching,8.Sensitization towards HLA class II antigens leads to increased incidence of major cardiac and cerebrovascular complications in addition to all-cause mortality in renal graft recipients,9.HLA DQ mismatching can lead to increased risk of rejection and allograft loss in spite being less polymorphic,10.In pre sensitized deceased donor kidney recipients ,it was found that mismatching of one or both HLA C antigens led to decreased graft survival,11.Having higher levels of pre transplant HLA-C DSA leads to increased chance of developing antibody mediated rejection in the first posttransplant year,12.In first transplant ,HLA-DP antibodies does not decrease allograft survival but it does so in case of second transplant,13714.Higher survival of renal allograft from siblings with non-inherited maternal alleles in comparison to survival of allografts from siblings with paternal alleles not inherited by the recipient .Certain degree of tolerance can result from exposure to donor antigens before transplantation,15.Eplet mismatching in HLA -DQ seems to have a significant risk for de novo DSA formation ,rejection and graft failure,16.Correlation between HLA mismatching and acute rejection was found to be independent of immunosuppressive regimen,2&3.HLA mismatching is considered s risk factor for development of non Hodgkin lymphoma,17 .Increased risk of post -transplant bone fracture is associated with HLA mismatches,18.More immunosuppressive therapy for higher risk of acute rejection is uncertain explanation.
REFERENCES:
1-Williams RC,Opelz G,McGarvey CJ,et al,The risk of transplant failure with HLA mismatch in first adult kidney allografts from deceased donors.Transplantation 2016;100:1094.
2-Lim WH ,Chadban SJ,Clayton P,et al,Human leucocyte antigen mismatches associated with increased risk of rejection,graft failure,and death independent of initial immunosuppression in renal transplant recipients.Clin Transplant 2012;26:E428.
3-Opelz G,Dohler B.Effect of human leucocyte antigen compatibility on kidney graft survival : comparative analysis of two decades. Transplantation 2007;84:137.
4-Dunn TB,Noreen H,Gillingham k,t al Revisiting traditional risk factors for rejection and graft loss after kidney transplantation .Am I Transplant 2011;11:2132.
5-Gilks WR,Bradley BA Gore SM,Klouda PT,Substantial benefits oftissue matching in renal transplantation.Transplantation 1987;43:669.
6-Doxiadis II,de Fijter JW Mallat MJ,et al Simpler and equitable allocation of kidneys from postmortem donors primarily based on ,et al ,HLA full HLA -DR compatibility .Transplantation 2007;83;1207.
7-Coupel S,Giral-Classe M,Karam G,et al,Ten-year survival of second kidney transplants :impact of immunologic factors and renal function at 12 months.Kidney Int 2003;64:674.
8-Meier-Kriesche HU,Scornik JC Susskind B,et alA lifetime versus a graft life approach redefines the importance ofHLA matching in kidney transplant patients, Transplantation 2009;88:23.
9-Malfait T,Emonds MP,Daniels L et al ,HLA Class II antibodies at the time of kidney transplantation and cardiovascular outcome: A retrospective cohort study ,Transplantation2020:104:823.
10-Lim WH,Chapman JRCoates PT,et al HLA-DQ mismatches and rejection in kidney transplant recipients ,Clin I Am Soc Nephrol 2016:11:875.
11-Tran TH ,Dohler B,Heinold A et al Deleterious impact of mismatching for human leucocyte antigen -C in presensitized recipients of kidney transplants,Transplantation,2011,92:419.
12-Aubert O,Bories MC,Suberbielle C,et al Risk of antibody -mediated rejection in kidney transplant with anti-HLA-C donor specific antibodies ,Am J Transplant 2014:14:1439.
13-Nelson KA,Youngs D ,Marks MH,Acute humoral rejection is associated with antibodies to HLA-DP,Am J Transplant 2005;5;245.
14-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.
15-Sanfilipo F, Transplantation tolerance –the search continues, N Engl J Med 1998.
16-Senev A,Coemans M,Lerut E, et al ,Eplet Mismatch Load and De Novo Occurrence of donor specific ant-HLA antibodies rejection,and graft failure afterkidney transplantation:An observational cohort study ,J Am Soc Nephrol 2020;31:2193.
17-Oplez G,Dohler B,Impact of HLA mismatching on incidence of posttransplantnon-hodgkin lymphoma after kidney transplantation,Transplantation2010;89:567.
18-Mutinga N,Brennan DC,Schnitzler MA, Consequences of eliminating HLA-B in deceased donor kidney allocation to increase minority transplantation,Am J Transplant 2005;5:1090.
Hosam El Din Fouda
3 years ago
HLA match has an important effect in kidney tx
The commonly used HLA-A. HLA-B. HLA DR
with mismatch range from 0 to 6 as each one of them has pair of loci coming from both parents.
Higher HLA matching lead to longer graft survival.and less post transplant complication
Including PTLD and bone fructures.better patient survival also documnted with better matching HLA.
HLA DR is the most important with decrease graft survival incidence with one mismatch and greater with ,2 mismatch.
lnduction with ATG plus steroids
and intensification of immuno suppression with mismatch carry risk of post tx sdverse effects like PTLD and infections.
Dear All Thank you for your replies. Feel free to contribute to the discussion for those who did not. Also, let us not forget week 2.
Balaji Kirushnan
3 years ago
Data from various registries demonstrate better survival rates with HLA matches between donor and recipient. Worst survival of patients with more number of HLA mismatches. Various countries relied on the importance of HLA Matching to improve the overall graft outcomes. Allocation schemes based on HLA matching vary worldwide. While European systems assign weights to A,B,C,DR matching, the US systems gives importance to primarily DR matching. HLA typing for waitlisted kidney transplant candidates is done by PCR technology. HLA for donor and waitlisted transplant candidate is performed for serological equivalents for HLA A,B,C, DR,DP, DQ, DR1 etc. When matching a donor to a recipient on HLA mismatch approach to organ allocation will maximize the number of patients considered to be a match with a deceased donor.
For example HLA A2 is one antigen were homozygosity is frequent. If donor has HLA A2 A2 and a recipient has HLA A2 A23 or HLA A2 A66 it is considered zero antigen mismatch as the donor has A2 homozygosity. And if donor has HLA A2A23 and recipient has HLA A2A66 it is considered 1 antigen mismatch. HLA A2 A23 in the donor and HLA A2 A23 in the recipient means a zero antigen mismatch.
Degree of mismatch between recipient and donor is primarily determined for HLA A,B,DR as they are highly expressed and highly polymorphism. Zero antigen mismatch between the recipient and donor maybe identified as the absence of HLA A,B,DR antigen in donor phenotype that is different from recipient HLA A,B,DR antigen of recipients.
A serologically defined zero antigen mismatch does not rule out allele level mismatches. 222 mismatches indicates 2A,2B and 2 DR antigens in donor phenotype are different from the those of the recipients. Kidney allocation is based on the number of HLA mismatches in UNOS and SRTR, but many studies show better survival of the allograft with better HLA matching. But using HLA Matching for allocation, limit the access to transplantation for recipients from under represented groups with rare HLA antigens not present in a primarily white donor pool.
The problem with HLA mismatch is sensitization. Exposure to non self HLA antigen can lead to antibodies against mismatched HLA antigens. HLA sensitization can result from prior exposure to HLA mismatch through pregnancy, blood transfusion, previous transplant, immune activation after any vaccine etc. For a sensitized patient donor who express HLA antigens against a patient who has preformed antibody should be avoided if possible. These are reported as unacceptable antigens.
This helps in creating a virtual cross match. Virtual cross match uses the results of the antibody tests along with the donor and patient HLA typing to predict a candidate compatibility.
UNOS has reported 13% graft failure with 1 HLA mismatch and 64% graft failure with 6 HLA mismatches. ANZDATA reported 7% graft failure with 1 HLA mismatch and 74% graft failure with 6 HLA mismatches. In general the more the mismatches worse is the graft survival.
Other antigens of HLA are also identified for mismatching and outcomes. HLA DQ mismatch is associated with an increased risk of rejection and allograft loss in kidney transplant recipients. In the UNOS study, HLA DQ mismatch has been found to have an increased risk of acute antibody mediated rejection in the later post transplant period which are mainly due to de novo HLA antibody production. The poor outcome was described with both living donor and deceased donor kidney transplant patients.
Outcome for Anti HLA C antibodies on graft outcome are controversial. around 40 to 50% of all the transplant candidates will have antibodies against HLA C. HLA DP antibodies are very rare and found only in 5 to 14% of all patients.
HLA mismatches were found to have a superior death with functioning graft in clinical trials due to Cardiovascular and infectious causes.
There has been a higher incidence of PTLD is patients with more HLA mismatches probably due to use of induction agents and other immunosuppressive agents.
Post transplant bone fractures have also been reported to be higher in these patients, although the exact mechanism is not known.
References:
Williams RC, Opelz G, McGarvey CJ, et al. The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts From Deceased Donors. Transplantation 2016; 100:1094.
Lim WH, Chadban SJ, Clayton P, et al. Human leukocyte antigen mismatches associated with increased risk of rejection, graft failure, and death independent of initial immunosuppression in renal transplant recipients. Clin Transplant 2012; 26:E428.
Esmat MD
3 years ago
HLA mismatching has been accompanied by poor graft survival (increase acute and chronic rejection) and patient survival. Although patient survival compares to waiting list is better. Furthermore, HLA mismatching has been associated with higher risk of death with functioning kidney allograft, post-transplant lymphoproliferative disorders and posttransplant bone fracture.
Ahmed Fouad Omar
3 years ago
Human leukocyte antigen (HLA) present on chromosome 6 is always an important biological barrier to a successful transplantation and has impacts on graft survival . However modern immunosuppressive agents minimized the effect of HLA compatibility. . In the revised United Kingdom kidney allocation scheme, HLA matching is no longer considered . But the latest European Renal Best Practice Transplantation Guidelines still recommended that matching of HLA-A, –B, and –DR whenever possible, while gave more weight to HLA-DR locus . HLA mismatching act as an important prognostic factor affecting both graft and recipient survivals. HLA- DR will have an important impact on graft survival while HLA- A has an insignificant role. HLA matching has a number of advantages, including improved graft function, fewer rejection episodes, longer graft survival and using less immunosuppression. Shi, X., Lv, J., Han, W. et al. What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients. BMC Nephrol19, 116 (2018)
Jamila Elamouri
3 years ago
HLA has two classes: HLA class I (A,B,C) and HLA class II (DR, DQ, Dp) Class I are expressed on all nucleated cells and produce peptides on MHC class I and signal to CD8T cell for killing. Class II are present on antigen-presenting cells (APC), mainly dendritic cells and B cells, these cells can sense antigens, engulf, process and load the antigens to activate CD4 T cells. In general, the risk of graft loss increases with increases in the mismatches MM for both the living donor (LD) and deceased donor (DD). This association has a linear order for both type of donors. There was 16% higher risk of allograft loss for 1 MM in DD and 62% for 5 and 6 MM. the effect of MM was higher in LD with 48% for 1 MM and 114% for 6 MM although, LD transplants survival rates were as long or longer than DD. The median survival for 0 MM was 25 years compared with 20 years for 1 MM, 18 years for 2 MM, 15 years for 3 MM and 12 years for higher MM The age of the donor has implication on outcomes. Older donors (≥ 45 yrs) were associated with worse outcomes in DD but not in LD. Older LD with well match (0 to 3 MM) has better graft survival than poorly matched (4 to 6 MM) younger DD. The effect of HLA MM in LD was classified in two groups, 1 to 3MM and 4 to 6 MM, this classification found to follow donor-recipient relationship types. Living related donor LRD 1st degree or living unrelated donor (LURD or LRD) HLA MM has stronger effect in Living donor than deceased donor and this effect significantly increases from the 1 to 3 MM than from 4 to 6 MM. So, one needs to weigh the poorer matched LD outcome with better matched DD outcome. Poorly matched (4-6 MM) LD had lower graft survival than a very well-matched (0-1 MM) DD. moreover, transplants from a 1-3 MM LD had comparable outcomes to the very well-matched (0-1 MM) DD group. Therefore, many studies support entering high HLA MM (4-6 MM) LD into donor paired exchange system. In addition to risk f rejection which can be decreased in part by good donor selection. Post-transplant patients are at risk of side effect of immunosuppression drugs as infection and malignancy. Squamous and basal cell skin cancers are the most common type followed by NHL/ post-transplant lymphoproliferative disorder (PTLD) and cervical cancer. There is bimodal distribution of cancer incidence with a peak of 6.6 years for NHL/ PTLD and 14.8 years for all other cancers.
reference
Kim JJ, Fuggle S V, Marks SD. Does HLA matching matter in the modern era of renal transplantation? Pediatr Nephrol [Internet]. 2021;36(1):31–40. Available from: https://doi.org/10.1007/s00467-019-04393-6
Wael Hassan
3 years ago
-HLA mismatch influences negatively on graft survival as it increase risk of acute rejection (cellular or humoral)and need more aggressive immunosuppressant whether induction or maintenance
-this aggressive immunosuppressant increase risk of infection and malignancy (kaposi sarcoma &PTLD)so it decrease patient survival
And also use of desensitization methods as plasma-pharesis&rituximab increase risk of infection and malignancy
-high rate of acute rejection specially if high DSA
fakhriya Alalawi
3 years ago
What is the effect of HLA mismatch in living and deceased donor transplantation on the following?
Graft survival
Williams RC et al. reported a linear relationship between HLA mismatch and allograft survival, in an analysis of 66,596 first adult transplants from living donors, he found that 1 mismatch conferred a 44% higher risk, whereas 6 mismatches conferred a two-fold higher risk of allograft failure. When using 0-mismatched full siblings as a reference, living-donor kidneys reduce the hazard of failure by approximately 34% when compared with deceased donors.
Moreover, Shi, X., et al, in a meta-analysis of 23 cohort studies covering 486,608 recipients, found HLA per mismatch was significantly 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).
Patient survival
In the same meta-analysis of Shi, X., et al, authors found in 4 cohorts analysis, included 180,766 recipients, found for each incremental increase of HLA mismatches, there was a higher risk of all-cause mortality rates (HR: 1.04; 95% CI: 1.02–1.07; P = 0.001).
Acute rejection rate
Several retrospective studies have demonstrated that HLA matching is associated with a lower risk of acute rejection among kidney transplant recipients Although most of these studies were performed in patients receiving cyclosporine-based immunosuppression, one study showed that the number of HLA mismatches was an independent risk factor for acute rejection (odds ratio [OR] 1.65 per HLA mismatch) in transplant patients receiving immunosuppression consisting of interleukin (IL)-2 receptor antibody induction, tacrolimus, mycophenolate mofetil, and glucocorticoids. Analyses of data from two large transplant registries found that the association between HLA mismatches and acute-rejection risk was independent of the transplant era and initial immunosuppressive regimen.
Post-transplant adverse events
Death with a functioning graft: HLA mismatching has been associated with a higher risk of death with a functioning kidney allograft. In a study of 177,584 deceased-donor kidney transplants performed between 1990 and 2009, the incidence of death with a functioning graft was 4.8 percent during the first post-transplant year and 7.7 percent during years 2 through 5 (approximately 2% per year).
The number of HLA-A, -B, and -DR mismatches correlated with a higher cumulative incidence of death with a functioning graft, from any cause, during the first three years post-transplant. This association was significant for death due to cardiovascular or infectious causes but not from malignancy.
Post-transplant lymphoproliferative disorders: Several studies have shown that HLA mismatching is an independent risk factor for the development of posttransplant non-Hodgkin lymphoma among kidney transplant recipients. As an example, in a study of 152,728 deceased-donor kidney transplant recipients from the Collaborative Transplant Study (CTS), an increased risk of posttransplant non-Hodgkin lymphoma was observed in patients with one (hazard ratio [HR] 1.21, 95% CI 1.00-1.45) and two (HR 1.56, 95% CI 1.21-1.99) HLA-DR mismatches. Similar findings were reported in an analysis of 9209 pediatric kidney transplant recipients, in which two HLA-DR mismatches were associated with a twofold higher risk of developing posttransplant non-Hodgkin lymphoma.
Post-transplant bone fractures — HLA mismatches are associated with an increased risk of post-transplant bone fractures in kidney transplant recipients. The mechanism behind this association between HLA mismatching and bone fractures is uncertain. HLA mismatches are associated with a higher risk of acute rejection, which is generally treated with more intensive immunosuppression that could adversely affect bone quality.
References:
1. Williams RC, Opelz G, Weil EJ, McGarvey CJ, Chakkera HA. The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts 2: Living Donors, Summary, Guide. Transplant Direct. 2017 Apr 7;3(5):e152.
2. Shi, X., Lv, J., Han, W. et al. What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients. BMC Nephrol19, 116 (2018).
3. MC Philogene. Kidney transplantation in adults: HLA matching and outcomes. Up-to-date. Updated: Sep 28, 2021. Accessed on 6 Nov 2021
4- Wissing KM, Fomegné G, Broeders N, et al. HLA mismatches remain risk factors for acute kidney allograft rejection in patients receiving quadruple immunosuppression with anti-interleukin-2 receptor antibodies. Transplantation 2008; 85:411.
Ben Lomatayo
3 years ago
HLA matching is associated with improved graft survival in deceased donor graft. The effect tend to be less in living donor graft whether related or unrelated. High numbers of HLA antibodies is a risk factor for DGF to start with( other factors as well donor age ,cold ischemia time ..) and increases rejection rates .DGF is less ~3% in living donation and more prominent in deceased donation ~20%. The presence of DGF means decrease graft survival, increase mortality, and increase rejection possibly to due to enhance graft immunogenicity after reperfusion. Patient survival is affected mainly by cardiovascular disease, infections and malignancy. In general the more HLA, the better the outcome but this should not be the only factor to determine kidney transplantation, and we know remaining on dialysis is much worse than getting transplanted. Relevant to living related donation HLA DRB1 two match is more important for graft survival. 0 HLA mismatch in unrelated living donation was show to be similar to any match > 0 HLA match
Dear All It was a good start, but feel free to add more contributions especially those who did not contribute much and did not contribute at all.
Hamdy Hegazy
3 years ago
I would like to thank you all those sharing their comments.
I will try to study Handbook of transplantation and find out the answers of the questions related to this scenario which I got most of them after reading your comments.
What is the effect of HLA mismatch in living and deceased donor transplantation on the following?
Graft survival
Patient survival
Acute rejection rate
Post-transplant adverse events
Prof Ahmad Halawa comments and questions:
Will you transplant 222 mismatched living kidneys and what immunosuppression you will use if there is DSA and without the presence of DSA?
Why do you think that HLA mismatching is associated with post-transplant complications? What is the link?
What is the average half-life of 222 mismatched kidney in living and deceased donor transplants? Please do not make a guess (read the handbook of Danovich or search for an answer) Some colleagues mentioned CDC crossmatch, do we have a better technique? None of you mentioned the role of DSA in categorizing the risks. Of course the presence of DSA makes the transplant associated with risk (depends on the degree of sensitization). There are a few questions to come. This scenario looks simple but it is a mindfield
What would be your immunosuppression for 222 mismatched transplants with no DSA?
What would be your immunosuppression for 222 mismatched transplants with DSA (MFI of 1345), but negative FCXM and CDC?
What is the relevance of HLA A2 and HLA A36 antigens?
this recipient consider high immunological risk with 6 mismatches and negative DSA so still can go for kidney transplant with ATG induction , followed by triple maintenance IS with tacrolimus based and MMF and DSA AB surveillance post transplant keep in consideration the higher HLA mismatches especially at the level of HLADR the higher the risk of DGF ,acute rejection and lower graft survival
for second scenario with 222 mismatches and negative CDC ,negative FCXM but DSA with MFI of 1345 , this will be depend on the local center protocol regarding the interpretation of the this MFI level , there is no standardization of MFI level as some centers consider its low level and need just monitoring after the transplantation as high immunological risk , but some they interpreted as positive with MFI >1000 , and decide a bout the desensitization prior to transplant by using modified desensitization protocol with IVIG 1gm/kg pre transplant and induction with same ATG followed by maintenance triple IS , tacrolimus based with DSA ab screening post transplant
What is the relevance of HLA A2 and HLA A36 antigens?
I believe the HLA-A2 is commonly sharing antigen in white population with homozygosity is more frequent, and such donor will likely be zero-mismatch for a patient with HLA-A2-A23, HlA -A2-A66, while donor with HLA A2-A23 will be zero-mismatch only for patient with HLA A2-A23 .
regarding the HLA A 36 antigen its specific to black race and im not sure about its interpretation .
Ahmed Saleh
3 years ago
HLA antibodies have been always considered an important biological barrier for successful renal transplantation (1).
However, that effect of HLA was minimized after the introduction of new immunosuppressive medications. The United kingdom allocation system has been modified over the years initially in 1995 where HLA-A similarity was eliminated similarly HLA-B similarity was eliminated in 2003, finally, in 2010, HLA matching is no longer considered (2).
On the other hand, European Renal Best Practice Transplantation Guidelines still recommend HLA -, HLA-B, and HLA-DR whenever possible which gave importance for DR locus in renal Tx (3). This inconsistency about the importance of HLA mismatching in the renal transplant practice made that topic always a hot topic for various discussions, research studies, and meta-analyses. Therefore Xinmiao Shi et al managed to perform this following meta-analysis which first meta-analysis to evaluate the magnitude effect of HLA mismatching on post-transplant survival outcomes of adult kidney transplantation (4). They had interesting results which were 1- HLA mismatch and overall graft failure:
Their analysis of Eleven studies (289,987 adult recipients), revealed with every increase in HLA mismatch there is a higher risk of overall graft failure.
On further categorization of HLA mismatch categories and relation to graft failure
· HLA- DR and overall graft failure
They analyzed eight studies including 152,105 adult recipients which revealed each incremental increase of HLA-DR mismatches was significantly associated with a 12% higher risk of overall graft failure. · HLA-B mismatches and overall graft failureThey analyzed 4 studies with 146,019 recipients which revealed each incremental increase of HLA-B mismatches was not associated with a higher risk of overall graft failure · HLA-A mismatches and overall graft failureThey studied Only 3 studies (40,000 recipients), which showed an insignificant association between HLA- A mismatch and graft failure in renal Tx recipients. 2- Recipient mortalityThey included 180,766 recipients from 4 cohorts. They concluded that Each incremental increase of HLA mismatches was associated with a higher risk of all-cause mortality ratesMoreover, Croke R et al (2010) had demonstrated in their study that HLA mismatch is associated with a higher risk of graft failure and rejection.
Conclusion
HLA mismatching act as an important prognostic factor affecting both graft and recipient survivals. HLA- DR will have an important impact on graft survival while HLA- A has an insignificant role. New Zealand study group had demonstrated in their research that HLA mismatch is associated with a higher risk of graft failure and rejection.
References 1- Al-Otaibi T, Gheith O, Mosaad A, Nampoory MR, Halim M, Said T, et al. Human leukocyte antigen-DR mismatched pediatric renal transplant: patient and graft outcome with different kidney donor sources. Exp Clin Transplant. 2015;13(Suppl 1):117–23.
2- Johnson RJ, Fuggle SV, O’Neill J, Start S, Bradley JA, Forsythe JL, et al. Factors influencing outcome after deceased heart beating donor kidney transplantation in the United Kingdom: an evidence base for a new national kidney allocation policy. Transplantation. 2010;89(4):379–86.
3- Abramowicz D, Cochat P, Claas FH, Heemann U, Pascual J, Dudley C, et al. European renal best practice guideline on kidney donor and recipient evaluation and perioperative care. Nephrol Dial Transplant. 2015;30(11):1790–7.
4- Shi, X., Lv, J., Han, W. et al. What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients. BMC Nephrol19, 116 (2018). https://doi.org/10.1186/s12882-018-0908-3
5- Croke R, Lim W, Chang S, Campbell S, Chadban S, Russ G, et al. HLA-mismatches increase risk of graft failure in renal transplant recipients initiated on cyclosporine but not tacrolimus. Nephrology. 2010;15:38.
saja Mohammed
3 years ago
kidney transplantation as an option of RRT still associated with better quality of life in comparison to dialysis but HLA mismatching still consider as important prognostic factor that affect both living and deceased donor kidney graft survival ,recipient survival and over all out come , the higher the mismatch the more the risk of graft rejection .Mismatches in HLA-DR antigen, 1 mismatches and 2 mismatches were all associated with higher risk of overall graft failure, with pooled HRs of 1.12 (95% CI: 1.04–1.21; P = 0.002) and 1.15 (95% CI: 1.05–1.25; P = 0.002)(1)
HLA-A mismatch associated with 6% risk of rejection while HLA-B mismatch have in significant risk on graft failure based on several studies but we should keep in mind each additional HLA mismatch increases the risk of graft failure
1-Reference, Shi et al. BMC Nephrology (2018) 19:116
2-Reference Transplantation ■ May 2016 ■ Volume 100 ■
Nazik Mahmoud
3 years ago
We concern about 6 HLA antigen matched between the donor and recipient,if we had zero mismatch that mean very good graft and patient survival, minimal immune suppression medications and less post transplant complications (infections ,malignancy and rejection )but this could be done in living donor as we can search for better matching but in deceased donor it may not available
Rania Mahmoud - Suspended
3 years ago
-The human leukocyte antigen (HLA) is a significant biological key to effective transplantation and has a major effect on graft survival.
-Human HLA genes are found on chromosome 6 and code for three major class I alleles (HLA-A, -B, and -C) as well as three significant class II alleles (HLA-DR, -DQ, -DP). HLA polymorphisms, particularly in the HLA-A, -B, and -DR loci, are key biological barriers to transplantation success.
-Mismatching HLA-DR has a serious influence on graft survival in recipients.
-In organ transplantation, HLA matching has a number of advantages, including improved graft function, fewer rejection events, longer graft life, and the chance for less immunosuppression.
-Mismatches are associated with more frequent rejection reactions, which necessitates higher immunosuppression, which increases the risk of infection and cancer. Sensitization can occur as a result of HLA mismatches, which might diminish the likelihood of a repeat transplant and lengthen the waiting period. Other parameters, including as donor aging, type, and immunosuppressive regimen, can, however, influence the benefit of matching.
-An increasing need for antirejection medicine was linked to an increase in the number of HLA mismatches in renal transplantation, which could account for an increased incidence of death with a working graft due to infection and cardiovascular disease.
-Based on the number of HLA-ABDR and HLA-DR mismatches in living donor and deceased donor kidney transplants, there is no significant difference in acute rejection rate and renal graft function up to 3 years utilizing our current immunosuppressive procedures. Medically suitable living donors produce better long-term outcomes than deceased donors, regardless of the amount of HLA-ABDR mismatches.
-Avoiding donor antigens to which a patient has antibodies, reducing antibody strength to an acceptable level, and/or using more intensive immunosuppression may be used as matching methods for sensitized patients.
References:
–What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients.Available at :https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-018-0908-3 (Accessed5/11/2021)-The impact of HLA-ABDR mismatch on acute rejection and graft function among Filipino kidney transplant recipients .Available at : https://www.oatext.com/pdf/TiT-10-231.pdf (Accessed 5/11/2021)
Mina Meshreky
3 years ago
First of all
●REGARDING HLA TISSUE TYPING : Serologic-based typing was the first standard method used to obtain donor and recipient HLA typing and was employed for more than 30 years. This technique uses a panel of reference sera (usually from multiparous women) that are known to contain antibodies to various HLA antigens.
● Lymphocytes from the donor or the recipient are added to several wells of plates having different sera.
Following an initial incubation step to allow binding between antibody and antigen, complement is added to wells, and a viability dye allows detection of cell lysis.
The presence of dead cells is a positive test.
Comparison of the serologic specificities of the different sera that reacted allows one to assign the HLA type.
●●Hla typing is done by 2 methods either serological or by Dna typing.
● DNA-based molecular methods include the following:
1- (((((Sequence-specific primers (SSP) typing))))
– This form of typing involves the use of primers designed to recognize a particular HLA sequence (allele) or group of similar alleles, such that the polymorphism to be detected is located at the 3′ end of the primer. DNA is first extracted from a blood sample and amplified by PCR using these primers. If both primers are able to bind to the DNA, then amplification occurs and can be detected by gel electrophoresis. The pattern of amplicons that are present allows for the assignment of the HLA genotype.
2- ((((Sequence-specific oligonucleotide probes (SSOP) typing ))))
– With SSOP typing, DNA is amplified using a set of primers that recognize a particular HLA locus. As with SSP typing, primers are designed to amplify the most polymorphic regions of the HLA gene (exons 2 and 3 for class I genes and exon 2 for class II genes).
3- ((((Real-time PCR (RT-PCR)-based typing)))))
– This form of typing is based upon the use of allele-specific PCR similar to SSP methods. However, instead of using gel electrophoresis, amplicons are detected in real time with the use of fluorescent dyes or probes. Each well contains sequence-specific primers such that if the allele is present, the DNA becomes amplified. The added cyanine dye binds to any amplified, double-stranded DNA and fluoresces.
4- ((((Sequence-based typing (SBT) – SBT, or Sanger-based sequencing)))))
is based upon the direct amplification and sequencing of the relevant exons using fluorescently labeled dideoxynucleotides. Since this method deciphers the specific nucleotide sequence of the amplified region, it allows for a high resolution typing. This sequence is then compared with known sequences of HLA alleles in the IPD-MGT/HLA database to assign the HLA typing.
5- ((((Next-generation sequencing (NGS))))))
– The advent of NGS techniques has enabled high-resolution typing with significantly reduced ambiguity as it allows for base calls to be assigned to the same (cis) or different (trans) alleles (also known as phasing).
●●Regarding ptn survival :
The incidence of death is 4.8% during the ( 1st ) Tx year and
7.7% during the 2 post Tx years up to 5th year
With the % increasing by every year.
The HLA-A + HLA- B + HLA- DR mismatches lead to death % that was found to be lesser than the % of death from other cause ( cardiovascular or 8nfection) but with a functioning graft.
●●Patient survival was higher among recipients of HLA-mismatched kidneys at
1 year ((89)) vs ((95)) percent,
5 years ((59)) vs ((86))%
Even compared with waitlisted candidates who eventually received a deceased-donor kidney, survival was higher among recipients of HLA-mismatched kidneys at
1 year ((94)) vs ((95)) %
5 years((74.4 ))vs ((86 ))%
●● Regarding the long Term graft survival Most transplants that are lost to acute rejection do so within the first year.
Later graft loss is primarily due to chronic rejection.
●●POST Tx ADVERSE OUTCOMES:
1-Post Tx lymphoproliferative disorders
2- Post Tx bony fractures ( mechansim is not yet establishedbut may be from increasing ( intensifying the dose of the i.suppressive ttt)
_____Risk of fractures after renal transplantation in the United States.
_____Nikkel LE, Hollenbeak CS, Fox EJ, Uemura T, Ghahramani N
______Transplantation. 2009 Jun;87(12):1846-51.
♧♧♧N.B. :
HLA-DR mismatches were associated with a twofold higher risk of developing posttransplant non-Hodgkin lymphoma
♧♧♧A limitation of strictly using HLA typing for organ allocation is the difficulty in finding well matched kidneys.
The United States United Network for Organ Sharing (UNOS) program mandates that six-antigen-matched grafts be given priority.
______Takemoto SK, Terasaki PI, Gjertson DW, Cecka JM
By mentioning this paragraph i meant (( in deceased renal tx ) : A limitation of strictly using HLA typing for organ allocation is the difficulty in finding well matched kidneys.
The United States United Network for Organ Sharing (UNOS) program mandates that six-antigen-matched grafts be given priority.
______Takemoto SK, Terasaki PI, Gjertson DW, Cecka JM
______N Engl J Med. 2000;343(15):1078.
Heba Wagdy
3 years ago
Graft survival:
The effect of each HLA mismatch is different, HLA-DR mismatches are corelated with poor long term survival (1)
the effect of DR mismatch mostly occur during first 6 months while that of B mismatch occur within 2 years (2)
According to (UNOS), it’s important to decrease mismatches and increase matches (3)
Anti HLA-DQ with or without other DSA lead to more acute rejection, increased risk of allograft loss and lower 5 year graft survival (4)
recipients with de novo DSA lave more recurrent acute rejection and antibody mediated rejection than those with negative DSA (5)
Patient survival:
one or more HLA mismatches increase risk of acute allograft rejection and require potent immunosuppression and induction with Thymoglobulin which leads to increased risk of infection which is a leading cause of mortality post transplant especially in early period
Acute rejection rate:
HLA mismatches increase the risk of development of acute rejection and subclinical rejection
increase sensitivity of pretransplant testing of anti HLA antibodies decrease the rate of acute and subclinical rejection
post transplant adverse events:
HLA mismatches increase risk of rejection which require intensification of immunosuppression using Thymoglobulin, high dose glucocrticoids or plasmapharesis which may lead to PTLD, diabetes, HTN, dyslipidemia, bone fractures and cardiovascular events.
(1) Coupel S, Giral-Classe M, Karam G, et al. Ten-year survival of second kidney transplants: impact of immunologic factors and renal function at 12 months. Kidney Int 2003; 64:674.
(2) Dialysis and Transplantation, Owen WF, Pereira BJ, Sayegh MH (Eds), WB Saunders, Philadelphia 2000. p.504
(3) Williams RC, Opelz G, McGarvey CJ, et al. The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts From Deceased Donors. Transplantation 2016; 100:1094.
(4) Freitas MC, Rebellato LM, Ozawa M, et al. The role of immunoglobulin-G subclasses and C1q in de novo HLA-DQ donor-specific antibody kidney transplantation outcomes. Transplantation 2013; 95:1113.
(5) Devos JM, Gaber AO, Teeter LD, et al. Intermediate-term graft loss after renal transplantation is associated with both donor-specific antibody and acute rejection. Transplantation 2014; 97:534.
graft and patient survival
living donor kidney allografts are associated with 34% reduced risk of kidney failure compared with any deceased donor kidney among all organ recipients with 1 to 6 mismatches.
the induction and immunosuppressive protocols are the same for allografts from deceased or living donors.
kidneys from deceased donors are associated with lowest impact of hla mismatch,kidneys from live related donors are associated with an intermediate hazard from HLA mismatch and kidneys from live unrelated donors are associated with a high impact from HLA mismatch.
HLA DR per mismatch was associated with a 12% higher risk of overall graft failure.compared with 0 DR mismatches, 1 and 2 mismatches were associated with 12 and 15% higher risk of overall graft failure respectively.
HLA A per mismatch was associated with a 6% higher risk of overall graft failure.
there was no significant association between HLA B mismatching and graft survival.
living allografts have smaller hazard ratios than deceased allografts within a mismatch category.like when there are 2 mismatches,living allografts have a significantly better survival than 0 mismatched deceased donor.however when there are 3 mismatches the hazard ratio for living allograft is not significantly different from the deceased.a live related 6 mismatch kidneys have a hazard ratio of 1.14,the confidence of which include 1.00.so in transplantation usually a living relative or a non relative with many HLA mismatches is preferable or of equal value to a closely matched deceased donor.
HLA mismatches lead to an increased incidence of acute rejection which requires intensive immunosuppression leading to side effects like infections,diabetes,avn of femur,hypertension,cardiovascular events
What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients
The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts 2: Living Donors, Summary, GuideRobert C. Williams, PhD,1 Gerhard Opelz, MD,2 E. Jennifer Weil, MD,1 Chelsea J. McGarvey, MD,3 and Harini A. Chakkera, MD4
HLA DR1,4,7, B8,12,40, A1,2,11 are associated with a significantly reduced risk of sensitization (15% less likely)
HLA B42,53 ,A 10,19,36 is associated with an increased risk of PRA responses(38% increased risk).
HLA phenotypes of ESRD patients are risk factors in the panel-reactive antibody (PRA) response
E Heise 1, C Manning, L Thacker
CDC negative,FCMX positive,
DSA absent- accept for transplant with thymoglobulin induction.
DSA class 1 and 2 present
MFI <1000- transplant with thymoglobulin induction
MFI 1000-10000- Plasmapharesis plus low dose IVIG plus ATG(target MFI<1000 OR FCMX negative with MFI< 1500)
MFI>10000 – Avoid transplant.
HLA desensitization based on results of the luminex technique in kidney transplant – A single-center experience
SB Bansal1, A Gade1, S Sinha2, A Mahapatra1, P Jha1, SK Sethi1
Asmaa Khudhur
3 years ago
Mismatch between donor and recipient is determined by HLA-A,HLA-B,HLA-DR each contain 2 Ag ,so 6 mismatch between donor and recipient are not matching.
The survival of patients who are highly sensitized due to HLA mismatch is lower than HLA matching kidney transplantation.
HLA-DR ,HLA-B Ag mismatch associated with poor graft outcome.
HLA-DQ mismatch is associated with poor long term survival.
2 HLA-DR mismatch in pediatric population preclude kidney transplantation due to higher degree of sensitization.
HLA-A2 associated with poor survival .
Transplantation from living donor is more better regarding graft survival and long term outcome in compare with deceased donor due to the effect of increase immunogenicity of deceased organ and the era of ischemia reperfusion injury.
Improve the IS protocol decrease the effect of mismatching.
HLA mismatch lead to the use of aggressive IS which ultimately lead to post transplant complications like DM HT ,dyslipidemia, infection ,cardiovascular events, bone fracture and PTLD.
A Well-matched Allograft From a Deceased Person Is Equivalent or Better in Survival to One From a Poorly Matched Living Donor
Ahmed Faisal
3 years ago
Typing and compatability of HLA is an essential step in kidney transplantation. Testing for histocomptability is aimed for assessment of mismatching between the donor and the recipient and therefore for classification of immunological risk of the recipient according to the the potential donors.
Zero mismatches of HLA has a higher rate of the graft survival than one or more of mismatches of HLA.
HLA A,B and DR has higher association with poor outcome of the recipient and the graft survival, in contrast to mismatching in HLA A alone which has a little effect.
Donor specific antibody (DSA) is the antibodies formed in the recipient against potential donors. It may be presented due to previous blood transfusion, previous transplantation and pregnancy. In this case, there is sensitization against the donor which carries a great risk for graft rejection and inferior outcomes.
DSA should be tested before transplantation by immunological laboratory techniques which done by cell-based method (complement dependent cytotoxicity and flowcytometry) and solid phase immunoassays (ELISA and Luminex).
Reference
Chari M, Kosi ME, Jim JK, Sharma A, Halawa A (2017) Crossmatching in Renal Transplantation by Non-Immunologists for Non-Immunologists. Urol Nephrol Open Access J 5(2): 00166. DOI: 10.15406/unoaj.2017.05.00166
Williams RC, et al. The risk of transplant failure with HLA mismatch in first adult kidney allografts 2: living donors, summary, guide. Transplant Direct. 2017;3(5):e152.
Nasrin Esfandiar
3 years ago
HLA mismatch is one of the most important parameters for graft survival, both among deceased and living donor kidney transplantation. Hence allocation systems for deceased donor such as UNOS are considering this parameter. In a research done by UNOS, the result showed that the risk of graft failure was increased with higher number of HLA mismatches; the rate of acute rejection was increased among kidney transplant patients with higher mismatches. Hazard ratio for lower graft survival was linearly related with HLA mismatch in living-related and living-unrelated and deceased donors. This increased hazard ratio was equal for HLA-A, B, and DR. Nowadays we can also use epitope mismatch (CREG-based mismatching) and eplet mismatch load. Different studies have shown the positive effect of HLA matching in graft survival. The best graft survival was seen in 0-mismatch living-related kidney transplant donors and the worst outcome in six-mismatch deceased donor. In recent studies an increase in HLA mismatch was associated with increased acute rejection rate and decrease in patient survival rate. In addition, complications such as PTLD and bone fracture were increased with an increased HLA mismatch number.
Ahmed Shehata
3 years ago
Human HLA genes are located on chromosome 6 and code for 3 major class I alleles (HLA-A, -B, -C) and 3 major class II alleles (HLA-DR, -DQ, -DP).
Polymorphisms in HLA, especially HLA-A, -B, and -DR loci, are important biological barriers to a successful transplantation
With the emergence of potent immunosuppressive agents that steadily improved the graft survival rates, the impact of HLA compatibility seems to be minimized, recent studies demonstrated that each incremental increase of HLA mismatches was significantly associated with higher risk of graft failure and rejection Increasing numbers of HLA mismatch in renal transplantation are associated with an increased need for antirejection therapy that might account for an increased incidence of death with functioning graft due to infection and cardiovascular disease
Dalia Ali
3 years ago
HLA matching provides benefits in improving
outcomes in kidney transplantation
HLA MATCHING AND TRANSPLANT OUTCOMES
Long-term graft survival — Most transplants that are lost to acute rejection do so within the first year. Later graft loss is primarily due to “chronic rejection,” a disorder that is more difficult to treat with existing immunosuppressive regimens
Multiple analyses have demonstrated that human leukocyte antigen (HLA) matching is associated with improved long-term graft survival ..In the 2008 annual report of the Scientific Registry of Transplant Recipients (SRTR), the five-year, deceased, nonextended-criteria donor allograft survival for zero versus six HLA-mismatched, deceased-donor kidneys was 75 and 66 percent, respectively
Long-term graft survival is also best in HLA-identical, particularly living-related, kidneys and worst in randomly matched cadaver kidneys
HLA-DQ mismatching is associated with lower graft survival independent of HLA-ABDR in living donor kidney transplants and deceased donor kidney transplants with cold ischemia time ≤17 hours, and a higher 1-year risk of acute rejection in living and deceased donor kidney transplants.
Patient survival compared with waiting list — Although graft survival of HLA-mismatched kidneys is reduced compared with HLA-matched kidneys, patient survival of highly sensitized recipients of HLA-mismatched kidneys is higher when compared with highly sensitized transplant candidates who remain on the waiting list and are undergoing dialysis.
Acute rejection — Several retrospective studies have demonstrated that HLA matching is associated with a lower risk of acute rejection among kidney transplant recipients..Although most of these studies were performed in patients receiving cyclosporine-based immunosuppression .
Death with a functioning graft — HLA mismatching has been associated with a higher risk of death with a functioning kidney allograft due to cardiovascular or infectious causes
Posttransplant lymphoproliferative disorders — Several studies have shown that HLA mismatching is an independent risk factor for the development of posttransplant non-Hodgkin lymphoma among kidney transplant recipients
Posttransplant bone fractures — HLA mismatches are associated with an increased risk of posttransplant bone fractures in kidney transplant recipients
Pediatric patients — Transplantation of pediatric patients presents additional challenges since these patients are more likely to require repeated transplantation. Thus, well-matched organs are a priority for pediatric patients and could potentially lead to longer wait times. This is in contradiction to the clinical management of pediatric patients where reducing time on dialysis is a more important objective since this impacts their neurologic development and growth. For this reason, all allocation systems (including Share 35 and the new KAS) have focused on quicker access to deceased kidney donors for pediatric transplant candidates These allocation changes have also allowed pediatric patients to receive the highest-quality donors (ie, those less than 35 years old and with a KDPI of 35 percent or less)
Pediatric patients also receive priority points for HLA-DR matching.
1. Yacoub R, Nadkarni GN, Cravedi P, et al. Analysis of OPTN/UNOS registry suggests the number of HLA matches and not mismatches is a stronger independent predictor of kidney transplant survival. Kidney Int 2018; 93:482.
2. Williams RC, Opelz G, McGarvey CJ, et al. The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts From Deceased Donors. Transplantation 2016; 100:1094.
3. Orandi BJ, Luo X, Massie AB, et al. Survival Benefit with Kidney Transplants from HLA-Incompatible Live Donors. N Engl J Med 2016; 374:940.
4. Beckingham IJ, Dennis MJ, Bishop MC, et al. Effect of human leucocyte antigen matching on the incidence of acute rejection in renal transplantation. Br J Surg 1994; 81:574.
Assafi Mohammed
3 years ago
The repeated reply was deleted Dr Assafi
Prof Ahmed Halawa
Last edited 3 years ago by Professor Ahmed Halawa
Fatima AlTaher
3 years ago
The degree of HLA mismatch has Longley been one of the most important determinants of immunological risk in in kidney transplant recipients, where the increasing number of HLA mismatch correlates with increased risk of acute rejection rejection specially AMR more than cellular rejection , also site of mismatch has its important impact as mismatch in the 2 Dr loci had more unfavorable outcome than HLA class I mismatch, regarding longevity of the graft. 1, 2
The development of novel immunosuppression drugs had encouraged transplantation with higher HLA mismatch numbers or even complete mismatch but this is associated with higher incidence of immunosuppressive drugs complication with poor patient outcome secondary to infections , malignancy and cardiovascular complications .3
Ref
1- Süsal C, Opelz G. Current role of human leukocyte antigen matching in kidney transplantation. Curr Opin Organ Transplant. 2013 Aug;18(4):438-44. doi: 10.1097/MOT.0b013e3283636ddf. PMID: 23838649.
2- Pratschke J, Dragun D, Hauser IA, Horn S, Mueller TF, Schemmer P, Thaiss F. Immunological risk assessment: The key to individualized immunosuppression after kidney transplantation. Transplant Rev (Orlando). 2016 Apr;30(2):77-84. doi: 10.1016/j.trre.2016.02.002. Epub 2016 Feb 18. PMID: 26965071. 3- Shi X, Lv J, Han W, Zhong X, Xie X, Su B, Ding J. What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients. BMC Nephrol. 2018 May 18;19(1):116. doi: 10.1186/s12882-018-0908-3. PMID: 29776389; PMCID: PMC5960106.
Human leukocyte antigen (HLA) is important biological barrier to a successful transplantation and has substantial impact on the prolongation of graft survival .
However, the emergency of modern immunosuppressive agents minimized the effect of HLA compatibility.
The US kidney allocation system was extensively modified to eliminated HLA-A similarity in 1995 and HLA-B similarity in 2003 .
In the revised United Kingdom kidney allocation scheme, HLA-A matching is no longer considered . But the latest European Renal Best Practice Transplantation Guidelines still recommended that matching of HLA-A, –B, and –DR whenever possible, while gave more weight to HLA-DR locus .
So far, the current kidney allocation guideline recommendations were inconsistent in term of HLA compatibility. Besides, for the primary aim to make the kidney last as long as possible, all the current kidney allocation systems were not perfect.
HLA per mismatch is significantly associated with increased risks of overall graft failure , death-censored graft failure and all-cause mortality .
Besides, HLA-DR mismatches were associated with worse overall graft survival. For HLA-A locus, the association was insignificant. No significant association between HLA-B locus and overall graft failure .In subgroup analyses, the recipient sample size and ethnicity maybe the potential sources of heterogeneity.
HLA mismatching was still a critical prognostic factor that affects graft and recipient survival. HLA-DR mismatching has a substantial impact on recipient’s graft survival. HLA-A mismatching has minor but insignificant impact on graft survival outcomes.
Mohamed Essmat
3 years ago
HLA typing and mismatch determination between the potential transplant recipient and donor is an important step for sure. Usually the HLA A-, B-, and DR- are typed for both the donor and the recipient and degree of mismatch is looked into. Although the survival of patients who are highly sensitized due to HLA mismatch is lower than those receiving HLA matching kidney, but survival remains higher when compared to those who receive hemodialysis or on waiting list. The more the mismatches the lower the degree of graft and patient’s survival and higher acute rejections. However, the importance of HLA matching has decreased relatively than before, and is now considered to be more important in deceased than in living donor due to the various effective immunosuppressive agents that are available nowadays. The incidence of delayed graft function as well as acute rejection rate is lower in first year with the higher HLA match. Increased incidence of DSAs with Class II HLA mismatch (HLA-DQ, DR) thus affecting the graft and patient’s survival . Post-transplant bone fractures are higher in recipients with HLA-DR mismatch.PTLD risk is also higher in transplants with HLA DR mismatch (21% increased risk with 1 HLA-DR mismatch and 56% increased risk in 2 HLA-DR mismatch). Refrences: Hung Do Nguyen, Rebecca Lucy Williams, Germaine Wong and Wai Hon Lim (February 13th 2013) Lim WH, Chadban SJ, Clayton P, et al. Human leukocyte antigen mismatches associated with increased risk of rejection, graft failure, and death independent of initial immunosuppression in renal transplant recipients.Clin Transplant. 2012; 26(4): E428. Opelz G, and Döhler B. Association of HLA mismatch with death with a functioning graft after kidney transplantation: a collaborative transplant study report. Am J Transplant. 2012; 12(11): 3031.
Ibrahim Omar
3 years ago
for the outcome of transplantation, living versus deceased donor is more successful than the degree of HLA matching. the outcome of living transplant with 100 % mismatch is equal to deceased transplant with 0 % mismatch.
thank you, prof.
the actual accurate data for transplant outcome for live versus deceased graft are available in all books. however, my concern is to pick-up the most valuable data to be written in short, so other colleagues can get it easily. of course no one can read the comments of all as it is too much time consuming. we can maximize the benefit of this time in reading new articles, gaining more experience of others, discussing interesting cases…. etc.
any how, to my knowledge as I passed before the SCE nephrology from UK in addition to MRCP and I read the textbook of Comprehensive clinical nephrology in detail for 8 times over 4 years, the outcome for grat survival and acute rejection rate is less for deceased grafts, in the 1 st year. after the 1st year, the outcome is almost similar for both live and deceased grafts. patient survival is also almost the same with no significant change.
Amer Hussein
3 years ago
HLA matching provides numerous benefits in organ transplantation including better graft function, fewer rejection episodes, longer graft survival, and the possibility of reduced immunosuppression. Mismatches are attended by more frequent rejection episodes that require increased immunosuppression that, in turn, can increase the risk of infection and malignancy. HLA mismatches also incur the risk of sensitization, which can reduce the opportunity and increase waiting time for a subsequent transplant.
In separate reports from the Collaborative Transplant Study, it was shown that HLA mismatches were associated with death with functioning graft and with posttransplant lymphoproliferative disease. Increasing numbers of HLA mismatch in renal transplantation were associated with an increased need for antirejection therapy that might account for an increased incidence of death with functioning graft due to infection and cardiovascular disease
Ahmed mehlis
3 years ago
As mentioned before
HLA mismatches goes with high risk of acute rejection and graft survival failure ..
HLA mismatches were associated with an incremental risk of rejection although the relative risk was higher for live donor kidney transplants. Increasing HLA-AB and HLA-DR mismatches were associated with a greater risk of acute rejection, graft failure, death-censored graft failure, and/or death. There was no consistent association between initial immunosuppressive regimen and outcomes.
Williams RC, Opelz G, McGarvey CJ, Weil EJ, Chakkera HA. The risk of transplant failure with HLA mismatch in first adult kidney allografts from deceased donors. Transplantation. 2016; 100: 1094–1102.
Doaa Elwasly
3 years ago
HLA mismatch is associated with adverse impact on graft survival.With the wide use ofimmunosuppressives that improved the graft survival rates, the impact of HLA compatibility impact decreased meanwhile the Australia and New Zealand Dialysis and Transplant Registry (ANZDTR) survey with 12,662 recipients yet expressed that increasing of HLA mismatches was significantly associated with higher risk of graft failure (1).
Poor graft outcomes could be related to high rejection risk risk especially antibody-mediated rejection . Decreased patient survival could be associated with immunosuppression consequences (2).
In particular, the use of anti-thymocyte immunoglobulin and post-transplant endoxan is a very attractive GVHD prophylaxis to reduce the risk of complications of HLA-incompatible transplantation. (3)
A linear relation of kidney survival with HLA mismatch for organs donated from deceased donors; 1 mismatch conferred a 13% higher risk while 6 mismatches conferred a 64% higher risk of graft failure. However, such association was not studied yet among living donors .It was suggested that HLA matching may not be as important in living donors as in deceased ones.(4)
Living-donor kidneys survive longer than those from deceased donors .(5)
1-Broeders N, Racapé J, Hamade A, Massart A, Hoang AD, Mikhalski D, et al. A new HLA allocation procedure of kidneys from deceased donors in the current era of immunosuppression. Transplant Proc. 2015;47(2):267–74.
2-Legendre C, Canaud G, Martinez F. Factors influencing long-term outcome after kidney transplantation. Transpl Int. 2014;27(1):19–27
3-Junya Isada.Impact of HLA incompatibility on transplant outcome.Clinical blood.2017 Vol. 58, No. 12, p. 2415-2424
4-Williams RC, Opelz G, McGarvey CJ, et al. The risk of transplant failure with HLA mismatch in first adult kidney allografts from deceased donors. Transplantation. 2016;100:1094–1102.
5-Robert C. Williams, Gerhard Opelz, E. Jennifer Weil, Chelsea J. McGarvey, and Harini A. Chakkera, The Risk of Transplant Failure With HLA
NEAMAH Mohammed - Suspended
3 years ago
HLA typing and the degree of incompatibility between the donor and the recipient are defined by the number of antigens that are mismatched at each of the HLA loci.
Transplantation of a kidney into a recipient who is sensitized against donor class I HLA antigens puts the recipient at high risk for hyperacute antibody-mediated rejection.
HLA-mismatched grafts have excellent graft outcomes without acute rejection, suggesting that under specific circumstances, certain HLA mismatches may be permissible, such as the lack of immunologic response against non-inherited maternal HLA antigens (NIMA) as a result of prenatal tolerance development.
a strong association between HLA-matching at the HLA-A, B, and DR loci and graft and patient outcomes, independent of donor type, initial immunosuppression, transplant era, and even the presence of DSA
The advantage of improved HLA-matching in reducing acute rejection risk in renal transplant recipients receiving cyclosporine-based immunosuppressive regimen.
HLA-mismatches remained an important determinant of acute rejection risk in renal transplant recipients receiving quadruple immunosuppression involving the use of interleukin-2 receptor antibody induction, tacrolimus, mycophenolate mofetil, and corticosteroids.
a recent analysis of the ANZDATA registry of live and deceased donor renal transplants between 1998 and 2009 demonstrated that the association between HLA-mismatches and acute rejection risk appeared to be independent of transplant era and initial immunosuppression, but this association appeared to be much stronger for live-donor transplants compared to deceased donor transplants.
The reduced benefit of 0-HLA-mismatched kidneys in recipients of deceased compared with live donor kidneys may be explained by the presence in unrelated deceased donors of apparently matched but actually mismatched splits of antigens, which is less frequently observed in biologically related living donors.
Shereen Yousef
3 years ago
Human HLA genes are located on chromosome 6 and code for 3 major class I alleles (HLA-A, -B, -C) and 3 major class II alleles (HLA-DR, -DQ, -DP). Polymorphisms in HLA, especially HLA-A, -B, and -DR loci, are important biological barriers to a successful transplantation 1.
With the emergence of potent immunosuppressive agents that steadily improved the graft survival rates, the impact of HLA compatibility seems to be minimized 2.
But the recent Australia and New Zealand Dialysis and Transplant Registry (ANZDTR) survey with 12,662 recipients still demonstrated that each incremental increase of HLA mismatches was significantly associated with higher risk of graft failure and rejection 3.
The meta-analysis suggested that HLA-DR per mismatch was significant associated with a 12% higher risk of overall graft failure HLA-A mismatching had an impact on overall graft survival .However, studies showd no significant association between HLA-B mismatching and overall graft survival .
the latest European Renal Best Practice Transplantation Guidelines still recommended that matching of HLA-A, -B, and -DR whenever possible, while gave more weight to HLA-DR locus 4.
Post-transplant long-term prognosis includes also the occurrence of complications like post-transplant lymphoproliferative disease (PTLD), post-transplant bone fractures, development of donor specific antibodies (DSAs) and death with a functioning graft all have higher incidence with HLA mismatches more with DR mismatche 5.
Reference
1- Broeders N, Racapé J, Hamade A, Massart A, Hoang AD, Mikhalski D, et al. A new HLA allocation procedure of kidneys from deceased donors in the current era of immunosuppression. Transplant Proc. 2015;47(2):267–74.
2- Süsal C, Opelz G. Current role of human leukocyte antigen matching in kidney transplantation. Curr Opin Organ Transplant. 2013;18(4):438–44.
3- Croke R, Lim W, Chang S, Campbell S, Chadban S, Russ G, et al. HLA-mismatches increase risk of graft failure in renal transplant recipients initiated on cyclosporine but not tacrolimus. Nephrology. 2010;15:38.
4- Abramowicz D, Cochat P, Claas FH, Heemann U, Pascual J, Dudley C, et al. European renal best practice guideline on kidney donor and recipient evaluation and perioperative care. Nephrol Dial Transplant. 2015;30(11):1790–7.
5- Weibe C, Gibson W, Blydt-Hansen TD et al. Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant 2012;12(5):1157-67.
Mahmud Islam
3 years ago
HLA mismatch detection is vital. the lower the ratio the best the survival both in recepients from deceased donors as well as living donors. in deceased donors along with modern immune suppression we had the chance to transplant patients with minimal mismatch (unrealted donors) . full match will lower the trasnplant ratio. In terms of graft survival the lower the mismatch the lower the risk of rejection and the better the survival of the graft. with high doses of immmune suppression adverse effects are more probable. the more the drug doses the more the complication either due to drugs it self or due to opportunistic infections. accordingly patient survival is adversely affected
What would be your immunosuppression for 222 mismatched transplants with no DSA?
This patient is considered high risk patient for rejection with 6 mismatches and carries the worse prognosis in terms of graft survival and should receive aggressive induction immunosuppression. this donor should receive rATG-thymoglobulin rather tham interleukin 2 antagonist.
for maintenance: CNI with optmal dose and target therapeutic level, steroisds and antimetabolite in particular MMF
For high risk patients and preformed DSA, recipients should initially receive desensitization strategies which include pretransplant treatment with high dose steroids with either rituximab or plasmapheresis, and induction therapy as in high risk patients.
Thanks, Mohamed I disagree with you, it depends on the crossmatch. If positive, desensitisation is required, but negative crossmatch does not require desensitisation, but augmented immunosuppression with aggressive induction.
There is linear relationship between HLA mismatch and decrease graft survival in deceased donor which mostly caused by increase the antigenicity of the graft and more exposure of its different HLA antigens caused by ischemia reperfusion injury
This relation in not exist in living donoation
Regarding immunosuppressant medications for 222 mismatch with no DSA ……. DSA and mismatch is not all the factors on which i will make my decision on
1ry kidney disease,age,cPRA even nonDSA and results of other cross match results should be considered
But supposed that whole risk is HLA 6mismatch so i will consider this patient moderate risk and go with depleting induction ATG 3mg/kg and triply immunosuppressant medications steroids/tac/MMF
If we have low MFI DSA and other factors are the same still patient at the same category with the same immunosuppressant medications except if was DQ DSA i may reject the donor
Finally there’s common HLA in certain population like HLA A2 and A36 and dsa against it will form great challenge to find donor with no DSA against it
1-The clinical trial showed a decreased incidence and severity of acute rejection when treated with rATG compared to basiliximab at 1 year (16% vs. 26%) and 5 years (15% vs. 27%) post-transplant, but similar incidences of graft loss, DGF, and death.
In moderately sensitized patients (positive DSA and negative flow crossmatch), induction with ATG resulted in reduced occurrence of de novo DSA (dnDSA) and AMR compared to basiliximab.
.Another randomized trial found a significantly reduced incidence as well as the severity of acute rejection in high immunological risk patients, defined by Kidney Disease Improving Global Outcomes (KDIGO) as a high number of MHC mismatches, younger recipient, older donor, PRA > 0%, presence of DSA, blood group incompatibility, DGF, and cold ischemic time > 24 h, treated with rATG versus basiliximab with acute rejection rates at 1 year (15% vs. 27%)
2-with DSA(MFI 1345) and FCXM negative, current evidence treatment with antibody removal does not seem justified. careful monitoring of post-transplant DSA level is appropriate.
3-Patient with serum carrying HLA-A2 antibodies may react with HLA-A2 as well as A68, A69, B57.as they share amino acid sequence stimulates HLA-A2(CROSS-REACTIVITY)
1-Hellemans R., Bosmans J.L., Abramowicz D. Induction Therapy for Kidney Transplant Recipients: Do We Still Need Anti-IL2 Receptor Monoclonal Antibodies? Am. J. Transplant. 2017;17:22–27. DOI: 10.1111/ajt.13884.
222 mismatched transplants no DSA: I would transplant him , High risk for acute rejection : Induction with ATG . steroid , MMF, TAC
222 mismatch DSA 1345 negative FCXM and CDC : I would transplant him , some centers preferer to do desensitization , others don’t. High risk for acute rejection : Induction with ATG. steroid , MMF, TAC
HLA A2 (CREG) Common REactive Group : This HLA antigen shares functional epitope with many other HLA antigens . so if a patient had anti HLA A2 ab , he will react with many HLA antigens like HLA-A2, -A23, -A24, -A68, and -A69 , and he will be highly sensitized (1) .
References:
(1) H. C. Sullivan1 , R. S. Liwski2 , R. A. Bray1 and H. M. Gebel1
The Road to HLA Antibody Evaluation: Do Not Rely on MFI
American Journal of Transplantation 2017; 17: 1455–1461
This is an excellent answer Mujtaba. Very impressed. You missed the easy part, which is the prevalence of HLA A2 in the community. It is the commonest HLA antigen. DSA against HLA A2 is a bad sign and confer less chance of matchbility.
1. What would be your immunosuppression for 222 mismatched transplants with no DSA?
Induction with ATG. Immunosuppression: Tac/ MMF/ Steroids
2. What would be your immunosuppression for 222 mismatched transplants with DSA (MFI of 1345), but negative FCXM and CDC?
Induction with ATG. Immunosuppression: Tac/MMF/ Steroids
No desensitization as cross match is negative.
3. What is the relevance of HLA A2 and HLA A36 antigens?
HKA A2 is the one of the most frequent class I HLA antigen.
HLA A36 is predominantly seen in Africa and rare outside Africa.
Reem Younis
3 years ago
For deceased donor kidneys, better HLA matching is associated with better graft survival.
-Graft survival in deceased donor kidneys is fallen progressive with increase HLA mismatch.
-HLA matching effect is much less pronounced for living donor kidneys.
-HLA-DR mismatch is a risk factor for acute rejection and post-transplant non Hodgkin lymphoma.
Ahmed Abdalla
3 years ago
the is a linear relationship between HLA mismatch and allograft survival. 1 mismatch conferred a 44% higher risk, whereas 6 mismatches conferred a twofold higher risk of allograft failure. When using 0-mismatched full siblings as a reference, living-donor kidneys reduce the hazard of failure by approximately 34% when compared with deceased donors.
HLA matching has a statistically significant and clinically important impact on short- and longer-term graft survival, even in the post-cyclosporine era. However, the impact of HLA mismatches is not linear over the entire range of zero to six mismatches, in that progressive increases in the number of mismatches from one to six have only a small effect on survival as compared with the large benefits afforded by the use of a graft with no mismatches .HLA-DQ mismatches are associated with acute rejection, independent of HLA-ABDR mismatches and initial immunosuppression.
Mohamed Fouad
3 years ago
Effect of HLA mismatch in living and deceased donor transplantation on graft survival and acute rejection rate Analysis of 93,782 kidney-only transplants in the United States over 10 years is the largest retrospective study to date to evaluate the effects of HLA-DQ mismatching on transplant outcomes in the era of modern HLA typing. Demonstrated that HLA-DQ mismatched kidneys have a higher risk of acute rejection when compared with HLA-DQ matched kidneys. HLA-DQ mismatching influences graft survival in living kidney donor recipients and in deceased kidney donor recipients with cold ischemic time ≤17 hours.
There is evidence that anti-DQ donor-specific antibodies are the predominant de novo donor-specific antibodies after transplantation and have a detrimental effect on outcomes (1,2,3). HLA epitope-mismatching at HLA-DQ loci has been shown to be associated with the development of anti-DQ donor-specific antibodies and transplant glomerulopathy (4,5). Wiebe et al. found that an HLA-DQ epitope-mismatched threshold of ≥17 was significantly associated with de novo anti-DQ donor-specific antibodies. After a median follow-up of 6.9 years, only 2.7% of recipients with <17 HLA-DQ epitope-mismatches developed de novo anti-DQ donor-specific antibodies (4). Sapir-Pichhadze et al. conducted a nested case-control study on 52 kidney transplant recipients with transplant glomerulopathy. In this study, an increasing number of HLA-DR and HLA-DQ epitope-mismatches were associated with the development of transplant glomerulopathy (5). All these findings suggest that we could potentially minimize immunogenic risks by avoiding HLA-DQ mismatches, thereby improving outcomes. However, identification of HLA epitope-mismatching is not routinely performed in most centers.
References 1. Willicombe M, Brookes P, Sergeant R, Santos-Nunez E, Steggar C, Galliford J, McLean A, Cook TH, Cairns T, Roufosse C, Taube D: De novo DQ donor-specific antibodies are associated with a significant risk of antibody-mediated rejection and transplant glomerulopathy. Transplantation 94: 172–177, 2012
2. Devos JM, Gaber AO, Teeter LD, Graviss EA, Patel SJ, Land GA, Moore LW, Knight RJ: Intermediate-term graft loss after renal transplantation is associated with both donor-specific antibody and acute rejection. Transplantation 97: 534–540, 2014 3. Tagliamacco A, Cioni M, Comoli P, Ramondetta M, Brambilla C, Trivelli A, Magnasco A, Biticchi R, Fontana I, Dulbecco P, Palombo D, Klersy C, Ghiggeri GM, Ginevri F, Cardillo M, Nocera A: DQ molecules are the principal stimulators of de novo donor-specific antibodies in nonsensitized pediatric recipients receiving a first kidney transplant. Transpl Int 27: 667–673, 2014
4. Wiebe C, Pochinco D, Blydt-Hansen TD, Ho J, Birk PE, Karpinski M, Goldberg A, Storsley LJ, Gibson IW, Rush DN, Nickerson PW: Class II HLA epitope matching-A strategy to minimize de novo donor-specific antibody development and improve outcomes. Am J Transplant 13: 3114–3122, 2013
5. Sapir-Pichhadze R, Tinckam K, Quach K, Logan AG, Laupacis A, John R, Beyene J, Kim SJ: HLA-DR and -DQ eplet mismatches and transplant glomerulopathy: A nested case-control study. Am J Transplant 15: 137–148, 2015
Mohammed Sobair
3 years ago
HLA matching is associated with greater graft survival and reduced rejection. HLA DR has greater effect compare to HLA -B ,(1),HLA DQ mismatch is also convey risk , recently recognize as cause of rejection and graft loss.. HLA mismatching is also associated with patient death with functioning graft(2) ,and there evidence ,though weak ,its related or risk factor for PTLPD (3).This effect is more pronounced in deceased donor compare live related donor .
improve of immunosuppression protocol attenuate the deleterious effect of mismatching in recent years compare to previous era.(4).
Reference:
1- Wai,H.LIM,Human leucocyte antigen mismatch associated with increase risk of rejection ,independent of initial immunosuppression in renal transplant recipient ,Clinical transplant 26,issue 4,428.
2-WOpelz G, Döhler B ,a Association of HLA mismatch with death with a functioning graft after kidney transplantation: a collaborative transplant study report.
Am J Transplant. 2012;12(11):3031. Epub 2012 Aug 17.
3- H.Maja Olhol Vase,et al ,HLA Associations and Risk of Posttransplant Lymphoproliferative Disorder in a Danish Population-Based cohort ,transplant Direct. 2015 Aug; 1(7): e25.4mEL-Hatra i.Arakama et al ,The impact of HLA -ABDR mismatch on acute rejection and graft failure ,among Filipino kidney transplant, OAT doi 10.15 761/tit,100231. Lim
Nandita Sugumar
3 years ago
In terms of patient survival, HLA incompatible live donor kidney transplant is a good option for sensitized patients in comparison with prolonged waiting time for deceased donor kidney transplant.
Tai, K; Yang, J. Presence of a survival benefit of HLA incompatible living donor kidney transplantation compared to waiting or HLA compatible deceased donor kidney transplantation with a long waiting time. Kidney International : 100 (1). Jul 2021. Pp 206-214. https://doi.org/10.1016/j.kint.2021.01.027
The HLA antigens are very important transplant antigen and matching between donor and receipiant is stone corner affecting long term graft survival and prevent early rejection .
Relative importance of HLA-A,-B, AND -DR:
The initial Collaborative Transplant Study (CTS) analysis showed that the great effect comes from the DR and B antigens, with minimal effect from the A antigens. Other study showed that DR matching having a much more effect than that of A or B
Another study revealed that HLA-DR mismatches have poor long-term survival .
The effect of each antigen appears at different times post transplant , with the great effect of DR and B mismatching usually appear within the first 6 months and 2 years post transplant , respectively .
Relative importance of HLA-DP AND -DQ :
HLA-DP is MHC class-II locus. Anti HLA DP antibodies are less common occurring in 5 to 14 percent of transplant recipients . The HLA-DP antibodies are more frequent in patients with second transplant , occurring in up to 45 %of subjects .
some studies suggested that anti HLA-DP antibodies does not reduce allograft survival in patients with first transplant , other studies revealed that these antibodies can reduce the allograft survival in patients with second transplant .
Transplant recipients with de novo persistent DQ only donor specific antibody (DSA) or de novo DQ plus other DSAs are susceptible to more acute rejection episodes , increased risk of allograft failure , and decreasing in 5 year allograft survival.
In kidney transplant recepiants with HLA mismatch noticed increased complications in long term post transplant Post-transplant as post transplant lymphoproliferative disease (PTLD), post-transplant bone fractures in addition to decreased graft survival.
Nandita Sugumar
3 years ago
GRAFT SURVIVAL
HLA mismatch has increased risk of graft failure with hazard ratio 1.06; confidence interval 95% with death censored graft failure HR 1.09, CI 95% and all cause mortality HR 1.04, CI 95% . HLA DR mismatch has a significant impact on recipient graft survival rates. HLA A mismatch has minor impact on graft survival outcomes. The study linked below shows HLA DR mismatch associated with 12% increase in risk of graft failure. HLA A mismatch is seen to be associated with 6% increase in risk of graft failure but the association was found to be insignificant. There was no significant association between HLA B mismatch and graft survival.
Ref:
Shi, X., Lv, J., Han, W. et al. What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients. BMC Nephrol 19, 116 (2018). https://doi.org/10.1186/s12882-018-0908-3
Weam Elnazer
3 years ago
A significant linear relationship of hazard ratios was associated with HLA mismatch and affects allograft survival even during the recent periods of increasing success in renal transplantation.
HLA mismatches are associated with greater risk of rejection, graft failure, and death independent of immunosuppression and transplant era.
The weight of the available evidence does suggest that ignoring HLA mismatches in organ allocation would have a detrimental effect on graft and patient outcomes in renal transplantation.
Wai H. Lima,b, Steve J. Chadbanb,c, Philip Claytonb , Charley A. Budgeond , Kevin Murrayd , Scott B. Campbellb,e, Solomon Cohneyb,f, Graeme R. Russb,g and Stephen P. McDonaldb,g Clin Transplant 2012 DOI: 10.1111/j.1399-0012.2012.01654.x
AMAL Anan
3 years ago
HLA mismatching was still a critical prognostic factor that affects graft and recipient survival. HLA-DR mismatching has a substantial impact on recipient’s graft survival. HLA-A mismatching has minor but not significant impact on graft survival outcomes. Further studies should be conducted to confirm the impact of HLA-A similarity.
Allografts from living donors survive longer than those from deceased donors but the role of HLA mismatching in living kidney donation is still in question.
Living kidney transplantation is the best therapeutic option to provide renal replacement therapy to patients with end-stage kidney disease.1-9 HLA matching is not currently part of the algorithm for donor determination in the United States except among deceased donors where 0 mismatches between kidney and recipient receive higher priority. We previously reported a linear relation of kidney survival with HLA mismatch for organs from deceased donors; 1 mismatch conferred a 13% higher risk and 6 mismatches conferred a 64% higher risk of allograft failure.
However, the same association has not been studied among living donor transplants. There are some reports that suggest HLA matching may not be as important in living donor kidney transplantation as it is in deceased donor kidney transplantation.
***Evaluation of a Potential Deceased Donor :
The donor evaluation process begins with an assessment of medical suitability. For example, a malignancy with
current metastatic disease renders the donor medically unsuitable. In light of the ongoing shortage of deceased donor
kidneys, these risks of transmission of a donor malignancy or infectious disease must be weighed against the risk of
continuing on dialysis to the patient awaiting transplantation. Consultation with the local OPO and hospitals is
essential to ensure that potential organ donors are not inappropriately excluded.
***Deceased donor process : from donor identification to transplantation
1-Donor identification.
2-Clinical triggers.
3-Referral to organ procurement organaization.
4-Assessment of medical suitability of the donor .
5-Authorisation for donation.
6- Organ donor management
7- Organ allocation.
8- Organ recovery surgery.
9- Organ preservation and transportation.
10- Organ transplantation.
***Factors determining the kidney donor profile index( KDPI) :
-Age.
-Height and weight.
-Ethnicity /Race.
-History of diabetes.
-Cause of death.
-Serum creatinine.
-HCV status.
-Donor meets DCD criteria.
*** Factors determing Expected post transplant survival (EPTS ):
-Age.
-Current diabetes status.
-Number of previous transplant.
-Receiving of chronic dialysis.
REFERENCES
1. Opelz G. Impact of HLA compatibility on survival of kidney transplants from unrelated live donors. Transplantation. 1997;64:1473–1475. [PubMed] [Google Scholar]
2. Davis CL, Delmonico FL. Living-donor kidney transplantation: a review of the current practices for the live donor. J Am Soc Nephrol. 2005;16:2098–2110. [PubMed] [Google Scholar]
3. Delmonico FL, Sheehy E, Marks WH, et al. Organ donation and utilization in the United States, 2004. Am J Transplant. 2005;5:862–873. [PubMed] [Google Scholar]
4. Park KS, Shin JH, Jang HR, et al. Impact of donor kidney function and donor age on poor outcome of living-unrelated kidney transplantation (KT) in comparison with living-related KT. Clin Transplant. 2014;28:953–960. [PubMed] [Google Scholar]
5. Orandi BJ, Garonzik-Wang JM, Massie AB, et al. Quantifying the risk of incompatible kidney transplantation: a multicenter study. Am J Transplant. 2014;14:1573–1580. [PubMed] [Google Scholar]
Tahani Hadi
3 years ago
HLA play an important role in immune response that affects graft survival, HLA match decrease risk of acute rejection and increase survival rate.
The role of HLA mismatch depend on number of mismatch ,risk factors of both donor and recipient and recipient sensitisation for example in pregnancy, blood transfusion and failed renal transplantation for those patients it’s important to avoid HLA mismatch .
Graft survival;
Studies found that, increased HLA mismatches are associated with risk of overall graft failure ,death –censored graft failure and all cause mortality .
Patient survival
Also studies found an increased risk of mortality in recipients with increased HLA mismatches .
Acute rejection rate
Several retrospective studies have demonstrated that HLA matching is associated with a lower risk of acute rejection among kidney transplant recipients Although most of these studies were performed in patients receiving cyclosporine-based immunosuppressant . The number of HLA mismatches was found to be an independent risk factor for acute rejection .
Post-transplant adverse events;
1-Death with a functioning graft:
The number of HLA-A, -B, and -DR mismatches correlated with a higher cumulative incidence of death with a functioning graft, from any cause, during the first three years post-transplant. This association was significant for death due to cardiovascular or infectious causes but not from malignancy.
2-Post-transplant lymphoproliferative disorders:
HLA-DR mismatches are associated with a twofold higher risk of developing post transplant non-Hodgkin lymphoma.
3-Post-transplant bone fractures;
HLA mismatches are associated with an increased risk of post-transplant bone fractures in kidney transplant recipients.
References:
1- Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017.
2. Williams RC, Opelz G, Weil EJ, McGarvey CJ, Chakkera HA. The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts 2: Living Donors, Summary, Guide. Transplant Direct. 2017 Apr 7;3(5):e152.
HLA matching has a number of advantages, including improved graft function, longer graft life, the chance for less immunosuppression and , fewer rejection events.
HLA mismatches are associated with more frequent rejection reactions, which necessitate higher immunosuppression, which increases the risk of infection and cancer. Sensitization can occur as a result of HLA mismatches, which might diminish the likelihood of a repeat transplant and lengthen the waiting period..
-Based on the number of HLA- and HLA-DR mismatches in living donor and deceased donor kidney transplants, there is a significant difference in renal graft survival up to 3 years utilizing our current immunosuppressive procedures
-Avoiding donor antigens to which a patient has antibodies, reducing antibody strength to an acceptable level, and/or using more intensive immunosuppression may be used as matching methods for sensitized patients.
Human leukocyte antigen (HLA) mismatches have been shown to adversely affect renal allograft outcomes and remain an important component of the allocation of deceased donor (DD) kidneys.
The ongoing importance of HLA mismatches on transplant outcomes in the era of more potent immunosuppression remains debatable.
Using Australia and New Zealand Dialysis and Transplant Registry, data for live and DD renal transplant recipients between 1998 and 2009 showed .
The association between the number of HLA mismatches and HLA-loci mismatches and outcomes were examined.
Of the 8036 renal transplant recipients, 59% had between 2 and 4 HLA mismatches.
Compared with 0 HLA mismatch, increasing HLA mismatches were associated with a higher risk of graft failure and patient death in the adjusted models.
HLA mismatches were associated with an incremental risk of rejection although the relative risk was higher for live donor kidney transplants.
Increasing HLA-AB and HLA-DR mismatches were associated with a greater risk of acute rejection, graft failure, death-censored graft failure, and/or death.
There was no consistent association between initial immunosuppressive regimen and outcomes. Our results corroborate and extend the previous registry analyses demonstrating that HLA mismatches are associated with poorer transplant outcomes independent of immunosuppression and transplant era.
The kidney Graft survival is better with no DSA than with any DSA. DSA is associated with higher incidence of antibody mediated rejection and chronic allograft nephropathy.
This correlation is supported by :
1- The presence of complement split product (C4d) is associated with antibody mediated allograft injury.
2- The association of donor anti HLA specific antibody with bad transplant result.
In the early post transplant period, the incidence of acute antibody mediated rejection is about 2-5%, but the incidence is increased to about 40% when recipient has a positive donor HLA specific antibody before transplantation or when he receive desensitization therapy.
Preexisting (pre transplant ) DSA and de novo DSA ( new emergent one ) is associated with bad allograft result.
Even with the presence of low titer DSA ( MFI level less than 3000 ) it may cause subtle graft damage, which may end with chronic allograft nephropathy.
DSA (De Novo) Development Risk Factors
There are many risk factors for the development of DSA,antibody mediated rejection and graft failure. Although Anti HLA class I antibody may play a role, the more important role is for HLA- class II antibody. Therefore the presence of HLA-DR, HLA- DQ,HLA–DP mismatch carry a higher risk for late onset antibody mediated rejection.
Risk factors are
– 2nd transplantation
– Pre transplant DSA
– Young(18–35 y )
– Deceased donor
– DR, DQ mismatch
– Non compliance-Non adherence
– Inadequate immune suppression
– Inflammatory process(infection)
– Rejection TCMR (Subclinical)
In their study, hidalgo et al,demonstrate dnDSA in 37% of recipient after years of transplantation , and the antibodies are mainly of dnDSA type ( 60%) directed against HLA –CLASS II mismatched antigen. Half of grafts was lost at five year of dnDSA detection. Another study by Wiebe et al, showed ten fold higher graft loss and 40% lower ten year graft survival in patient with positive dnDSA than without these antibodies. 24% graft failure, after 3 years of dnDSA detection has been demonstrated by Everly et al. Everly et al, demonstrated a 24% graft failure after 3 years of dnDSA detection .(10)
The complement fixing DSA has worse graft outcome than with non complement fixing. Graft survival at 5 year is 54% with complement fixing DSA which is far less than survival with non complement fixing DSA of 93%.
HLA mismatch negatively affect long-term graft survival. HLA-DR matching appears the most powerful in this context, but the number of mismatches is important.
Incidence of DGF Increases with HLA mismatch.
incidence of acute rejection Increased too, subsequent usage of immunosuppressive drugs may exposes patient to infection and malignancy which may affect patient survival
higher degree of HLA mismatching is associated with worse transplant outcome
UNOS registry : there was a 13 percent higher risk of graft failure with one HLA mismatch and a 64 percent higher risk with six HLA mismatch
Australian and New Zealand Dialysis and Transplant Registry that included living and deceased donor kidney transplant recipients increasing HLA mismatches were associated with a higher risk of graft failure
Relative importance of specific HLA antigens: several studies have demonstrated that mismatches at individual HLA loci do not have equal weight with regards to transplant outcomes( there is strong association between HLA matching HLA -A, -B and -DR loci)
long term graft survival is better in HLA matching in both deceased and living donors
patient survival of highly sensitized recipients of HLA mismatched kidneys is higher when compared with highly sensitized transplant candidates who remain in the waiting list
HLA matching is associated with a lower risk of acute rejection
HLA matching has been associated with higher risk of death with a functioning kidney allograft
HLA matching is an independent risk factor for development of post transplant non hodgkin lymphoma
UP TO Date
cross matching between donor and recipient has been a corner stone in transplantation work up.
possibilities ranges from zero mismatch to 6 mismatches.
several studies proved that the degree of mismatch is proportionally associated with poor transplantation outcome and poor prognosis.
In the transplant registry (1), there was a significant prolonged survival among zero mismatched recipients and those with positive mismatches.
on contrary to graft survival, a large transplantation trial (2) has shown results that recipients of mismatched kidney had better long term survival than those who never got kidney transplantation or those who received transplant from matched deceases donor.
Many trials (4-5) are in concordance that acute rejection rates are significantly less among recipients of matched kidney transplant.
HLA mismatch is associated with some post transplantation adverse effect including bone fracture. up to 9% as reported in one large retrospective study.(5).
references:
1 – The Scientific Registry of Transplant Recipients http://www.ustransplant.org (Accessed on February 02, 2010).
2- Orandi BJ, Luo X, Massie AB, Garonzik-Wang JM, Lonze BE, Ahmed R, 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. Survival Benefit with Kidney Transplants from HLA-Incompatible Live Donors. N Engl J Med. 2016 Mar 10;374(10):940-50. doi: 10.1056/NEJMoa1508380. PMID: 26962729; PMCID: PMC4841939.
3- McKenna RM, Lee KR, Gough JC, Jeffery JR, Grimm PC, Rush DN, Nickerson P. Matching for private or public HLA epitopes reduces acute rejection episodes and improves two-year renal allograft function. Transplantation. 1998 Jul 15;66(1):38-43. doi: 10.1097/00007890-199807150-00006. PMID: 9679819.
4- Wissing KM, Fomegné G, Broeders N, Ghisdal L, Hoang AD, Mikhalski D, Donckier V, Vereerstraeten P, Abramowicz D. HLA mismatches remain risk factors for acute kidney allograft rejection in patients receiving quadruple immunosuppression with anti-interleukin-2 receptor antibodies. Transplantation. 2008 Feb 15;85(3):411-6. doi: 10.1097/TP.0b013e31816349b5. PMID: 18322434.
5- Nikkel LE, Hollenbeak CS, Fox EJ, Uemura T, Ghahramani N. Risk of fractures after renal transplantation in the United States. Transplantation. 2009 Jun 27;87(12):1846-51. doi: 10.1097/TP.0b013e3181a6bbda. PMID: 19543063.
What is the effect of HLA mismatch in living and deceased donor transplantation on the following?
The HLA match between recipient and donor for HLA A-B-C and DR antigen can affect both graft and patient survival for both living and DD program the higher the mismatch 4 -6mismatch associated with lower graft survival and higher the risk of DGF , acute rejection in first year and subsequent Chronic AMR and post transplant infection , PTLD and cardiovascular death
so zero-mismatch refer to absent of an HLA-A-B-C and DR antigen to donor phenotype but with moving to molecular level of HLA-typing may not recognize the HLA antigen at allel level that mean the serologically reported as zero-mismatch dose not rule out allel level mismatch, while six mismatch means that 2A,2B,2 DR antigen in the donor phenotype are different from those of the recipient , with high immunological risk for DGF, rejection and reduced graft survival ,and over all mortality due to increase risk of infection , metabolic complications with cardiovascular events so kidney allocation program based on the number of HLA mismatch considered important predictor for risk of DGF, one year acute ejection rate and 10 years graft survival for both living donor and DD transplant based on different data from varies registers since 1987TILL 2013 by UNOS , revised in 2014 , SRTR ,ANZDATA.
based on data from SRTR that found the mismatch for HLA-A, -B, and -DR has been associated with a higher risk of HLA sensitization in both adult and pediatric patients who are relisted for a second kidney transplant. the risk of sensitization increased by 37% for six-mismatch in HLA A-B-, DR antigens as they carry the most polymorphism.
references
1-up to date “Kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing”.)
2-hi, X., Lv, J., Han, W. et al. What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients. BMC Nephrol 19, 116 (2018).
Increasing extent of HLA mismatching results in worsening transplant outcomes.in case of deceased donors,13 %increased risk of graft failure was found with HLA mismatch. The risk increases to &64%with six HLA mismatches,1.Studies involving both live and deceased donors revealed that one HLA mismatch was associated with 7 % higher risk of graft failure compared to74%with six HLA mismatches,2.Certain mismatches at HLA loci ;namely HLA -A,B&DR ones ,;as being most polymorphic, have their impact on patient and graft outcomes,3,4.HLA-DR mismatching has more impact than HLA -Bor A,5,6.In addition ,HLA-DR mismatches with rejection episodes are associated with worse long-term survival,7. with increasing HLA mismatching,8.Sensitization occurs in 10% of cases with zero mismatching and is 37%with increasing HLA mismatching,8.Sensitization towards HLA class II antigens leads to increased incidence of major cardiac and cerebrovascular complications in addition to all-cause mortality in renal graft recipients,9.HLA DQ mismatching can lead to increased risk of rejection and allograft loss in spite being less polymorphic,10.In pre sensitized deceased donor kidney recipients ,it was found that mismatching of one or both HLA C antigens led to decreased graft survival,11.Having higher levels of pre transplant HLA-C DSA leads to increased chance of developing antibody mediated rejection in the first posttransplant year,12.In first transplant ,HLA-DP antibodies does not decrease allograft survival but it does so in case of second transplant,13714.Higher survival of renal allograft from siblings with non-inherited maternal alleles in comparison to survival of allografts from siblings with paternal alleles not inherited by the recipient .Certain degree of tolerance can result from exposure to donor antigens before transplantation,15.Eplet mismatching in HLA -DQ seems to have a significant risk for de novo DSA formation ,rejection and graft failure,16.Correlation between HLA mismatching and acute rejection was found to be independent of immunosuppressive regimen,2&3.HLA mismatching is considered s risk factor for development of non Hodgkin lymphoma,17 .Increased risk of post -transplant bone fracture is associated with HLA mismatches,18.More immunosuppressive therapy for higher risk of acute rejection is uncertain explanation.
REFERENCES:
1-Williams RC,Opelz G,McGarvey CJ,et al,The risk of transplant failure with HLA mismatch in first adult kidney allografts from deceased donors.Transplantation 2016;100:1094.
2-Lim WH ,Chadban SJ,Clayton P,et al,Human leucocyte antigen mismatches associated with increased risk of rejection,graft failure,and death independent of initial immunosuppression in renal transplant recipients.Clin Transplant 2012;26:E428.
3-Opelz G,Dohler B.Effect of human leucocyte antigen compatibility on kidney graft survival : comparative analysis of two decades. Transplantation 2007;84:137.
4-Dunn TB,Noreen H,Gillingham k,t al Revisiting traditional risk factors for rejection and graft loss after kidney transplantation .Am I Transplant 2011;11:2132.
5-Gilks WR,Bradley BA Gore SM,Klouda PT,Substantial benefits oftissue matching in renal transplantation.Transplantation 1987;43:669.
6-Doxiadis II,de Fijter JW Mallat MJ,et al Simpler and equitable allocation of kidneys from postmortem donors primarily based on ,et al ,HLA full HLA -DR compatibility .Transplantation 2007;83;1207.
7-Coupel S,Giral-Classe M,Karam G,et al,Ten-year survival of second kidney transplants :impact of immunologic factors and renal function at 12 months.Kidney Int 2003;64:674.
8-Meier-Kriesche HU,Scornik JC Susskind B,et alA lifetime versus a graft life approach redefines the importance ofHLA matching in kidney transplant patients, Transplantation 2009;88:23.
9-Malfait T,Emonds MP,Daniels L et al ,HLA Class II antibodies at the time of kidney transplantation and cardiovascular outcome: A retrospective cohort study ,Transplantation2020:104:823.
10-Lim WH,Chapman JRCoates PT,et al HLA-DQ mismatches and rejection in kidney transplant recipients ,Clin I Am Soc Nephrol 2016:11:875.
11-Tran TH ,Dohler B,Heinold A et al Deleterious impact of mismatching for human leucocyte antigen -C in presensitized recipients of kidney transplants,Transplantation,2011,92:419.
12-Aubert O,Bories MC,Suberbielle C,et al Risk of antibody -mediated rejection in kidney transplant with anti-HLA-C donor specific antibodies ,Am J Transplant 2014:14:1439.
13-Nelson KA,Youngs D ,Marks MH,Acute humoral rejection is associated with antibodies to HLA-DP,Am J Transplant 2005;5;245.
14-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.
15-Sanfilipo F, Transplantation tolerance –the search continues, N Engl J Med 1998.
16-Senev A,Coemans M,Lerut E, et al ,Eplet Mismatch Load and De Novo Occurrence of donor specific ant-HLA antibodies rejection,and graft failure afterkidney transplantation:An observational cohort study ,J Am Soc Nephrol 2020;31:2193.
17-Oplez G,Dohler B,Impact of HLA mismatching on incidence of posttransplantnon-hodgkin lymphoma after kidney transplantation,Transplantation2010;89:567.
18-Mutinga N,Brennan DC,Schnitzler MA, Consequences of eliminating HLA-B in deceased donor kidney allocation to increase minority transplantation,Am J Transplant 2005;5:1090.
HLA match has an important effect in kidney tx
The commonly used HLA-A. HLA-B. HLA DR
with mismatch range from 0 to 6 as each one of them has pair of loci coming from both parents.
Higher HLA matching lead to longer graft survival.and less post transplant complication
Including PTLD and bone fructures.better patient survival also documnted with better matching HLA.
HLA DR is the most important with decrease graft survival incidence with one mismatch and greater with ,2 mismatch.
lnduction with ATG plus steroids
and intensification of immuno suppression with mismatch carry risk of post tx sdverse effects like PTLD and infections.
Refrences,
https://www.uptodate.com/contents/kidney-transplantation-in-adults-hla-matching-and-outcomes/abstract/1
https://www.uptodate.com/contents/kidney-transplantation-in-adults-hla-matching-and-outcomes/abstra
S.V. Fuggle, J.E. Allen, R.J. Johnson, et al.
Dear All
Thank you for your replies. Feel free to contribute to the discussion for those who did not. Also, let us not forget week 2.
Data from various registries demonstrate better survival rates with HLA matches between donor and recipient. Worst survival of patients with more number of HLA mismatches. Various countries relied on the importance of HLA Matching to improve the overall graft outcomes. Allocation schemes based on HLA matching vary worldwide. While European systems assign weights to A,B,C,DR matching, the US systems gives importance to primarily DR matching. HLA typing for waitlisted kidney transplant candidates is done by PCR technology. HLA for donor and waitlisted transplant candidate is performed for serological equivalents for HLA A,B,C, DR,DP, DQ, DR1 etc. When matching a donor to a recipient on HLA mismatch approach to organ allocation will maximize the number of patients considered to be a match with a deceased donor.
For example HLA A2 is one antigen were homozygosity is frequent. If donor has HLA A2 A2 and a recipient has HLA A2 A23 or HLA A2 A66 it is considered zero antigen mismatch as the donor has A2 homozygosity. And if donor has HLA A2A23 and recipient has HLA A2A66 it is considered 1 antigen mismatch. HLA A2 A23 in the donor and HLA A2 A23 in the recipient means a zero antigen mismatch.
Degree of mismatch between recipient and donor is primarily determined for HLA A,B,DR as they are highly expressed and highly polymorphism. Zero antigen mismatch between the recipient and donor maybe identified as the absence of HLA A,B,DR antigen in donor phenotype that is different from recipient HLA A,B,DR antigen of recipients.
A serologically defined zero antigen mismatch does not rule out allele level mismatches. 222 mismatches indicates 2A,2B and 2 DR antigens in donor phenotype are different from the those of the recipients. Kidney allocation is based on the number of HLA mismatches in UNOS and SRTR, but many studies show better survival of the allograft with better HLA matching. But using HLA Matching for allocation, limit the access to transplantation for recipients from under represented groups with rare HLA antigens not present in a primarily white donor pool.
The problem with HLA mismatch is sensitization. Exposure to non self HLA antigen can lead to antibodies against mismatched HLA antigens. HLA sensitization can result from prior exposure to HLA mismatch through pregnancy, blood transfusion, previous transplant, immune activation after any vaccine etc. For a sensitized patient donor who express HLA antigens against a patient who has preformed antibody should be avoided if possible. These are reported as unacceptable antigens.
This helps in creating a virtual cross match. Virtual cross match uses the results of the antibody tests along with the donor and patient HLA typing to predict a candidate compatibility.
UNOS has reported 13% graft failure with 1 HLA mismatch and 64% graft failure with 6 HLA mismatches. ANZDATA reported 7% graft failure with 1 HLA mismatch and 74% graft failure with 6 HLA mismatches. In general the more the mismatches worse is the graft survival.
Other antigens of HLA are also identified for mismatching and outcomes. HLA DQ mismatch is associated with an increased risk of rejection and allograft loss in kidney transplant recipients. In the UNOS study, HLA DQ mismatch has been found to have an increased risk of acute antibody mediated rejection in the later post transplant period which are mainly due to de novo HLA antibody production. The poor outcome was described with both living donor and deceased donor kidney transplant patients.
Outcome for Anti HLA C antibodies on graft outcome are controversial. around 40 to 50% of all the transplant candidates will have antibodies against HLA C. HLA DP antibodies are very rare and found only in 5 to 14% of all patients.
HLA mismatches were found to have a superior death with functioning graft in clinical trials due to Cardiovascular and infectious causes.
There has been a higher incidence of PTLD is patients with more HLA mismatches probably due to use of induction agents and other immunosuppressive agents.
Post transplant bone fractures have also been reported to be higher in these patients, although the exact mechanism is not known.
References:
HLA mismatching has been accompanied by poor graft survival (increase acute and chronic rejection) and patient survival. Although patient survival compares to waiting list is better. Furthermore, HLA mismatching has been associated with higher risk of death with functioning kidney allograft, post-transplant lymphoproliferative disorders and posttransplant bone fracture.
Human leukocyte antigen (HLA) present on chromosome 6 is always an important biological barrier to a successful transplantation and has impacts on graft survival . However modern immunosuppressive agents minimized the effect of HLA compatibility. .
In the revised United Kingdom kidney allocation scheme, HLA matching is no longer considered . But the latest European Renal Best Practice Transplantation Guidelines still recommended that matching of HLA-A, –B, and –DR whenever possible, while gave more weight to HLA-DR locus .
HLA mismatching act as an important prognostic factor affecting both graft and recipient survivals. HLA- DR will have an important impact on graft survival while HLA- A has an insignificant role.
HLA matching has a number of advantages, including improved graft function, fewer rejection episodes, longer graft survival and using less immunosuppression.
Shi, X., Lv, J., Han, W. et al. What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients. BMC Nephrol 19, 116 (2018)
HLA has two classes:
HLA class I (A,B,C) and HLA class II (DR, DQ, Dp)
Class I are expressed on all nucleated cells and produce peptides on MHC class I and signal to CD8T cell for killing.
Class II are present on antigen-presenting cells (APC), mainly dendritic cells and B cells, these cells can sense antigens, engulf, process and load the antigens to activate CD4 T cells.
In general, the risk of graft loss increases with increases in the mismatches MM for both the living donor (LD) and deceased donor (DD). This association has a linear order for both type of donors. There was 16% higher risk of allograft loss for 1 MM in DD and 62% for 5 and 6 MM. the effect of MM was higher in LD with 48% for 1 MM and 114% for 6 MM although, LD transplants survival rates were as long or longer than DD.
The median survival for 0 MM was 25 years compared with 20 years for 1 MM, 18 years for 2 MM, 15 years for 3 MM and 12 years for higher MM
The age of the donor has implication on outcomes. Older donors (≥ 45 yrs) were associated with worse outcomes in DD but not in LD. Older LD with well match (0 to 3 MM) has better graft survival than poorly matched (4 to 6 MM) younger DD.
The effect of HLA MM in LD was classified in two groups, 1 to 3MM and 4 to 6 MM, this classification found to follow donor-recipient relationship types. Living related donor LRD 1st degree or living unrelated donor (LURD or LRD)
HLA MM has stronger effect in Living donor than deceased donor and this effect significantly increases from the 1 to 3 MM than from 4 to 6 MM. So, one needs to weigh the poorer matched LD outcome with better matched DD outcome.
Poorly matched (4-6 MM) LD had lower graft survival than a very well-matched (0-1 MM) DD. moreover, transplants from a 1-3 MM LD had comparable outcomes to the very well-matched (0-1 MM) DD group. Therefore, many studies support entering high HLA MM (4-6 MM) LD into donor paired exchange system.
In addition to risk f rejection which can be decreased in part by good donor selection. Post-transplant patients are at risk of side effect of immunosuppression drugs as infection and malignancy. Squamous and basal cell skin cancers are the most common type followed by NHL/ post-transplant lymphoproliferative disorder (PTLD) and cervical cancer. There is bimodal distribution of cancer incidence with a peak of 6.6 years for NHL/ PTLD and 14.8 years for all other cancers.
reference
Kim JJ, Fuggle S V, Marks SD. Does HLA matching matter in the modern era of renal transplantation? Pediatr Nephrol [Internet]. 2021;36(1):31–40. Available from: https://doi.org/10.1007/s00467-019-04393-6
-HLA mismatch influences negatively on graft survival as it increase risk of acute rejection (cellular or humoral)and need more aggressive immunosuppressant whether induction or maintenance
-this aggressive immunosuppressant increase risk of infection and malignancy (kaposi sarcoma &PTLD)so it decrease patient survival
And also use of desensitization methods as plasma-pharesis&rituximab increase risk of infection and malignancy
-high rate of acute rejection specially if high DSA
What is the effect of HLA mismatch in living and deceased donor transplantation on the following?
Williams RC et al. reported a linear relationship between HLA mismatch and allograft survival, in an analysis of 66,596 first adult transplants from living donors, he found that 1 mismatch conferred a 44% higher risk, whereas 6 mismatches conferred a two-fold higher risk of allograft failure. When using 0-mismatched full siblings as a reference, living-donor kidneys reduce the hazard of failure by approximately 34% when compared with deceased donors.
Moreover, Shi, X., et al, in a meta-analysis of 23 cohort studies covering 486,608 recipients, found HLA per mismatch was significantly 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).
In the same meta-analysis of Shi, X., et al, authors found in 4 cohorts analysis, included 180,766 recipients, found for each incremental increase of HLA mismatches, there was a higher risk of all-cause mortality rates (HR: 1.04; 95% CI: 1.02–1.07; P = 0.001).
Several retrospective studies have demonstrated that HLA matching is associated with a lower risk of acute rejection among kidney transplant recipients Although most of these studies were performed in patients receiving cyclosporine-based immunosuppression, one study showed that the number of HLA mismatches was an independent risk factor for acute rejection (odds ratio [OR] 1.65 per HLA mismatch) in transplant patients receiving immunosuppression consisting of interleukin (IL)-2 receptor antibody induction, tacrolimus, mycophenolate mofetil, and glucocorticoids. Analyses of data from two large transplant registries found that the association between HLA mismatches and acute-rejection risk was independent of the transplant era and initial immunosuppressive regimen.
Death with a functioning graft: HLA mismatching has been associated with a higher risk of death with a functioning kidney allograft. In a study of 177,584 deceased-donor kidney transplants performed between 1990 and 2009, the incidence of death with a functioning graft was 4.8 percent during the first post-transplant year and 7.7 percent during years 2 through 5 (approximately 2% per year).
The number of HLA-A, -B, and -DR mismatches correlated with a higher cumulative incidence of death with a functioning graft, from any cause, during the first three years post-transplant. This association was significant for death due to cardiovascular or infectious causes but not from malignancy.
Post-transplant lymphoproliferative disorders: Several studies have shown that HLA mismatching is an independent risk factor for the development of posttransplant non-Hodgkin lymphoma among kidney transplant recipients. As an example, in a study of 152,728 deceased-donor kidney transplant recipients from the Collaborative Transplant Study (CTS), an increased risk of posttransplant non-Hodgkin lymphoma was observed in patients with one (hazard ratio [HR] 1.21, 95% CI 1.00-1.45) and two (HR 1.56, 95% CI 1.21-1.99) HLA-DR mismatches. Similar findings were reported in an analysis of 9209 pediatric kidney transplant recipients, in which two HLA-DR mismatches were associated with a twofold higher risk of developing posttransplant non-Hodgkin lymphoma.
Post-transplant bone fractures — HLA mismatches are associated with an increased risk of post-transplant bone fractures in kidney transplant recipients. The mechanism behind this association between HLA mismatching and bone fractures is uncertain. HLA mismatches are associated with a higher risk of acute rejection, which is generally treated with more intensive immunosuppression that could adversely affect bone quality.
References:
1. Williams RC, Opelz G, Weil EJ, McGarvey CJ, Chakkera HA. The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts 2: Living Donors, Summary, Guide. Transplant Direct. 2017 Apr 7;3(5):e152.
2. Shi, X., Lv, J., Han, W. et al. What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients. BMC Nephrol 19, 116 (2018).
3. MC Philogene. Kidney transplantation in adults: HLA matching and outcomes. Up-to-date. Updated: Sep 28, 2021. Accessed on 6 Nov 2021
4- Wissing KM, Fomegné G, Broeders N, et al. HLA mismatches remain risk factors for acute kidney allograft rejection in patients receiving quadruple immunosuppression with anti-interleukin-2 receptor antibodies. Transplantation 2008; 85:411.
HLA matching is associated with improved graft survival in deceased donor graft. The effect tend to be less in living donor graft whether related or unrelated. High numbers of HLA antibodies is a risk factor for DGF to start with( other factors as well donor age ,cold ischemia time ..) and increases rejection rates .DGF is less ~3% in living donation and more prominent in deceased donation ~20%. The presence of DGF means decrease graft survival, increase mortality, and increase rejection possibly to due to enhance graft immunogenicity after reperfusion. Patient survival is affected mainly by cardiovascular disease, infections and malignancy. In general the more HLA, the better the outcome but this should not be the only factor to determine kidney transplantation, and we know remaining on dialysis is much worse than getting transplanted. Relevant to living related donation HLA DRB1 two match is more important for graft survival. 0 HLA mismatch in unrelated living donation was show to be similar to any match > 0 HLA match
Thank you all for your contributions.
Just to remind you that HLA 36 is common in the black race, while HLA A2 is the commonest HLA antigen in the white population.
Dear All
It was a good start, but feel free to add more contributions especially those who did not contribute much and did not contribute at all.
I would like to thank you all those sharing their comments.
I will try to study Handbook of transplantation and find out the answers of the questions related to this scenario which I got most of them after reading your comments.
What is the effect of HLA mismatch in living and deceased donor transplantation on the following?
Prof Ahmad Halawa comments and questions:
Will you transplant 222 mismatched living kidneys and what immunosuppression you will use if there is DSA and without the presence of DSA?
Why do you think that HLA mismatching is associated with post-transplant complications? What is the link?
What is the average half-life of 222 mismatched kidney in living and deceased donor transplants?
Please do not make a guess (read the handbook of Danovich or search for an answer)
Some colleagues mentioned CDC crossmatch, do we have a better technique?
None of you mentioned the role of DSA in categorizing the risks. Of course the presence of DSA makes the transplant associated with risk (depends on the degree of sensitization).
There are a few questions to come. This scenario looks simple but it is a mindfield
this recipient consider high immunological risk with 6 mismatches and negative DSA so still can go for kidney transplant with ATG induction , followed by triple maintenance IS with tacrolimus based and MMF and DSA AB surveillance post transplant keep in consideration the higher HLA mismatches especially at the level of HLADR the higher the risk of DGF ,acute rejection and lower graft survival
for second scenario with 222 mismatches and negative CDC ,negative FCXM but DSA with MFI of 1345 , this will be depend on the local center protocol regarding the interpretation of the this MFI level , there is no standardization of MFI level as some centers consider its low level and need just monitoring after the transplantation as high immunological risk , but some they interpreted as positive with MFI >1000 , and decide a bout the desensitization prior to transplant by using modified desensitization protocol with IVIG 1gm/kg pre transplant and induction with same ATG followed by maintenance triple IS , tacrolimus based with DSA ab screening post transplant
I believe the HLA-A2 is commonly sharing antigen in white population with homozygosity is more frequent, and such donor will likely be zero-mismatch for a patient with HLA-A2-A23, HlA -A2-A66, while donor with HLA A2-A23 will be zero-mismatch only for patient with HLA A2-A23 .
regarding the HLA A 36 antigen its specific to black race and im not sure about its interpretation .
HLA antibodies have been always considered an important biological barrier for successful renal transplantation (1).
However, that effect of HLA was minimized after the introduction of new immunosuppressive medications. The United kingdom allocation system has been modified over the years initially in 1995 where HLA-A similarity was eliminated similarly HLA-B similarity was eliminated in 2003, finally, in 2010, HLA matching is no longer considered (2).
On the other hand, European Renal Best Practice Transplantation Guidelines still recommend HLA -, HLA-B, and HLA-DR whenever possible which gave importance for DR locus in renal Tx (3).
This inconsistency about the importance of HLA mismatching in the renal transplant practice made that topic always a hot topic for various discussions, research studies, and meta-analyses.
Therefore Xinmiao Shi et al managed to perform this following meta-analysis which first meta-analysis to evaluate the magnitude effect of HLA mismatching on post-transplant survival outcomes of adult kidney transplantation (4).
They had interesting results which were
1- HLA mismatch and overall graft failure:
Their analysis of Eleven studies (289,987 adult recipients), revealed with every increase in HLA mismatch there is a higher risk of overall graft failure.
On further categorization of HLA mismatch categories and relation to graft failure
· HLA- DR and overall graft failure
They analyzed eight studies including 152,105 adult recipients which revealed each incremental increase of HLA-DR mismatches was significantly associated with a 12% higher risk of overall graft failure.
· HLA-B mismatches and overall graft failureThey analyzed 4 studies with 146,019 recipients which revealed each incremental increase of HLA-B mismatches was not associated with a higher risk of overall graft failure
· HLA-A mismatches and overall graft failureThey studied Only 3 studies (40,000 recipients), which showed an insignificant association between HLA- A mismatch and graft failure in renal Tx recipients.
2- Recipient mortalityThey included 180,766 recipients from 4 cohorts. They concluded that Each incremental increase of HLA mismatches was associated with a higher risk of all-cause mortality ratesMoreover, Croke R et al (2010) had demonstrated in their study that HLA mismatch is associated with a higher risk of graft failure and rejection.
Conclusion
HLA mismatching act as an important prognostic factor affecting both graft and recipient survivals. HLA- DR will have an important impact on graft survival while HLA- A has an insignificant role. New Zealand study group had demonstrated in their research that HLA mismatch is associated with a higher risk of graft failure and rejection.
References 1- Al-Otaibi T, Gheith O, Mosaad A, Nampoory MR, Halim M, Said T, et al. Human leukocyte antigen-DR mismatched pediatric renal transplant: patient and graft outcome with different kidney donor sources. Exp Clin Transplant. 2015;13(Suppl 1):117–23.
2- Johnson RJ, Fuggle SV, O’Neill J, Start S, Bradley JA, Forsythe JL, et al. Factors influencing outcome after deceased heart beating donor kidney transplantation in the United Kingdom: an evidence base for a new national kidney allocation policy. Transplantation. 2010;89(4):379–86.
3- Abramowicz D, Cochat P, Claas FH, Heemann U, Pascual J, Dudley C, et al. European renal best practice guideline on kidney donor and recipient evaluation and perioperative care. Nephrol Dial Transplant. 2015;30(11):1790–7.
4- Shi, X., Lv, J., Han, W. et al. What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients. BMC Nephrol 19, 116 (2018). https://doi.org/10.1186/s12882-018-0908-3
5- Croke R, Lim W, Chang S, Campbell S, Chadban S, Russ G, et al. HLA-mismatches increase risk of graft failure in renal transplant recipients initiated on cyclosporine but not tacrolimus. Nephrology. 2010;15:38.
kidney transplantation as an option of RRT still associated with better quality of life in comparison to dialysis but HLA mismatching still consider as important prognostic factor that affect both living and deceased donor kidney graft survival ,recipient survival and over all out come , the higher the mismatch the more the risk of graft rejection .Mismatches in HLA-DR antigen, 1 mismatches and 2 mismatches were all associated with higher risk of overall graft failure, with pooled HRs of 1.12 (95% CI: 1.04–1.21; P = 0.002) and 1.15 (95% CI: 1.05–1.25; P = 0.002)(1)
HLA-A mismatch associated with 6% risk of rejection while HLA-B mismatch have in significant risk on graft failure based on several studies but we should keep in mind each additional HLA mismatch increases the risk of graft failure
1-Reference, Shi et al. BMC Nephrology (2018) 19:116
2-Reference Transplantation ■ May 2016 ■ Volume 100 ■
We concern about 6 HLA antigen matched between the donor and recipient,if we had zero mismatch that mean very good graft and patient survival, minimal immune suppression medications and less post transplant complications (infections ,malignancy and rejection )but this could be done in living donor as we can search for better matching but in deceased donor it may not available
-The human leukocyte antigen (HLA) is a significant biological key to effective transplantation and has a major effect on graft survival.
-Human HLA genes are found on chromosome 6 and code for three major class I alleles (HLA-A, -B, and -C) as well as three significant class II alleles (HLA-DR, -DQ, -DP). HLA polymorphisms, particularly in the HLA-A, -B, and -DR loci, are key biological barriers to transplantation success.
-Mismatching HLA-DR has a serious influence on graft survival in recipients.
-In organ transplantation, HLA matching has a number of advantages, including improved graft function, fewer rejection events, longer graft life, and the chance for less immunosuppression.
-Mismatches are associated with more frequent rejection reactions, which necessitates higher immunosuppression, which increases the risk of infection and cancer. Sensitization can occur as a result of HLA mismatches, which might diminish the likelihood of a repeat transplant and lengthen the waiting period. Other parameters, including as donor aging, type, and immunosuppressive regimen, can, however, influence the benefit of matching.
-An increasing need for antirejection medicine was linked to an increase in the number of HLA mismatches in renal transplantation, which could account for an increased incidence of death with a working graft due to infection and cardiovascular disease.
-Based on the number of HLA-ABDR and HLA-DR mismatches in living donor and deceased donor kidney transplants, there is no significant difference in acute rejection rate and renal graft function up to 3 years utilizing our current immunosuppressive procedures. Medically suitable living donors produce better long-term outcomes than deceased donors, regardless of the amount of HLA-ABDR mismatches.
-Avoiding donor antigens to which a patient has antibodies, reducing antibody strength to an acceptable level, and/or using more intensive immunosuppression may be used as matching methods for sensitized patients.
References:
–What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients.Available at :https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-018-0908-3 (Accessed5/11/2021)-The impact of HLA-ABDR mismatch on acute rejection and graft function among Filipino kidney transplant recipients .Available at :
https://www.oatext.com/pdf/TiT-10-231.pdf (Accessed 5/11/2021)
First of all
●REGARDING HLA TISSUE TYPING : Serologic-based typing was the first standard method used to obtain donor and recipient HLA typing and was employed for more than 30 years. This technique uses a panel of reference sera (usually from multiparous women) that are known to contain antibodies to various HLA antigens.
● Lymphocytes from the donor or the recipient are added to several wells of plates having different sera.
Following an initial incubation step to allow binding between antibody and antigen, complement is added to wells, and a viability dye allows detection of cell lysis.
The presence of dead cells is a positive test.
Comparison of the serologic specificities of the different sera that reacted allows one to assign the HLA type.
●●Hla typing is done by 2 methods either serological or by Dna typing.
● DNA-based molecular methods include the following:
1- (((((Sequence-specific primers (SSP) typing))))
– This form of typing involves the use of primers designed to recognize a particular HLA sequence (allele) or group of similar alleles, such that the polymorphism to be detected is located at the 3′ end of the primer. DNA is first extracted from a blood sample and amplified by PCR using these primers. If both primers are able to bind to the DNA, then amplification occurs and can be detected by gel electrophoresis. The pattern of amplicons that are present allows for the assignment of the HLA genotype.
2- ((((Sequence-specific oligonucleotide probes (SSOP) typing ))))
– With SSOP typing, DNA is amplified using a set of primers that recognize a particular HLA locus. As with SSP typing, primers are designed to amplify the most polymorphic regions of the HLA gene (exons 2 and 3 for class I genes and exon 2 for class II genes).
3- ((((Real-time PCR (RT-PCR)-based typing)))))
– This form of typing is based upon the use of allele-specific PCR similar to SSP methods. However, instead of using gel electrophoresis, amplicons are detected in real time with the use of fluorescent dyes or probes. Each well contains sequence-specific primers such that if the allele is present, the DNA becomes amplified. The added cyanine dye binds to any amplified, double-stranded DNA and fluoresces.
4- ((((Sequence-based typing (SBT) – SBT, or Sanger-based sequencing)))))
is based upon the direct amplification and sequencing of the relevant exons using fluorescently labeled dideoxynucleotides. Since this method deciphers the specific nucleotide sequence of the amplified region, it allows for a high resolution typing. This sequence is then compared with known sequences of HLA alleles in the IPD-MGT/HLA database to assign the HLA typing.
5- ((((Next-generation sequencing (NGS))))))
– The advent of NGS techniques has enabled high-resolution typing with significantly reduced ambiguity as it allows for base calls to be assigned to the same (cis) or different (trans) alleles (also known as phasing).
●●Regarding ptn survival :
The incidence of death is 4.8% during the ( 1st ) Tx year and
7.7% during the 2 post Tx years up to 5th year
With the % increasing by every year.
The HLA-A + HLA- B + HLA- DR mismatches lead to death % that was found to be lesser than the % of death from other cause ( cardiovascular or 8nfection) but with a functioning graft.
●●Patient survival was higher among recipients of HLA-mismatched kidneys at
1 year ((89)) vs ((95)) percent,
5 years ((59)) vs ((86))%
Even compared with waitlisted candidates who eventually received a deceased-donor kidney, survival was higher among recipients of HLA-mismatched kidneys at
1 year ((94)) vs ((95)) %
5 years((74.4 ))vs ((86 ))%
●● Regarding the long Term graft survival Most transplants that are lost to acute rejection do so within the first year.
Later graft loss is primarily due to chronic rejection.
●●POST Tx ADVERSE OUTCOMES:
1-Post Tx lymphoproliferative disorders
2- Post Tx bony fractures ( mechansim is not yet establishedbut may be from increasing ( intensifying the dose of the i.suppressive ttt)
_____Risk of fractures after renal transplantation in the United States.
_____Nikkel LE, Hollenbeak CS, Fox EJ, Uemura T, Ghahramani N
______Transplantation. 2009 Jun;87(12):1846-51.
♧♧♧N.B. :
HLA-DR mismatches were associated with a twofold higher risk of developing posttransplant non-Hodgkin lymphoma
♧♧♧A limitation of strictly using HLA typing for organ allocation is the difficulty in finding well matched kidneys.
The United States United Network for Organ Sharing (UNOS) program mandates that six-antigen-matched grafts be given priority.
______Takemoto SK, Terasaki PI, Gjertson DW, Cecka JM
______N Engl J Med. 2000;343(15):1078.
By mentioning this paragraph i meant (( in deceased renal tx ) : A limitation of strictly using HLA typing for organ allocation is the difficulty in finding well matched kidneys.
The United States United Network for Organ Sharing (UNOS) program mandates that six-antigen-matched grafts be given priority.
______Takemoto SK, Terasaki PI, Gjertson DW, Cecka JM
______N Engl J Med. 2000;343(15):1078.
Graft survival:
Patient survival:
Acute rejection rate:
post transplant adverse events:
(1) Coupel S, Giral-Classe M, Karam G, et al. Ten-year survival of second kidney transplants: impact of immunologic factors and renal function at 12 months. Kidney Int 2003; 64:674.
(2) Dialysis and Transplantation, Owen WF, Pereira BJ, Sayegh MH (Eds), WB Saunders, Philadelphia 2000. p.504
(3) Williams RC, Opelz G, McGarvey CJ, et al. The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts From Deceased Donors. Transplantation 2016; 100:1094.
(4) Freitas MC, Rebellato LM, Ozawa M, et al. The role of immunoglobulin-G subclasses and C1q in de novo HLA-DQ donor-specific antibody kidney transplantation outcomes. Transplantation 2013; 95:1113.
(5) Devos JM, Gaber AO, Teeter LD, et al. Intermediate-term graft loss after renal transplantation is associated with both donor-specific antibody and acute rejection. Transplantation 2014; 97:534.
graft and patient survival
living donor kidney allografts are associated with 34% reduced risk of kidney failure compared with any deceased donor kidney among all organ recipients with 1 to 6 mismatches.
the induction and immunosuppressive protocols are the same for allografts from deceased or living donors.
kidneys from deceased donors are associated with lowest impact of hla mismatch,kidneys from live related donors are associated with an intermediate hazard from HLA mismatch and kidneys from live unrelated donors are associated with a high impact from HLA mismatch.
HLA DR per mismatch was associated with a 12% higher risk of overall graft failure.compared with 0 DR mismatches, 1 and 2 mismatches were associated with 12 and 15% higher risk of overall graft failure respectively.
HLA A per mismatch was associated with a 6% higher risk of overall graft failure.
there was no significant association between HLA B mismatching and graft survival.
living allografts have smaller hazard ratios than deceased allografts within a mismatch category.like when there are 2 mismatches,living allografts have a significantly better survival than 0 mismatched deceased donor.however when there are 3 mismatches the hazard ratio for living allograft is not significantly different from the deceased.a live related 6 mismatch kidneys have a hazard ratio of 1.14,the confidence of which include 1.00.so in transplantation usually a living relative or a non relative with many HLA mismatches is preferable or of equal value to a closely matched deceased donor.
HLA mismatches lead to an increased incidence of acute rejection which requires intensive immunosuppression leading to side effects like infections,diabetes,avn of femur,hypertension,cardiovascular events
The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts 2: Living Donors, Summary, GuideRobert C. Williams, PhD,1 Gerhard Opelz, MD,2 E. Jennifer Weil, MD,1 Chelsea J. McGarvey, MD,3 and Harini A. Chakkera, MD4
What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients
The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts 2: Living Donors, Summary, GuideRobert C. Williams, PhD,1 Gerhard Opelz, MD,2 E. Jennifer Weil, MD,1 Chelsea J. McGarvey, MD,3 and Harini A. Chakkera, MD4
HLA DR1,4,7, B8,12,40, A1,2,11 are associated with a significantly reduced risk of sensitization (15% less likely)
HLA B42,53 ,A 10,19,36 is associated with an increased risk of PRA responses(38% increased risk).
HLA phenotypes of ESRD patients are risk factors in the panel-reactive antibody (PRA) response
E Heise 1, C Manning, L Thacker
CDC negative,FCMX positive,
DSA absent- accept for transplant with thymoglobulin induction.
DSA class 1 and 2 present
MFI <1000- transplant with thymoglobulin induction
MFI 1000-10000- Plasmapharesis plus low dose IVIG plus ATG(target MFI<1000 OR FCMX negative with MFI< 1500)
MFI>10000 – Avoid transplant.
HLA desensitization based on results of the luminex technique in kidney transplant – A single-center experience
SB Bansal1, A Gade1, S Sinha2, A Mahapatra1, P Jha1, SK Sethi1
Mismatch between donor and recipient is determined by HLA-A,HLA-B,HLA-DR each contain 2 Ag ,so 6 mismatch between donor and recipient are not matching.
The survival of patients who are highly sensitized due to HLA mismatch is lower than HLA matching kidney transplantation.
HLA-DR ,HLA-B Ag mismatch associated with poor graft outcome.
HLA-DQ mismatch is associated with poor long term survival.
2 HLA-DR mismatch in pediatric population preclude kidney transplantation due to higher degree of sensitization.
HLA-A2 associated with poor survival .
Transplantation from living donor is more better regarding graft survival and long term outcome in compare with deceased donor due to the effect of increase immunogenicity of deceased organ and the era of ischemia reperfusion injury.
Improve the IS protocol decrease the effect of mismatching.
HLA mismatch lead to the use of aggressive IS which ultimately lead to post transplant complications like DM HT ,dyslipidemia, infection ,cardiovascular events, bone fracture and PTLD.
A Well-matched Allograft From a Deceased Person Is Equivalent or Better in Survival to One From a Poorly Matched Living Donor
Typing and compatability of HLA is an essential step in kidney transplantation. Testing for histocomptability is aimed for assessment of mismatching between the donor and the recipient and therefore for classification of immunological risk of the recipient according to the the potential donors.
Zero mismatches of HLA has a higher rate of the graft survival than one or more of mismatches of HLA.
HLA A,B and DR has higher association with poor outcome of the recipient and the graft survival, in contrast to mismatching in HLA A alone which has a little effect.
Donor specific antibody (DSA) is the antibodies formed in the recipient against potential donors. It may be presented due to previous blood transfusion, previous transplantation and pregnancy. In this case, there is sensitization against the donor which carries a great risk for graft rejection and inferior outcomes.
DSA should be tested before transplantation by immunological laboratory techniques which done by cell-based method (complement dependent cytotoxicity and flowcytometry) and solid phase immunoassays (ELISA and Luminex).
Reference
Chari M, Kosi ME, Jim JK, Sharma A, Halawa A (2017) Crossmatching in Renal Transplantation by Non-Immunologists for Non-Immunologists. Urol Nephrol Open Access J 5(2): 00166. DOI: 10.15406/unoaj.2017.05.00166
Williams RC, et al. The risk of transplant failure with HLA mismatch in first adult kidney allografts 2: living donors, summary, guide. Transplant Direct. 2017;3(5):e152.
HLA mismatch is one of the most important parameters for graft survival, both among deceased and living donor kidney transplantation. Hence allocation systems for deceased donor such as UNOS are considering this parameter. In a research done by UNOS, the result showed that the risk of graft failure was increased with higher number of HLA mismatches; the rate of acute rejection was increased among kidney transplant patients with higher mismatches. Hazard ratio for lower graft survival was linearly related with HLA mismatch in living-related and living-unrelated and deceased donors. This increased hazard ratio was equal for HLA-A, B, and DR. Nowadays we can also use epitope mismatch (CREG-based mismatching) and eplet mismatch load. Different studies have shown the positive effect of HLA matching in graft survival. The best graft survival was seen in 0-mismatch living-related kidney transplant donors and the worst outcome in six-mismatch deceased donor. In recent studies an increase in HLA mismatch was associated with increased acute rejection rate and decrease in patient survival rate. In addition, complications such as PTLD and bone fracture were increased with an increased HLA mismatch number.
Human HLA genes are located on chromosome 6 and code for 3 major class I alleles (HLA-A, -B, -C) and 3 major class II alleles (HLA-DR, -DQ, -DP).
Polymorphisms in HLA, especially HLA-A, -B, and -DR loci, are important biological barriers to a successful transplantation
With the emergence of potent immunosuppressive agents that steadily improved the graft survival rates, the impact of HLA compatibility seems to be minimized, recent studies demonstrated that each incremental increase of HLA mismatches was significantly associated with higher risk of graft failure and rejection
Increasing numbers of HLA mismatch in renal transplantation are associated with an increased need for antirejection therapy that might account for an increased incidence of death with functioning graft due to infection and cardiovascular disease
HLA matching provides benefits in improving
outcomes in kidney transplantation
HLA MATCHING AND TRANSPLANT OUTCOMES
Long-term graft survival — Most transplants that are lost to acute rejection do so within the first year. Later graft loss is primarily due to “chronic rejection,” a disorder that is more difficult to treat with existing immunosuppressive regimens
Multiple analyses have demonstrated that human leukocyte antigen (HLA) matching is associated with improved long-term graft survival ..In the 2008 annual report of the Scientific Registry of Transplant Recipients (SRTR), the five-year, deceased, nonextended-criteria donor allograft survival for zero versus six HLA-mismatched, deceased-donor kidneys was 75 and 66 percent, respectively
Long-term graft survival is also best in HLA-identical, particularly living-related, kidneys and worst in randomly matched cadaver kidneys
HLA-DQ mismatching is associated with lower graft survival independent of HLA-ABDR in living donor kidney transplants and deceased donor kidney transplants with cold ischemia time ≤17 hours, and a higher 1-year risk of acute rejection in living and deceased donor kidney transplants.
Patient survival compared with waiting list — Although graft survival of HLA-mismatched kidneys is reduced compared with HLA-matched kidneys, patient survival of highly sensitized recipients of HLA-mismatched kidneys is higher when compared with highly sensitized transplant candidates who remain on the waiting list and are undergoing dialysis.
Acute rejection — Several retrospective studies have demonstrated that HLA matching is associated with a lower risk of acute rejection among kidney transplant recipients..Although most of these studies were performed in patients receiving cyclosporine-based immunosuppression .
Death with a functioning graft — HLA mismatching has been associated with a higher risk of death with a functioning kidney allograft due to cardiovascular or infectious causes
Posttransplant lymphoproliferative disorders — Several studies have shown that HLA mismatching is an independent risk factor for the development of posttransplant non-Hodgkin lymphoma among kidney transplant recipients
Posttransplant bone fractures — HLA mismatches are associated with an increased risk of posttransplant bone fractures in kidney transplant recipients
Pediatric patients — Transplantation of pediatric patients presents additional challenges since these patients are more likely to require repeated transplantation. Thus, well-matched organs are a priority for pediatric patients and could potentially lead to longer wait times. This is in contradiction to the clinical management of pediatric patients where reducing time on dialysis is a more important objective since this impacts their neurologic development and growth. For this reason, all allocation systems (including Share 35 and the new KAS) have focused on quicker access to deceased kidney donors for pediatric transplant candidates These allocation changes have also allowed pediatric patients to receive the highest-quality donors (ie, those less than 35 years old and with a KDPI of 35 percent or less)
Pediatric patients also receive priority points for HLA-DR matching.
1. Yacoub R, Nadkarni GN, Cravedi P, et al. Analysis of OPTN/UNOS registry suggests the number of HLA matches and not mismatches is a stronger independent predictor of kidney transplant survival. Kidney Int 2018; 93:482.
2. Williams RC, Opelz G, McGarvey CJ, et al. The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts From Deceased Donors. Transplantation 2016; 100:1094.
3. Orandi BJ, Luo X, Massie AB, et al. Survival Benefit with Kidney Transplants from HLA-Incompatible Live Donors. N Engl J Med 2016; 374:940.
4. Beckingham IJ, Dennis MJ, Bishop MC, et al. Effect of human leucocyte antigen matching on the incidence of acute rejection in renal transplantation. Br J Surg 1994; 81:574.
The repeated reply was deleted Dr Assafi
Prof Ahmed Halawa
The degree of HLA mismatch has Longley been one of the most important determinants of immunological risk in in kidney transplant recipients, where the increasing number of HLA mismatch correlates with increased risk of acute rejection rejection specially AMR more than cellular rejection , also site of mismatch has its important impact as mismatch in the 2 Dr loci had more unfavorable outcome than HLA class I mismatch, regarding longevity of the graft. 1, 2
The development of novel immunosuppression drugs had encouraged transplantation with higher HLA mismatch numbers or even complete mismatch but this is associated with higher incidence of immunosuppressive drugs complication with poor patient outcome secondary to infections , malignancy and cardiovascular complications .3
Ref
1- Süsal C, Opelz G. Current role of human leukocyte antigen matching in kidney transplantation. Curr Opin Organ Transplant. 2013 Aug;18(4):438-44. doi: 10.1097/MOT.0b013e3283636ddf. PMID: 23838649.
2- Pratschke J, Dragun D, Hauser IA, Horn S, Mueller TF, Schemmer P, Thaiss F. Immunological risk assessment: The key to individualized immunosuppression after kidney transplantation. Transplant Rev (Orlando). 2016 Apr;30(2):77-84. doi: 10.1016/j.trre.2016.02.002. Epub 2016 Feb 18. PMID: 26965071.
3- Shi X, Lv J, Han W, Zhong X, Xie X, Su B, Ding J. What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients. BMC Nephrol. 2018 May 18;19(1):116. doi: 10.1186/s12882-018-0908-3. PMID: 29776389; PMCID: PMC5960106.
HLA
Human leukocyte antigen (HLA) is important biological barrier to a successful transplantation and has substantial impact on the prolongation of graft survival .
However, the emergency of modern immunosuppressive agents minimized the effect of HLA compatibility.
The US kidney allocation system was extensively modified to eliminated HLA-A similarity in 1995 and HLA-B similarity in 2003 .
In the revised United Kingdom kidney allocation scheme, HLA-A matching is no longer considered . But the latest European Renal Best Practice Transplantation Guidelines still recommended that matching of HLA-A, –B, and –DR whenever possible, while gave more weight to HLA-DR locus .
So far, the current kidney allocation guideline recommendations were inconsistent in term of HLA compatibility. Besides, for the primary aim to make the kidney last as long as possible, all the current kidney allocation systems were not perfect.
HLA per mismatch is significantly associated with increased risks of overall graft failure , death-censored graft failure and all-cause mortality .
Besides, HLA-DR mismatches were associated with worse overall graft survival. For HLA-A locus, the association was insignificant. No significant association between HLA-B locus and overall graft failure .In subgroup analyses, the recipient sample size and ethnicity maybe the potential sources of heterogeneity.
HLA mismatching was still a critical prognostic factor that affects graft and recipient survival. HLA-DR mismatching has a substantial impact on recipient’s graft survival. HLA-A mismatching has minor but insignificant impact on graft survival outcomes.
HLA typing and mismatch determination between the potential transplant recipient and donor is an important step for sure.
Usually the HLA A-, B-, and DR- are typed for both the donor and the recipient and degree of mismatch is looked into. Although the survival of patients who are highly sensitized due to HLA mismatch is lower than those receiving HLA matching kidney, but survival remains higher when compared to those who receive hemodialysis or on waiting list.
The more the mismatches the lower the degree of graft and patient’s survival and higher acute rejections. However, the importance of HLA matching has decreased relatively than before, and is now considered to be more important in deceased than in living donor due to the various effective immunosuppressive agents that are available nowadays.
The incidence of delayed graft function as well as acute rejection rate is lower in first year with the higher HLA match.
Increased incidence of DSAs with Class II HLA mismatch (HLA-DQ, DR) thus affecting the graft and patient’s survival .
Post-transplant bone fractures are higher in recipients with HLA-DR mismatch.PTLD risk is also higher in transplants with HLA DR mismatch (21% increased risk with 1 HLA-DR mismatch and 56% increased risk in 2 HLA-DR mismatch).
Refrences:
Hung Do Nguyen, Rebecca Lucy Williams, Germaine Wong and Wai Hon Lim (February 13th 2013)
Lim WH, Chadban SJ, Clayton P, et al. Human leukocyte antigen mismatches associated with increased risk of rejection, graft failure, and death independent of initial immunosuppression in renal transplant recipients. Clin Transplant. 2012; 26(4): E428.
Opelz G, and Döhler B. Association of HLA mismatch with death with a functioning graft after kidney transplantation: a collaborative transplant study report. Am J Transplant. 2012; 12(11): 3031.
for the outcome of transplantation, living versus deceased donor is more successful than the degree of HLA matching. the outcome of living transplant with 100 % mismatch is equal to deceased transplant with 0 % mismatch.
Thanks, Ibrahim
Please expand more on your answer
thank you, prof.
the actual accurate data for transplant outcome for live versus deceased graft are available in all books. however, my concern is to pick-up the most valuable data to be written in short, so other colleagues can get it easily. of course no one can read the comments of all as it is too much time consuming. we can maximize the benefit of this time in reading new articles, gaining more experience of others, discussing interesting cases…. etc.
any how, to my knowledge as I passed before the SCE nephrology from UK in addition to MRCP and I read the textbook of Comprehensive clinical nephrology in detail for 8 times over 4 years, the outcome for grat survival and acute rejection rate is less for deceased grafts, in the 1 st year. after the 1st year, the outcome is almost similar for both live and deceased grafts. patient survival is also almost the same with no significant change.
HLA matching provides numerous benefits in organ transplantation including better graft function, fewer rejection episodes, longer graft survival, and the possibility of reduced immunosuppression. Mismatches are attended by more frequent rejection episodes that require increased immunosuppression that, in turn, can increase the risk of infection and malignancy. HLA mismatches also incur the risk of sensitization, which can reduce the opportunity and increase waiting time for a subsequent transplant.
In separate reports from the Collaborative Transplant Study, it was shown that HLA mismatches were associated with death with functioning graft and with posttransplant lymphoproliferative disease. Increasing numbers of HLA mismatch in renal transplantation were associated with an increased need for antirejection therapy that might account for an increased incidence of death with functioning graft due to infection and cardiovascular disease
As mentioned before
HLA mismatches goes with high risk of acute rejection and graft survival failure ..
HLA mismatches were associated with an incremental risk of rejection although the relative risk was higher for live donor kidney transplants. Increasing HLA-AB and HLA-DR mismatches were associated with a greater risk of acute rejection, graft failure, death-censored graft failure, and/or death. There was no consistent association between initial immunosuppressive regimen and outcomes.
Williams RC, Opelz G, McGarvey CJ, Weil EJ, Chakkera HA. The risk of transplant failure with HLA mismatch in first adult kidney allografts from deceased donors. Transplantation. 2016; 100: 1094–1102.
HLA mismatch is associated with adverse impact on graft survival.With the wide use ofimmunosuppressives that improved the graft survival rates, the impact of HLA compatibility impact decreased meanwhile the Australia and New Zealand Dialysis and Transplant Registry (ANZDTR) survey with 12,662 recipients yet expressed that increasing of HLA mismatches was significantly associated with higher risk of graft failure (1).
Poor graft outcomes could be related to high rejection risk risk especially antibody-mediated rejection . Decreased patient survival could be associated with immunosuppression consequences (2).
In particular, the use of anti-thymocyte immunoglobulin and post-transplant endoxan is a very attractive GVHD prophylaxis to reduce the risk of complications of HLA-incompatible transplantation. (3)
A linear relation of kidney survival with HLA mismatch for organs donated from deceased donors; 1 mismatch conferred a 13% higher risk while 6 mismatches conferred a 64% higher risk of graft failure. However, such association was not studied yet among living donors . It was suggested that HLA matching may not be as important in living donors as in deceased ones.(4)
Living-donor kidneys survive longer than those from deceased donors .(5)
1-Broeders N, Racapé J, Hamade A, Massart A, Hoang AD, Mikhalski D, et al. A new HLA allocation procedure of kidneys from deceased donors in the current era of immunosuppression. Transplant Proc. 2015;47(2):267–74.
2-Legendre C, Canaud G, Martinez F. Factors influencing long-term outcome after kidney transplantation. Transpl Int. 2014;27(1):19–27
3-Junya Isada.Impact of HLA incompatibility on transplant outcome.Clinical blood. 2017 Vol. 58, No. 12, p. 2415-2424
4-Williams RC, Opelz G, McGarvey CJ, et al. The risk of transplant failure with HLA mismatch in first adult kidney allografts from deceased donors. Transplantation. 2016;100:1094–1102.
5-Robert C. Williams, Gerhard Opelz, E. Jennifer Weil, Chelsea J. McGarvey, and Harini A. Chakkera, The Risk of Transplant Failure With HLA
Human HLA genes are located on chromosome 6 and code for 3 major class I alleles (HLA-A, -B, -C) and 3 major class II alleles (HLA-DR, -DQ, -DP). Polymorphisms in HLA, especially HLA-A, -B, and -DR loci, are important biological barriers to a successful transplantation 1.
With the emergence of potent immunosuppressive agents that steadily improved the graft survival rates, the impact of HLA compatibility seems to be minimized 2.
But the recent Australia and New Zealand Dialysis and Transplant Registry (ANZDTR) survey with 12,662 recipients still demonstrated that each incremental increase of HLA mismatches was significantly associated with higher risk of graft failure and rejection 3.
The meta-analysis suggested that HLA-DR per mismatch was significant associated with a 12% higher risk of overall graft failure HLA-A mismatching had an impact on overall graft survival .However, studies showd no significant association between HLA-B mismatching and overall graft survival .
the latest European Renal Best Practice Transplantation Guidelines still recommended that matching of HLA-A, -B, and -DR whenever possible, while gave more weight to HLA-DR locus 4.
Post-transplant long-term prognosis includes also the occurrence of complications like post-transplant lymphoproliferative disease (PTLD), post-transplant bone fractures, development of donor specific antibodies (DSAs) and death with a functioning graft all have higher incidence with HLA mismatches more with DR mismatche 5.
Reference
1- Broeders N, Racapé J, Hamade A, Massart A, Hoang AD, Mikhalski D, et al. A new HLA allocation procedure of kidneys from deceased donors in the current era of immunosuppression. Transplant Proc. 2015;47(2):267–74.
2- Süsal C, Opelz G. Current role of human leukocyte antigen matching in kidney transplantation. Curr Opin Organ Transplant. 2013;18(4):438–44.
3- Croke R, Lim W, Chang S, Campbell S, Chadban S, Russ G, et al. HLA-mismatches increase risk of graft failure in renal transplant recipients initiated on cyclosporine but not tacrolimus. Nephrology. 2010;15:38.
4- Abramowicz D, Cochat P, Claas FH, Heemann U, Pascual J, Dudley C, et al. European renal best practice guideline on kidney donor and recipient evaluation and perioperative care. Nephrol Dial Transplant. 2015;30(11):1790–7.
5- Weibe C, Gibson W, Blydt-Hansen TD et al. Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant 2012;12(5):1157-67.
HLA mismatch detection is vital. the lower the ratio the best the survival both in recepients from deceased donors as well as living donors. in deceased donors along with modern immune suppression we had the chance to transplant patients with minimal mismatch (unrealted donors) . full match will lower the trasnplant ratio. In terms of graft survival the lower the mismatch the lower the risk of rejection and the better the survival of the graft. with high doses of immmune suppression adverse effects are more probable. the more the drug doses the more the complication either due to drugs it self or due to opportunistic infections. accordingly patient survival is adversely affected
Dear All
Firstly, thank you for your replies. Most importantly, you read the replies before you and make your mind based on reading.
Secondly, lets us translate this discussion into clinical contexts:
This patient is considered high risk patient for rejection with 6 mismatches and carries the worse prognosis in terms of graft survival and should receive aggressive induction immunosuppression. this donor should receive rATG-thymoglobulin rather tham interleukin 2 antagonist.
for maintenance: CNI with optmal dose and target therapeutic level, steroisds and antimetabolite in particular MMF
For high risk patients and preformed DSA, recipients should initially receive desensitization strategies which include pretransplant treatment with high dose steroids with either rituximab or plasmapheresis, and induction therapy as in high risk patients.
Thanks, Mohamed
I disagree with you, it depends on the crossmatch. If positive, desensitisation is required, but negative crossmatch does not require desensitisation, but augmented immunosuppression with aggressive induction.
I admire your contribution, my friend. Keep going
There is linear relationship between HLA mismatch and decrease graft survival in deceased donor which mostly caused by increase the antigenicity of the graft and more exposure of its different HLA antigens caused by ischemia reperfusion injury
This relation in not exist in living donoation
Regarding immunosuppressant medications for 222 mismatch with no DSA ……. DSA and mismatch is not all the factors on which i will make my decision on
1ry kidney disease,age,cPRA even nonDSA and results of other cross match results should be considered
But supposed that whole risk is HLA 6mismatch so i will consider this patient moderate risk and go with depleting induction ATG 3mg/kg and triply immunosuppressant medications steroids/tac/MMF
If we have low MFI DSA and other factors are the same still patient at the same category with the same immunosuppressant medications except if was DQ DSA i may reject the donor
Finally there’s common HLA in certain population like HLA A2 and A36 and dsa against it will form great challenge to find donor with no DSA against it
1-The clinical trial showed a decreased incidence and severity of acute rejection when treated with rATG compared to basiliximab at 1 year (16% vs. 26%) and 5 years (15% vs. 27%) post-transplant, but similar incidences of graft loss, DGF, and death.
In moderately sensitized patients (positive DSA and negative flow crossmatch), induction with ATG resulted in reduced occurrence of de novo DSA (dnDSA) and AMR compared to basiliximab.
.Another randomized trial found a significantly reduced incidence as well as the severity of acute rejection in high immunological risk patients, defined by Kidney Disease Improving Global Outcomes (KDIGO) as a high number of MHC mismatches, younger recipient, older donor, PRA > 0%, presence of DSA, blood group incompatibility, DGF, and cold ischemic time > 24 h, treated with rATG versus basiliximab with acute rejection rates at 1 year (15% vs. 27%)
2-with DSA(MFI 1345) and FCXM negative, current evidence treatment with antibody removal does not seem justified. careful monitoring of post-transplant DSA level is appropriate.
3-Patient with serum carrying HLA-A2 antibodies may react with HLA-A2 as well as A68, A69, B57.as they share amino acid sequence stimulates HLA-A2(CROSS-REACTIVITY)
1-Hellemans R., Bosmans J.L., Abramowicz D. Induction Therapy for Kidney Transplant Recipients: Do We Still Need Anti-IL2 Receptor Monoclonal Antibodies? Am. J. Transplant. 2017;17:22–27. DOI: 10.1111/ajt.13884.
2-DOI:10.1093/med/9780199215669.003.19
3-Gabriel M.Danovitch
I could not understand (222) mismatched term
https://cran.r-project.org/web/packages/transplantr/vignettes/hla_mismatch_grade.html
??? (222)
it means
HLA- A: 2 mismatches
HLA- B: 2 mismatches
HLA- DR: 2 mismatches
References:
(1) H. C. Sullivan1 , R. S. Liwski2 , R. A. Bray1 and H. M. Gebel1
The Road to HLA Antibody Evaluation: Do Not Rely on MFI
American Journal of Transplantation 2017; 17: 1455–1461
This is an excellent answer Mujtaba. Very impressed. You missed the easy part, which is the prevalence of HLA A2 in the community. It is the commonest HLA antigen. DSA against HLA A2 is a bad sign and confer less chance of matchbility.
1. What would be your immunosuppression for 222 mismatched transplants with no DSA?
Induction with ATG. Immunosuppression: Tac/ MMF/ Steroids
2. What would be your immunosuppression for 222 mismatched transplants with DSA (MFI of 1345), but negative FCXM and CDC?
Induction with ATG. Immunosuppression: Tac/MMF/ Steroids
No desensitization as cross match is negative.
3. What is the relevance of HLA A2 and HLA A36 antigens?
HKA A2 is the one of the most frequent class I HLA antigen.
HLA A36 is predominantly seen in Africa and rare outside Africa.
For deceased donor kidneys, better HLA matching is associated with better graft survival.
-Graft survival in deceased donor kidneys is fallen progressive with increase HLA mismatch.
-HLA matching effect is much less pronounced for living donor kidneys.
-HLA-DR mismatch is a risk factor for acute rejection and post-transplant non Hodgkin lymphoma.
the is a linear relationship between HLA mismatch and allograft survival.
1 mismatch conferred a 44% higher risk, whereas 6 mismatches conferred a twofold higher risk of allograft failure. When using 0-mismatched full siblings as a reference, living-donor kidneys reduce the hazard of failure by approximately 34% when compared with deceased donors.
HLA matching has a statistically significant and clinically important impact on short- and longer-term graft survival, even in the post-cyclosporine era. However, the impact of HLA mismatches is not linear over the entire range of zero to six mismatches, in that progressive increases in the number of mismatches from one to six have only a small effect on survival as compared with the large benefits afforded by the use of a graft with no mismatches
.HLA-DQ mismatches are associated with acute rejection, independent of HLA-ABDR mismatches and initial immunosuppression.
Effect of HLA mismatch in living and deceased donor transplantation on graft survival and acute rejection rate
Analysis of 93,782 kidney-only transplants in the United States over 10 years is the largest retrospective study to date to evaluate the effects of HLA-DQ mismatching on transplant outcomes in the era of modern HLA typing. Demonstrated that HLA-DQ mismatched kidneys have a higher risk of acute rejection when compared with HLA-DQ matched kidneys. HLA-DQ mismatching influences graft survival in living kidney donor recipients and in deceased kidney donor recipients with cold ischemic time ≤17 hours.
There is evidence that anti-DQ donor-specific antibodies are the predominant de novo donor-specific antibodies after transplantation and have a detrimental effect on outcomes (1,2,3). HLA epitope-mismatching at HLA-DQ loci has been shown to be associated with the development of anti-DQ donor-specific antibodies and transplant glomerulopathy (4,5). Wiebe et al. found that an HLA-DQ epitope-mismatched threshold of ≥17 was significantly associated with de novo anti-DQ donor-specific antibodies. After a median follow-up of 6.9 years, only 2.7% of recipients with <17 HLA-DQ epitope-mismatches developed de novo anti-DQ donor-specific antibodies (4). Sapir-Pichhadze et al. conducted a nested case-control study on 52 kidney transplant recipients with transplant glomerulopathy. In this study, an increasing number of HLA-DR and HLA-DQ epitope-mismatches were associated with the development of transplant glomerulopathy (5). All these findings suggest that we could potentially minimize immunogenic risks by avoiding HLA-DQ mismatches, thereby improving outcomes. However, identification of HLA epitope-mismatching is not routinely performed in most centers.
References
1. Willicombe M, Brookes P, Sergeant R, Santos-Nunez E, Steggar C, Galliford J, McLean A, Cook TH, Cairns T, Roufosse C, Taube D: De novo DQ donor-specific antibodies are associated with a significant risk of antibody-mediated rejection and transplant glomerulopathy. Transplantation 94: 172–177, 2012
2. Devos JM, Gaber AO, Teeter LD, Graviss EA, Patel SJ, Land GA, Moore LW, Knight RJ: Intermediate-term graft loss after renal transplantation is associated with both donor-specific antibody and acute rejection. Transplantation 97: 534–540, 2014
3. Tagliamacco A, Cioni M, Comoli P, Ramondetta M, Brambilla C, Trivelli A, Magnasco A, Biticchi R, Fontana I, Dulbecco P, Palombo D, Klersy C, Ghiggeri GM, Ginevri F, Cardillo M, Nocera A: DQ molecules are the principal stimulators of de novo donor-specific antibodies in nonsensitized pediatric recipients receiving a first kidney transplant. Transpl Int 27: 667–673, 2014
4. Wiebe C, Pochinco D, Blydt-Hansen TD, Ho J, Birk PE, Karpinski M, Goldberg A, Storsley LJ, Gibson IW, Rush DN, Nickerson PW: Class II HLA epitope matching-A strategy to minimize de novo donor-specific antibody development and improve outcomes. Am J Transplant 13: 3114–3122, 2013
5. Sapir-Pichhadze R, Tinckam K, Quach K, Logan AG, Laupacis A, John R, Beyene J, Kim SJ: HLA-DR and -DQ eplet mismatches and transplant glomerulopathy: A nested case-control study. Am J Transplant 15: 137–148, 2015
HLA matching is associated with greater graft survival and reduced rejection. HLA DR has greater effect compare to HLA -B ,(1),HLA DQ mismatch is also convey risk , recently recognize as cause of rejection and graft loss.. HLA mismatching is also associated with patient death with functioning graft(2) ,and there evidence ,though weak ,its related or risk factor for PTLPD (3).This effect is more pronounced in deceased donor compare live related donor .
improve of immunosuppression protocol attenuate the deleterious effect of mismatching in recent years compare to previous era.(4).
Reference:
1- Wai,H.LIM,Human leucocyte antigen mismatch associated with increase risk of rejection ,independent of initial immunosuppression in renal transplant recipient ,Clinical transplant 26,issue 4,428.
2-WOpelz G, Döhler B ,a Association of HLA mismatch with death with a functioning graft after kidney transplantation: a collaborative transplant study report.
Am J Transplant. 2012;12(11):3031. Epub 2012 Aug 17.
3- H.Maja Olhol Vase,et al , HLA Associations and Risk of Posttransplant Lymphoproliferative Disorder in a Danish Population-Based cohort ,transplant Direct. 2015 Aug; 1(7): e25.4mEL-Hatra i.Arakama et al ,The impact of HLA -ABDR mismatch on acute rejection and graft failure ,among Filipino kidney transplant, OAT doi 10.15 761/tit,100231.
Lim
In terms of patient survival, HLA incompatible live donor kidney transplant is a good option for sensitized patients in comparison with prolonged waiting time for deceased donor kidney transplant.
Tai, K; Yang, J. Presence of a survival benefit of HLA incompatible living donor kidney transplantation compared to waiting or HLA compatible deceased donor kidney transplantation with a long waiting time. Kidney International : 100 (1). Jul 2021. Pp 206-214.
https://doi.org/10.1016/j.kint.2021.01.027
The HLA antigens are very important transplant antigen and matching between donor and receipiant is stone corner affecting long term graft survival and prevent early rejection .
Relative importance of HLA-A,-B, AND -DR:
The initial Collaborative Transplant Study (CTS) analysis showed that the great effect comes from the DR and B antigens, with minimal effect from the A antigens. Other study showed that DR matching having a much more effect than that of A or B
Another study revealed that HLA-DR mismatches have poor long-term survival .
The effect of each antigen appears at different times post transplant , with the great effect of DR and B mismatching usually appear within the first 6 months and 2 years post transplant , respectively .
Relative importance of HLA-DP AND -DQ :
HLA-DP is MHC class-II locus. Anti HLA DP antibodies are less common occurring in 5 to 14 percent of transplant recipients . The HLA-DP antibodies are more frequent in patients with second transplant , occurring in up to 45 %of subjects .
some studies suggested that anti HLA-DP antibodies does not reduce allograft survival in patients with first transplant , other studies revealed that these antibodies can reduce the allograft survival in patients with second transplant .
Transplant recipients with de novo persistent DQ only donor specific antibody (DSA) or de novo DQ plus other DSAs are susceptible to more acute rejection episodes , increased risk of allograft failure , and decreasing in 5 year allograft survival.
In kidney transplant recepiants with HLA mismatch noticed increased complications in long term post transplant Post-transplant as post transplant lymphoproliferative disease (PTLD), post-transplant bone fractures in addition to decreased graft survival.
GRAFT SURVIVAL
HLA mismatch has increased risk of graft failure with hazard ratio 1.06; confidence interval 95% with death censored graft failure HR 1.09, CI 95% and all cause mortality HR 1.04, CI 95% . HLA DR mismatch has a significant impact on recipient graft survival rates. HLA A mismatch has minor impact on graft survival outcomes. The study linked below shows HLA DR mismatch associated with 12% increase in risk of graft failure. HLA A mismatch is seen to be associated with 6% increase in risk of graft failure but the association was found to be insignificant. There was no significant association between HLA B mismatch and graft survival.
Ref:
Shi, X., Lv, J., Han, W. et al. What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients. BMC Nephrol 19, 116 (2018). https://doi.org/10.1186/s12882-018-0908-3
A significant linear relationship of hazard ratios was associated with HLA mismatch and affects allograft survival even during the recent periods of increasing success in renal transplantation.
HLA mismatches are associated with greater risk of rejection, graft failure, and death independent of immunosuppression and transplant era.
The weight of the available evidence does suggest that ignoring HLA mismatches in organ allocation would have a detrimental effect on graft and patient outcomes in renal transplantation.
Robert C Williams 1, Gerhard Opelz, Chelsea J McGarvey, E Jennifer Weil, Harini A Chakker PMID: 26901078 PMCID: PMC8086563 DOI: 10.1097/TP.0000000000001115
Wai H. Lima,b, Steve J. Chadbanb,c, Philip Claytonb , Charley A. Budgeond , Kevin Murrayd , Scott B. Campbellb,e, Solomon Cohneyb,f, Graeme R. Russb,g and Stephen P. McDonaldb,g Clin Transplant 2012 DOI: 10.1111/j.1399-0012.2012.01654.x
HLA mismatching was still a critical prognostic factor that affects graft and recipient survival. HLA-DR mismatching has a substantial impact on recipient’s graft survival. HLA-A mismatching has minor but not significant impact on graft survival outcomes. Further studies should be conducted to confirm the impact of HLA-A similarity.
Allografts from living donors survive longer than those from deceased donors but the role of HLA mismatching in living kidney donation is still in question.
Living kidney transplantation is the best therapeutic option to provide renal replacement therapy to patients with end-stage kidney disease.1-9 HLA matching is not currently part of the algorithm for donor determination in the United States except among deceased donors where 0 mismatches between kidney and recipient receive higher priority. We previously reported a linear relation of kidney survival with HLA mismatch for organs from deceased donors; 1 mismatch conferred a 13% higher risk and 6 mismatches conferred a 64% higher risk of allograft failure.
However, the same association has not been studied among living donor transplants. There are some reports that suggest HLA matching may not be as important in living donor kidney transplantation as it is in deceased donor kidney transplantation.
***Evaluation of a Potential Deceased Donor :
The donor evaluation process begins with an assessment of medical suitability. For example, a malignancy with
current metastatic disease renders the donor medically unsuitable. In light of the ongoing shortage of deceased donor
kidneys, these risks of transmission of a donor malignancy or infectious disease must be weighed against the risk of
continuing on dialysis to the patient awaiting transplantation. Consultation with the local OPO and hospitals is
essential to ensure that potential organ donors are not inappropriately excluded.
***Deceased donor process : from donor identification to transplantation
1-Donor identification.
2-Clinical triggers.
3-Referral to organ procurement organaization.
4-Assessment of medical suitability of the donor .
5-Authorisation for donation.
6- Organ donor management
7- Organ allocation.
8- Organ recovery surgery.
9- Organ preservation and transportation.
10- Organ transplantation.
***Factors determining the kidney donor profile index( KDPI) :
-Age.
-Height and weight.
-Ethnicity /Race.
-History of diabetes.
-Cause of death.
-Serum creatinine.
-HCV status.
-Donor meets DCD criteria.
*** Factors determing Expected post transplant survival (EPTS ):
-Age.
-Current diabetes status.
-Number of previous transplant.
-Receiving of chronic dialysis.
REFERENCES
1. Opelz G. Impact of HLA compatibility on survival of kidney transplants from unrelated live donors. Transplantation. 1997;64:1473–1475. [PubMed] [Google Scholar]
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HLA play an important role in immune response that affects graft survival, HLA match decrease risk of acute rejection and increase survival rate.
The role of HLA mismatch depend on number of mismatch ,risk factors of both donor and recipient and recipient sensitisation for example in pregnancy, blood transfusion and failed renal transplantation for those patients it’s important to avoid HLA mismatch .