This article, retrospectively reviewed performed HLAi-rTX in the UK(UHCW) between 2003 to 2018. Out of 165 patients, 134 patients were analyzed in this study after exclusion of 31 patients for the followings:
· No consent(1 patient).
· Presence of ABOi or combined HLAi and ABOi(23 patients).
· Didn’t proceed to transplant(7 patients).
Patient’s selection was based on the status of crossmatch, and the reactivity to donor HLA antigens was measured by:
· CDCXM.
· FCXM.
· Microbead assay(Bead).
Baseline crossmatch status pretransplant were categorized as follows:
· Bead positive only(FC-ve, CDC-ve).
· Positive FCXM(Bead+ve, CDC-ve).
· CDC+ve (FCXM+ve and Bead+ve).
The used immunosuppression protocol was as follows:
· DFPP on alternate days for 5 sessions.
· Basiliximab 20 mg; 2 doses were given at day 0 and day 4.
· Intra-operative IV dose of 500 mg of Methylprednisolone.
· The triple of TAC, MMF and Prednisolone.
Post-transplant serum sample for antibody analysis were taken daily for the first 2 weeks and then 3 times a week for the next 2 weeks.
For treatment of rejection episodes, the followings were used:
· Combination of 3 doses of Methylprednisolone and OKT-3(before 2007).
· ATG replaced OKT-3 after 2007.
HLAi-rTX outcome
Graft Survival at 1, 5 and 10 y:
· The graft survival for CDC positive group was 83%, 64%, and 40% at 1, 5, and 10 y, respectively. CDC positive group is associated with the worst graft survival in comparison to FCXM+ve and Bead+ve. CDC positive female patients were lower in graft survival than male patients although statistically insignificant.
· The graft survival for FC-positive patient group was 100%, 93%, and 77% at 1, 5, and 10 y, respectively.
· Bead positive patient group was 95%, 86%, and 82% at 1, 5, and 10 y, respectively.
· In respect to DSA specificity(HLA class I,II or both) there there is no significant difference between these 3 groups.
Patient Survival
· no difference in patient survival rate between the 3 groups based on DSA level.
· There was also no difference in patient survival based on CDC titer or antibody specificity to HLA class (I, II, or I+II).
· lower survival in the females but not reaching statistical significance.
Rejection and Graft Survival Outcomes
· The 1-, 5-, and 10-y graft survival for patients who had rejection was 93%, 77%, and 54% when compared with those who did not have rejection which was 97%, 91%, and 82%.
· In patients diagnosed with AMR(including suspicious diagnosis of AMR), the 1, 5, and 10 ygraft survival rate was 91%, 77%, and 49% respectively which was significantly lower than those without rejection.
· The 10-y graft survival of BPAR(AMR) was lower at 39% which was statistically significant.
· The graft survival of patients with TCMR was 87% at 1, 5, and 10 y with no significant difference in overall graft survival when compared with patients who had no rejection.
· The estimated graft survival of patients with mixed rejection is comparable to AMR.( as the numbers were low this did not reach statistical significance).
· The graft survival decreases with increasing number of rejection episodes. With single rejection episode the graft survival rates were 95%, 82%, and 67% and with 2 or more rejection episodes it was 85%, 61%, and 15% at 1, 5, and 10 y, respectively.
· No significant decline in the long-term graft survival when rejection occurs in the first 2 weeks post-transplant with rates of 97%, 91%, and 82% at 1, 5, and 10 y.
· Significantly, lower graft survival in those with rejection episodes after 2 weeks post-transplant with rates of 84%, 49%, and 27%. The rates of graft survival for those with episodes before and after the 2 weeks were 89%, 78%, and 31%. Results were similar when BPAR cases were only analyzed. Study conclusion
The long-term graft survival and patient survival in HLAi transplant is similar and equivalent to deceased donor transplant.
HLAi transplantation is associated with poor outcome in the followings:
· CDC titer of >1 in 2.
· Antibody-positive female patients.
· Unresolving or recurrence of AMR. Limitations of the study:
· Single center study. Results may not necessarily be national or extrapolated.
· Limited number of cases.
· Protocols were not standardized(retrospective study). Strength of the study:
· The first long-term study of a relatively large cohort of HLAi transplants that shows equivalent graft and patient survival to deceased donor transplantation.
Study type: retrospective cohort study
Level of evidence: 2 a
Nandita Sugumar
2 years ago
Summary
HLA incompatible renal transplant appears to one of the better options for sensitized patients. This article focuses on long term survival rates of patient and graft in comparison with deceased donor transplant.
Finding compatible donors for highly sensitized patients are a challenge. Desensitization can be considered for these patients however outcome may to always be as expected. With the increase in sensitized patients, then requirement for understanding HLAi transplants increase.
Female patients with DSA could have potential for poorer graft and patient survival in comparison with male patients.
AMR in these patients can have serious graft survival consequences in comparison with TCMR.
Exclusion of highest immunological risk cases, defined as CDC titer of >1 in 2 can give 10 yr graft survival of 75%. AMR or TCMR occurring in the first few weeks post transplant has better chances of survival.
Type of study
Retrospective cohort study
Level of evidence is 3
Last edited 2 years ago by Nandita Sugumar
Theepa Mariamutu
2 years ago
HLA Antibody Incompatible Renal Transplantation: Long-term Outcomes Similar to Deceased Donor Transplantation
Please summarize this article
HLAi KT has been decreasing in trend as increasing in PKE program and changes in local allocation policies. However, there is need for HLAi KT when there is difficulties in compatible donor through Aim of the study: to determine the long-term outcome in HLA I- transplant including both graft and patient survival over 10 years Follow up and recognize the main factors that affect the long-term outcome.
PKE is difficult. Studies have reported that increased survival with HLAi compared to patient remaining inn dialysis. Although there is advancement in antibodies detection and screening, HLA typing and desensitisation, graft rejection remains a major obstacle in achieving more successful long-term outcome. There is lack of 10-year outcome data for HLAi KT, so this study done to show 10-year patient outcome and graft survival data and determine the key factors that determining long te
Methods and materials:
Retrospective cohort of sensitised patients from UHCW, single tertiary international referring centre with good experience in HLAi kidney transplant , they included total of 134 HLAi KT from 2003-2018, with long follow up period of 10 years (median of 6.9 years). Data including patient clinical characteristics and immunological and histocompatibility data are collected from the NHS and national records from the referring local centres and compare these data to three groups
1 – first time DCD UK cohort group
2-First-time DD transplant UHCW cohort (local centre)
3-standard living donor transplant of UHCW. they include sensitised patients with HLA
AB – by CDCX, FXCM and SAB, they exclude the combined HLAi, ABOi KT
All patients have similar maintenance triple IS with tacrolimus, MMF, prednisolone and induction with basiliximab D0, D4. Antibody measurements were taken daily for 2 weeks then 3 times a week for next 2weeks
All patients have similar maintenance triple IS with tacrolimus, MMF, prednisolone and induction with basiliximab D0, D4
Discussion:
Generally, Long-term graft survival and patients’ survival in this cohort for HLAi transplantation was comparable to DCD cohort but significant difference of graft and patient survival compared to living donor cohort. The centre was high-risk cohort and more than half of cases they had previous transplantation, so the result was encouraging.
Patients with baseline positive CDC XM (CDC titer > 1 in 2) associated with lower graft survival.the graft survival for low CDC titre similar to CDC negative KT.
Female KTR with DSAs had lower graft survival compared to males.pregnancy stimulated DSAs rebound more aggressively . studies in pregnancy showed anti-inflammatory state in pregnancy with increased in the T helper 2 cytokines and immune modulatory proteins with a shift postpartum.
AMR was the only rejection type that significantly reduced graft survival when compared to TCMR or no rejection. Graft survival about 49% at 10 year if there was AMR compared 82.4% if no rejection.
When the acute rejection happens within 2 weeks, the graft survival comparable to those did not had rejection. However when the rejection happens after 2 weeks , it has significant impact on graft survival. More than 1 rejection episode cause significant reduction in graft survival.
Limitations of the study:
Retrospective design from local centre, small sample size with risk of bias
Protocols not standardised
Strength of the study:
Long- term follow up and large cohort of HLAi transplant
What is type of this study?
Retrospective large cohort study
What is the level of evidence?
Level of evidence 3
ahmed saleeh
2 years ago
Level 3 evidence
Retrospective study
Summary :
Studies have reported an increase in patient survival with HLAi renal transplantation in comparison to patients remaining on the waiting list or on dialysis
graft rejection remains a major obstacle in achieving more successful long-term outcomes in HLAi renal transplantations, which is further compounded by the lack of effective treatment for antibody-mediated rejection (AMR).
this report provides reassurance that HLAi transplantation can, overall, offer good long-term outcomes for highly sensitized patients with a low prospect of a compatible donor.
Graft survival for the group with a positive baseline CDC crossmatch is signicantly lower when compared with the FC- and Bead-positive groups.
The graft survival of the CDC low titer group was similar to the CDC negative group
patients with complement xing HLA class I DSAs had inferior graft survival compared with HLA class II DSAs
female recipients with DSAs had poorer graft and patient survival compared with male recipients.
proinammatory state postpartum in general and increased sensitivity to pregnancy induced antigens specically, could result in decreased graft and patient survival.
AMR is considered to be a disease process with a continuum of severity, beginning at any time after transplantation and developing at varying levels of intensity, progressively leading to the development of chronic allograft damage, dysfunction, and loss.
the earlier rejections seem to be more effectively treated, for operational reasons, as above, or perhaps because of fundamental immunologic reasons, thereby limiting AMR progression.
MICHAEL Farag
3 years ago
INTRODUCTION HLA-specific antibodies have been considered a significant barrier to successful kidney transplantation. In the mid-1980s, pretransplant antibody removal, or desensitization, was pioneered to overcome this barrier, but these have tended to be high risk transplants with inferior outcomes. Moreover, in recent years, there has been a downward trend of HLA antibody incompatible (HLAi) renal transplantation worldwide. However; The reason for the global decrease in HLAi kidney transplantation is the concomitant increase in the paired kidney exchange (PKE) programs and the changes in the local allocation policies. Moreover, with the increase in fast track and extended criteria donors, it is likely that more patients will be sensitized in the coming years because of the reduced longevity of these kidneys and lower levels of HLA matching,7 thus potentially increasing the need for HLAi transplantation. Therefore, it becomes important to determine the benefits or detriment of such transplantations so that we can use this appropriately to optimize patient care. Studies have reported an increase in patient survival with HLAi renal transplantation in comparison to patients remaining on the waiting list or on dialysis. MATERIALS AND METHODS Patients A retrospective study was conducted at the University Hospitals Coventry and Warwickshire (UHCW) NHS Trust, which is a UK tertiary international referral center for HLAi transplants. Patients sensitized to HLA antigens were selected for antibody incompatible transplantation if they had reactivity with donor HLA antigens measured by cytotoxic-dependent crossmatch (CDC), #ow cytometry crossmatches (FC), or microbead assay (Bead). Patients who had ABO incompatibility or had combined HLAi and ABOi transplants were excluded. Pretransplant patients were typically treated with 5 alternate day sessions of double filtration plasmapheresis (DFPP) with the aim of achieving negative #ow crossmatch at the time of surgery. In some cases, depending on the starting levels of DSA, fewer or more sessions of DFPP were administered and the transplant was performed in the presence of FC-positive crossmatch. Immunosuppression Protocols Immunosuppression consisted of mycophenolate mofetil, tacrolimus, and prednisolone. methylprednisolone 500mg was given as a single intravenous dose intraoperatively. Two doses of basiliximab 20mg were given, at days 0 and 4. Posttransplant serum samples for antibody analysis were taken daily for the !rst 2 wk and then 3 times a week for the next 2 wk Treatment of Rejection Rejection was diagnosed by renal biopsy or clinically if there was rapid onset of oliguria with a rise in both serum creatinine and in DSA levels. During the initial few years of our AiT program, rejection was treated with high dose of methylprednisolone for 3 d and with OKT3 (muromomab-CD3) if the rejection was steroid resistant. After 2007, antithymocyte globulin (ATG, Genzyme) replaced OKT3 HLA Antibody Testing
Lymphocyte crossmatching was performed at baseline (pretreatment) and using a serum sample taken within 24h pretransplant according to our previous description
Data Analysis Patient Survival and Graft Survival
Overall, patient survival and death-censored graft survival were analyzed.
Crossmatch Status
Patients were divided into 3 groups: CDC, FC, and Bead based on the crossmatch assay on the pretreatment/pretransplant serum samples. If the patients underwent DFPP before transplant, pretreatment samples before the start of the first DFPP session were used. If not, the pretransplantation serum sample was used. One-, 5-, and 10-y graft and patient survival were analyzed, and outcomes were compared between the groups.
HLA Antibodies The study subjects were categorized based on their donorspeci!c antibody (DSA) status (class I, class II, class I+II antibody groups). One-, 5-, and 10-y graft survival outcomes between the groups were analyzed.
Rejection Patients were classified as those who had rejection and those who did not based on renal biopsy.
Each case was confirmed by independent review, and all cases reported as “suspicious rejection” were included as rejection, and comparative 1-, 5-, and 10-y graft survival were analyzed.
Statistical Analysis Statistical analysis of comparison between groups was performed with nonparametric testing for interdependent groups using IBM SPSS Version 25.0.
CONCLUSIONS Long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation. There are certain subgroups, in particular those with a crossmatch CDC titer of >1 in 2, antibody-positive female patients, and unresolving or recurrence of AMR, which are
associated with a poor prognosis. Given that the need for HLAi transplantation exists and is likely to increase in the future, despite PKE programs, further large studies looking at risk stratification, early diagnosis, and management of rejection are needed.
Retrospective study to revealed long-term outcomes of HLAi transplantation. Level evidence III.
Ahmed Omran
3 years ago
Paid kidney exchange programs have been decreasing the number of HLA-incompatible kidney transplants and modifying local allocation policies. It was shown that HLA i patients have better survival in comparison with those who remain on dialysis. Other measures such as advances in detection and screening of antibody detection, HLA typing, and patient desensitization have improved the outcome of HLA i transplants.
This is a single-center retrospective cohort study from 2003 to 2018.
Pre-transplant protocols included that patients with positive FCXM underwent five sessions on alternate days of plasmapheresis aiming at turn to negative antibodies. Some cases underwent extra sessions and others underwent transplantation with low titers and weakly positive FCXM.
Basiliximab 20mg on D0 and D4, methylprednisolone 500mg intraoperatively ,and maintenance with TAC ,MMF, and prednisone were the most commonly used protocol.
Antibody dosage in the first two weeks was evaluated daily and then three-time a week.
Patients were divided into three groups based on XM: CDC, FC, and Luminex.
Rejection was diagnosed by biopsy or clinically ; by serum creatinine and DSA levels.
Patients with FCXM and beads had better results than those who were CDC-positive. Titers greater than 1 had significant clinical worsening and graft loss.
No difference was found in mortality in the three groups based on DSA values but the higher number of rejections was an important predictor for graft loss. The later rejection time ;greater than two weeks ,the decreased graft survival.
AMR was the only rejection pattern which significantly reduced graft survival in comparison with TCMR or no rejection in this study. Earlier rejections were treated more effectively. Level of evidence: III
kumar avijeet
3 years ago
1.This article actually describes the outcome of HLAi tx ,where pts with either CDC+/FCXM +/DSA+ included and treated with dfpp mostly 5 sessions and transplanted with crossmatch negative with basiliximab, steroid,tac,mmf triple immunesuppression.
The outcome at 1,5,10yr-
Patient survival 95%,90%,85% respectively
Graft survival 95%,85%,70% respectively
Which was simillar to 1st time deceased donor transplant.
Some groups like-
Female with ab positive
Patient with cdc ag positive >1 out of 2
Recurrent or persistant abmr have prognosis.
This is a retrospective study
Level of evidence 3
Mahmud Islam
3 years ago
This a review with expert opinion reflecting results of previous data so it is with level evidence of IV
This paper draws attention to the importance of sensitization as a rock on the way to successful transplantation stressing the importance of preventing sensitization as a better option.
In our practice, we prefer kidney paired donation in case of very highly sensitized recipients with no mismatch but some centers perform desensitization with IVIG plus plasmapheresis.
summary of the paper:
sensitization is still a big problem. factors contributing are multiple pregnancies, blood transfusions, and prior transplant history. highly sensitized (PRA>85-100%) are at risk of hyperacute rejection.
HLA is extremely polymorphic. since the immune system is not educated for any other HLA molecule than self, the immune response is expected and antibody formation maybe even formed against paternal HLA antigens inherited from the father during the gestational period. sensitization by blood transfusion is less wide than immunization by pregnancy. since Luminex advented the term unacceptable antigens is more dominant than pure PRA measured with CDC. MFI measured by SAB immunoassays should be interpreted carefully due to many factors. prozone effect, antibody titers, and binding capacity are important.
the new kidney allocation system increased the rate of transplantation of highly sensitized patients. Highly sensitized patients (i.E PRA>98%) are given priority to those with 99% or 100%.
the travel of organs through this policy may lead to an increase in cold ischemia in case of long distances. the 6-month graft survival may not be affected but longer graft survival needs to be determined.
Within eurotransplant program, the acceptable mismatch (AM) program reduced the waiting time of highly sensitized patients dramatically.
Kidney paired donation is still superior to transplanting highly sensitized patients. in KPD programs HLA and or AMO incompatible patient-donor couples are entered into dedicated match rounds to find the highest matching possible chances. still transplanting highly sensitized patients through this program is not well utilized. Sill we need to expand the program overseas to maximize benefit.
Desensitization
even after KDP still, there are patients highly sensitized but maybe to less extent. for these and other acceptable sensitized cases, desensitization is a chance for transplantation. very high levels of DSA are still resistant so we need to define suitable criteria for desensitization. high dose IVIG or low dose IVIG plus plasmapheresis are utilized. Novel drugs are now available like bortezomib and streptococcus pyogenes derived IgG- degrading enzyme.
Mohamed Essmat
3 years ago
This is a retrospective study of class 3 evidence HLA incompatible transplants are associated with high immunological risk. Studies showed that HLAi transplant is associated with better patient survival than dialysis or remaining on the waiting list. This study aimed to investigate the long-term outcome of HLAi transplant in highly sensitized patients. Patients and methods: A retrospective study included 134 patients with HLAi transplants. Sensitized patients with positive CDC, FCXM or microbead assay were selected, treated with plasmapheresis till achieve negative FCXM before transplant, however, some cases had positive FCXM before transplantation ABO incompatible transplants were excluded. Results: Patient and graft survival estimates of HLAi cohort were similar to those seen in first time deceased donor transplant and were significantly worse when compared with standard live donor transplant. Positive baseline CDC crossmatch (with high titer) was associated with significantly lower graft survival compared to FCXM and bead positive groups. Conclusion: Long-term graft and patient survival in HLAi transplant are worse when compared with standard live donor transplantation but the same as deceased donor transplant .
Hamdy Hegazy
3 years ago
retrospective cohort study
level IIIB evidence
Jamila Elamouri
3 years ago
HLA Antibody Incompatible Renal Transplantation:Long-term Outcomes Similar to Deceased DonorTransplantation
HLA compatible transplantation is the best available option for ESRD patients. With increasing the number of sensitizing patients on the waiting list, this option becomes scantly available. Desensitization has been developed to remove the immunological (DSA) barrier to transplantation. with this still, there is a need for more offers to transplant these patients. Recently, HLA antibody incompatible (HLAi) renal transplant has decreased worldwide. Ultimately; a study of the benefits and risks of HLAi transplantation is needed to optimize patient care. Many studies have shown short and long term benefits of HLAi transplants. Long term outcome is still scanty. Methodology
A retrospective study includes patients with HLAi renal transplantation between 2003 and 2018. At “UHCW” which is UK tertiary international referral centre for HLAi transplants.
After the collection of the data. Comparison of the overall patient and graft survival data of the HLAi study cohort with (i) first-time deceased donor renal transplant, UK cohort, (ii) first-time deceased donor transplant, (iii) UHCW (their centre) cohort, (iv) the standard live donor transplant of UHCW cohort. Sensitized patients were selected for antibody incompatible transplantation if they had reactivity with donor HLA antigens assessed by CDC, FCXM, or microbead assay. Pretransplant patients underwent double filtration plasmapheresis (DFPP) for about 5 sessions with aim of achieving a negative flow crossmatch at the time of surgery. Some cases depend on DSA level the transplant was performed in presence of positive FCXM. Patients who had ABO incompatibility or had combined HLAi and ABOi transplants were excluded.
Immunosuppression protocol
Induction with methylprednisolone 500 mg single dose and basiliximab two doses. Maintenance with MMF, tacrolimus, and prednisolone.
Postoperatively DSA was monitored daily in the 1st 2wks the on alternate days for the next 2 wks.
The rejection has been diagnosed by the biopsy or clinically in the presence of oliguria with both raise in creatinine and in DSA levels.
It was treated with high dose methylprednisolone for 3 days and OKT3 or ATG if steroid resistance. HLA Antibody Testing
HLA Abs were analyzed by microbead assay. Lymphocyte crossmatch was performed at baseline (pretreatmaet) and within 24 hrs pretransplant.
Data Analysis:
Classified according to; patient and graft survival, cross-match status, HLA antibodies and rejection (the timing of rejection as rejection occurring within the first 2 weeks after transplantation or after the first 2 weeks post-transplantation.
Result:
Overall, the patient’s survival was 95%, 90%, and 81%. And the graft survival was 95%. 85%, and 70% at 1, 5, and 10 years respectively. This was similar to the first-time deceased donor transplant cohort.
For the pretreatment CDC positive crossmatch group the graft survival was significantly low at 83%. 64%. And 40% at 1, 5, 10 years respectively. Female patients had a worse outcome in both patient and graft survival, although it did not reach significance. This may be due to increased sensitization during pregnancy. those who develop single early rejection episode has a good outcome whereas, those who develop rejection after the first 2 weeks or recurrent rejections have worse outcome.
Conclusion:
In conclusion the long term patient and graft survival outcomes for HLAi transplants similar to deceased donor transplant
Level 3 B evidence.
Ofonime Udoh
3 years ago
SUMMARY
The presence of HLA-specific antibodies in a recipient is considered a barrier to transplantation, and the measures that have been used to reduce this antibody load before transplantation, eg, desensitization, have ended up with inferior outcomes. The incidence of HLA-incompatible [HLAi] transplants greatly reduced with the introduction of Paired Kidney Exchange programs and other allocation programs that aid tranaplantation. However, with the increase of these programs, including the Extended Criteria donors and fast track programs that tend to end up with reduced logevity of the grafts, there is going to be ain increase insensitization. Also for the highly sensitized patients who are unable to get donors with the new allocation prgrams HLAi transplants wil have to be done. Hence the need to study the outcomes of HLAi transplants on the graft and patient survival.
Materials and Methods: This is a retrospective study done in University Hospitals Coventry and Warwikshire NHS Trust on patients who underwent HLAi between 2003 and 2018.The overall patient and graft survival data of the cholrt was compared with [i]first time deceased donor renal tramnsplanmt UK cohort, [ii] first time deceased donor transplant, [iii]UHCW cohort and [iv] standard live donor transplant of UHCW cohort. The patients for the HLAi- transplant were selected if they had antibodies detected by CDC, FCXM or Microbead assay. Exclused wer those who had ABO-incompatibiltiy and those who had both ABO-i and HLA-i. The patients were treated with Double Filtration Plasmapheresis [DFPP] with the aim of achieveing a negative FCXM at the time of surgery; the sessions of DFPP varied with the starting levels of DSA.
Immunosuppresion was done with MMF, Tacrolimus and Prednisolone. Methylprednisolone was given as a single Intravenous dose intaroperatively: 500mg. Basiliximab was given 20mg on days 0 and 4. Post transplant serym samples for antibodies count was taken daily for the first 2 weeks and then 3 times a week for the next 2 weeks.
Rejection was diagnosed clinically [oliguria and rising serum creatinine levels] or with a renal biosy. Treatment of rejection was done with high doses of M<ethyprednisolone for 3 days and OKT3 if the rejection was steroid resistant; and after 2007 ATG replaced OKT3.
RESULTS
The median follow up for the HLAi cohort was 6.93 years. On comparingh this HLAi cohort with the 4 listed cohorts, there was
significant difference in patient and graft survival between the live donor UHCW cohort versus the other cohorts
no signifiant difference in patient and graft survival between the other cohorts [ie, excluding the live donor UHCW cohort]
TYPE OF STUDY: Retrospective study
LEVEL OF EVIDENCE: Level 3
saja Mohammed
3 years ago
Summary:
Introduction :
HLA-I kidney transplant limited to highly sensitization recipients that failed to be involved in KPD and improved in allocation programs with prioritizing the sensitized patients in KAS which helped in improving the better allocation for matched donor and reduce waiting list ,so HLAI transplantation have been reduced its use limited to < 1.5% in UK, but on the other hand there is ongoing increase need for HLAI transplantation due to increasing numbers of highly sensitized kidney transplant especially with the use of fast path of extended criteria donor kidney transplantation with lower graft survival , so we need to assess the benefit of HLAI transplantation as many studies shows conflicting results in short and intermediate FU regarding patient outcome with HLAI transplant compared to stay on long-term dialysis.
Aim of the study: to determine the long-term outcome in HLA I- transplant including both graft and patient survival over 10 years FU and recognize the main factors that affect the long-term outcome.
Methods and martials:
In this retrospective cohort of sensitized patients from single tertiary international referring center with good experience in HLAi kidney transplant , they included total of 134 HLA I kidney transplantation from the period of 2003-2018, with long FU period of 10 years with a median of 6.9 years all data including patient clinical characteristics and immunological and histocompatibility data are collected from the NHS and national records from the referring local centers and compare these data to three groups ,1 – first time DD UK cohort group , 2-Firsttime DD transplant UHCWUHCW cohort ( local centre) , 3-standrard living donor transplant of UHCW. they include sensitized patients with HLA AB – by CDCX, FXCM and SAB, they exclude the combined HALI, ABOI kidney transplant.
All patients have homogenous maintenance triple IS with tacrolimus, MMF, prednisolone and induction with basiliximab D0, D4
Frequent DSA monitoring immediate post transplantation period with daily DSA for the first two then three times /week for two weeks by using SAB assay
Diagnosis of acute rejection based on biopsy proven plus circulatory DSA, they included suspicious cases of rejection and treated as AR.
Factors that associated with long-term outcome including baseline degree of sensitization and rejection form and response to treatment.
Discussion:
Over all long-term graft survival and patients’ survival in this cohort for HLAI transplantation was similar to DD cohort but significant difference of graft and patient survival compared to living donor transplant cohort give the fact that in high-risk cohort more than half of cases they had previous transplantation.
Patients with baseline positive CDCXM The higher level of the CDCXM positivity with titer > 1 in 2 associated with lower graft survival.
Female recipients with DSAs have lower graft survival compared to males, this may be explained in part due to pregnancy associated proinflammatory status with the risk of DSA rebound
AMR which occurs > 2weeks post-transplantation with frequent rejections episodes all associated with lower graft survival compared to no rejection or TCMR.
Lower rate of TCMR in this cohort with comparable graft survival while AMR associated with significantly lower graft survival of 49% compared to > 81% in nonrejection cases. Limitations of the study:
Retrospective design from local center, small sample size with risk of bias
Protocols not standardized Strength of the study:
Long- term fu for large cohort of HLA I transplant with compared groups Identify the importance of early diagnosis of AMR before two weeks will improve and impact the long-term grafts survival
What is type of this study?
Retrospective large cohort from single international tertiary with long follow up time that allow for proper assessment of secondary outcome
What is the level of evidence?
Level of evidence 111B
Ahmed Abd El Razek
3 years ago
summary
INTRODUCTION
HLA incompatible Tx is preferred when finding a suitable donor for highly sensitized patients is difficult.
Desensitization can be considered. Patients’ with HLA incompatible renal Tx have better survival compared to those who remained on dialysis waiting for compatible donor.
The whole main barrier was graft rejection and lack of effective treatment of ABMR. MATERIALS AND METHODS Patients
A retrospective study, Patients who underwent HLAi renal transplantation between .2003 and 2018 were included .They compared the overall patient and graft survival data of the HLAi study cohort with deceased donor renal transplant.
Patients sensitized to HLA antigens were selected for antibody incompatible transplantation if they had reactivity with donor HLA antigens assessed by cytotoxic-dependent cross match (CDC), flow cytometry cross matches (FC), or micro bead assay (Bead).
Pretransplant patients were typically treated with 5 plasmapheresis sessions.
Immunosuppression Protocols
Protocol included mycophenolate mofetil, tacrolimus, and prednisolone.
Methylprednisolone 500 mg was given as a single intravenous dose intraoperative. Two doses of basiliximab 20 mg were administered at days 0 and 4.
Treatment of Rejection
High dose of methylprednisolone for 3 d and with OKT3 (muromomab-CD3) or antithymocyte globulin (ATG, Genzyme) if the rejection was steroid resistant. HLA Antibody Testing
Lymphocyte cross matching was performed at baseline (pretreatment) and another serum sample taken within 24 h pretransplant.
Data Analysis
Classified according to; patient survival and graft survival, cross match status, HLA antibodies and rejection (the timing of rejection as rejection occurring within the first 2 wk. after transplantation and after the first 2 wk. of transplantation).
RESULTS
HLA incompatible recipients were similar to deceased donor graft recipients about 95%patient survival and 95% graft survival on first year post renal tx.
CDC positive cross match recipients were of lower values (83%) regarding patient survival and graft survival when compared to those of CDC negative cross matches.
Female patients were worse in general regarding patient and graft survival.
ABMR is the most frequent type of rejection associated with decline in graft survival by 10 years when compared to those who had no rejection episodes.
Rejection episodes that occurred early postoperative and lasted for 2 weeks caused significant reduction in graft compared to those of single early rejection treated episode.
CONCLUSIONS
HLA incompatible graft and patient survival is comparable to deceased donor Tx and can achieve more improvement by avoiding high CDC titer cases.
Antibody positive female recipients have worse long term survival.
Resolution of early rejection episode is associated with good long term survival.
Type of study:
Retrospective cohort single center study.
Level of evidence:
level 3.
Wee Leng Gan
3 years ago
HLA Antibody incompatible Renal Transplantation.
This is a retrospective cohort single center study at UHCW with level 3 evidence.
The objective is to study the long term outcome for HLA antibody incompatible ( HLAi ) renal transplantation in term of patients and graft survival factors. The study subjects were classified based on their donor specific antibody (DSA) status (class I, class II, class I+II antibody groups). Outcomes were compared with groups defined by baseline crossmatch status and the type and timings of rejection episodes.
A total of 134 HLAi renal transplant recipients were successfully recruited and analyzed from 2003 until 2018 with median follow up of 6.93 years. 82 % were female with mean age of 42.93 years old. The living donor transplant constituted 88.1% and 12% were deceased donor transplant. 45.5% of study population had medical comorbidities before transplantation. 61.9% of study population had previous history of transplantation. Immunosuppressant protocol included mycophenolate mofetil, tacrolimus, and prednisolone. Single dose IV methylprednisolone 500mg was given as a single intravenous dose intraoperatively. Two doses of basiliximab 20mg were given, at days 0 and 4. In the event of rejection, high dose IV methylprednisolone was given for 3 days along with OKT3 (muromomab-CD3) if steroid resistant. Antithymocyte globulin (ATG, Genzyme) replaced OKT3 after 2007. The overall patient survival was 95%, 90%, and 81%; and graft survival was 95%, 85%, and 70% at 1, 5, and 10 years, respectively. The graft survival for pretreatment cytotoxic-dependent crossmatch (CDC) positive crossmatch group was significantly low compared to Bead/CDC, P=0.007 and CDC/Flow, P=0.001 which were statistically significant. Antibody-mediated rejection significantly reduced graft survival. Single early rejection episode has good graft and patient survival. Female had poor graft and patient survival, however it was not statistically significant.
Limitation of this study include retrospective single center study without standardisation of protocol which lead to bias in the outcomes. On the other hand, this is the pilot study that involved long duration with relatively large cohort of HLAi transplants which serve as the strength of this paper.
In summary, long term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation.
Balaji Kirushnan
3 years ago
Retrospective cohort study and the level of evidence is level 3
Highly sensitized patients are known to be waiting on HD and they have an overall inferior survival as compared to transplanted patients. Paired kidney exchange and HLA i renal transplants are the way forward for these patients who have high level of HLA antibodies. HLA incompatible renal transplantation still remains one of best therapeutic options for a subgroup of patients who are highly sensitized. Not many studies have addressed the long-term graft and patient survival.
This was a retrospective cohort study conducted at UHCW NHS trust. This a center for approved HLAi renal transplants. 134 HLA incompatible renal transplantation patients from 2003 to 2018 with a median follow of 6.93 years were analyzed to estimate patient and graft survivals. Outcomes were compared with groups defined by baseline crossmatch status and the type and timings of rejection episodes. They had also compared the outcome between the first time deceased donor transplant at their center and with the entire cohort. They also compared the results of the HLAi renal transplants with the live transplant cohort at UK and their center.
The overall patient survival was 95%, 90%, and 81%; and graft survival was 95%, 85%, and 70% at 1, 5, and 10 y, respectively. This was similar to the first-time deceased donor transplant cohort. CDC positive cross match transplants fared worse. The graft survival for pretreatment cytotoxic-dependent crossmatch (CDC) positive crossmatch group was significantly low at 83%, 64%, and 40% at 1, 5, and 10 y, respectively. Female patients in general fared worse in both patient and graft survival outcomes in each of the 3 groups based on pretreatment crossmatch, although this did not reach statistical significance. This is probably due to increased sensitization in pregnancy. Antibody-mediated rejection was the most frequent type of rejection with significant decline in graft survival by 10 y when compared with no rejection. Rejection that occurred or continued to occur after the first 2 weeks of transplantation caused a significant reduction in graft survivals whereas good outcomes were seen in those with a single early rejection episode.
so in conclusions the 1, 5, and 10 year HLA incompatible graft and patient survival is comparable to deceased donor transplantation and can be further improved by excluding high-CDC titer cases. Antibody-positive female patients show worse long-term survival. Resolution of early rejection is associated with good long-term graft survival.
Drtalib Salman
3 years ago
Surprising thing in this study why they use baciliximab induction although patients higher immunological risk and should use ATG instead ???
Drtalib Salman
3 years ago
Please summaries this article:
In the United Kingdom, although approximately 40% of patients on the transplant waiting list are sensitized with HLA – specific antibodies, only 1.5% of the kidney transplantations performed last year were HLA i renal transplantations. the reason for the global decrease in HLA i kidney transplantation is the concomitant increase in the paired kidney exchange (PKE) programs and the changes in the local allocation policies.
Studies have reported an increase in patient survival with HLA i renal transplantation in comparison to patients remaining on the waiting list.
a recent study from the United Kingdom did not show any survival benefit in patients undergoing HLA i in comparison to those who remain on dialysis.
graft rejection remains a major obstacle in achieving more successful long-term outcomes in HLA i renal transplantations, which is further compounded by the lack of effective treatment for antibody-mediated rejection (AMR).
MATERIALS AND METHODS
Patients A retrospective study was conducted at the University Hospitals Coventry and Warwickshire (UHCW) NHS Trust, which is a UK tertiary international referral center for HLA i transplants between 2003 and 2018.
Patients sensitized to HLA antigens were selected for antibody incompatible transplantation if they had reactivity with donor HLA antigens measured by cytotoxic-dependent crossmatch (CDC), #ow cytometry crossmatches (FC), or microbead assay (Bead). Patients who had ABO incompatibility or had combined HLAi and ABOi transplants were excluded.
Immunosuppression consisted of mycophenolate mofetil, tacrolimus, and prednisolone as previously described12 and methylprednisolone 500mg was given as a single intravenous dose intraoperatively. two doses of basiliximab 20mg were given, at days 0 and 4. Posttransplant serum samples for antibody analysis were taken daily for the first 2 w k and then 3 times a week for the next 2 wk. RESULTS:
A total of 165 consecutive antibody incompatible transplants performed at our unit were reviewed and a final of 134 was analyzed in this study. Thirty-one patients were excluded for the following reasons, patient did not provide consent, 23 patients had blood group (ABO) incompatibility, or both HLA and ABO incompatibility, and 7 did not proceed to transplant .
Graft survival was also analyzed with respect to DSA specificity. The transplants were divided on the basis of antibody specificity for donor HLA class I, class II, or both. Although there appeared to be poor early graft survival in the group with both class I and II DSAs, overall, there is no significant difference between these 3 groups . CONCLUSION
There was no difference in patient survival between the 3 groups based on DSA levels characterized by Bead positive (FC–, CDC–), FC positive (Bead+, CDC–), and CDC positive (FC+, Bead+).
As the number of rejection episodes increases, the graft survival decreases, rejection occurring only within the first 2 wk of transplantation did not cause any significant decline in the long-term graft survival when compared with rejection-free patients with rates of 97%, 91%, and 82% at 1, 5, and 10 y, P=0.95. In contrast, graft survival was significantly lower in those with rejection occurring for the first time after 2 wk .
there was a significant difference in overall patient and graft survival between the HLAi study cohort and the standard live donor transplant cohort at our center. Given the higher risk nature of our cases, more than half of whom had repeat transplants, this report provides reassurance that HLAi transplantation can, overall, offer good long-term outcomes for highly sensitized patients with a low prospect of a compatible donor.
We did not find any statistical differences in death-censored graft survival when comparing cases with either HLA class I, class II, or both class I and II DSAs.
We also saw a trend in which female recipients with DSAs had poorer graft and patient survival compared with male recipients, this does not reach statistical significance.
AMR was the only rejection type that significantly reduced graft survival in comparison to TCMR or no rejection in our study. our analysis extends the time frame and is consistent with findings from similar studies showing significantly lower 5-y graft survival in patients who had AMR.
No signi!cant difference was observed in graft survival probability between patients who only had rejection within the first 2 wk following transplantation and those who had no rejection at all. However, there was a significant impact on graft survival if rejection occurred after the first 2 wk of transplantation.
What is type of this study?
retrospective study
What is the level of evidence?
level 3
Hinda Hassan
3 years ago
This is a retrospective study conducted at at the University Hospitals Coventry and Warwickshire (UHCW) NHS Trust, a UK tertiary international referral center for HLA incompatible transplants. It included 134 HLA incompatible renal transplantation patients from 2003 to 2018.
The patient and graft survival estimates were compared with
1. first-time deceased donor renal transplant, UK cohort
2. first-time deceased donor transplant, UHCW cohort
3. the standard live donor transplant of UHCW cohort from the same time period
There was a significant difference in patient survival between these cohorts between the live UHCW donor and all other donor types .The patient survival was 95% at 1 year, 90% at 5 year, and 81% at 10 years. the graft survival was 95%, 85%, and 70% at 1, 5, and 10 y, respectively.
Graft survival was analyzed in term of baseline (immediately pretreatment) DSA levels characterized by Bead positive only, FC positive (Bead+, CDC–), and CDC positive (FC+, Bead+). The graft survival for CDC positive group was 83%, 64%, and 40% at 1, 5, and 10 y, respectively, which is significantly lower than the other 2 groups. The graft survival for FC-positive patient group was 100%, 93%, and 77%, and Bead positive patient group was 95%, 86%, and 82% at 1, 5, and 10 irrespectively. Within the CDC+ group, overall outcome is poorer for the female recipients, although not statistically significant. In those with a CDC+ titer of 1 in 2 or below, graph survival matches the CDC negative group. The group with a CDC+ titer of >1 in 2 have significantly worse outcome compared with the low titer group .there was difference in graft survival based on class of donor-specific antibodies. The graft survival in antibody-mediated rejection was 91%, 77%, and 49% when compared with rejection-free patients with survival of 97%, 91%, and 82% at 1, 5, and 10 y. Number of rejection episodes if > 2, the graft survival rate were significantly lower. If rejection occurred or continued to occur after 2 wk, the graft survival was significantly lower.
So, long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation.
this is a retrospective cohort so the level of evidence is 3
MOHAMMED GAFAR medi913911@gmail.com
3 years ago
RETROSPECTIVE STUDY LEVEL OF EVIDENCE 3
INTRODUCTION
HLA incomaptible transplantion numbers had decreased in uk due to concominant incresase in PKE program and changes in local allocation policies.
For these highly sensitized patients, desensitization could be considered via a combined approach wherein the recipi- ents are offered a lower immunologic risk donor through the PKE or directly from their potential donors after risk stratification .
MATERILAS AND METHODS
PATIENTS,
A retrospective study was conducted at the University Hospitals Coventry and Warwickshire (UHCW)
Patients who underwent HLAi renal transplantation between 2003 and 2018 were included . .
patient slection if they have positive cdc or fxcm or singla antigen beads positive.
plex 5 seesion used befor transplantion aiming for neagtive cross match
IMMUNOSUPPRESION USED,
methylpred 500 mg iv intraop, with basilixmab 20 mg day 0 and day 4
maintinace of fk and mmf , pred
TREATMENT OF REJECTION,
befor 2007 , okt3 if steroid resitance
after 2007 atg if steroid resitance .
HLA ANTIBODY TESTING,
using microbead assys.
DATA ANALYSIS,
Patient survival ; Calculated from the date of Tx to the date of death or last follow up
Graft survival ; Date of Tx to the date of graft failure or last follow up
Graft failure ; Return to dialysis
HLA ANTIBODIES ,
Class I, Class II or both 1, 2
1,5,10y graft survival were compared between groups.
Rejection
Based on biopsy ; rejection VS no rejection
Type of rejection ; AMR, TCMR, or Mixed
Number of rejection episodes ;no rejection, 1, or >=2
Timing of rejection ; first 2 weeks after Tx or after 2 weeks post-Tx
1,5,10 y graft survival were compared between groups
Statistical analysis
non-parametric test = comparison between groups.
Kaplan-Meier = survival estimate.
Chi-square = statistical significant.
P value < 0.05 = statistically significant.
RESULTS,
At 1,5,10 year follow up:
1-Patient survival was 95%, 90%,85% 2-Graft survival was 95%, 85%, 70% 3-The results were similar to the first time deceased donor transplant cohort. 4-Graft survival for pretreatment CDC positive patients were lower at 1,5,10 year compared to other groups. 5-Low CDC titer has results similar to CDC negative patients. 6-Females showed lower patient and graft survival in the 3 groups 7-ABMR was the most frequent type of rejection with significant decline in graft survival by 10 years when compared to no rejection
CARLOS TADEU LEONIDIO
3 years ago
Please summarise this article
INTRODUCTION
In the United Kingdom, although approximately 40% of patients on the transplant waiting list are sensitized with HLA-specifc antibodies, only 1.5% of the kidney transplantations performed last year were HLA incompatible (HLAi) renal transplantations. The reason for the global decrease in HLAi kidney transplantation is the concomitant increase in the paired kidney exchange (PKE) programs and the changes in the local allocation policies, allied to desensitization via a combined approach wherein the recipients are offered a lower immunologic risk donor.
Moreover, with the increase in fast track and extended criteria donors, it is likely that more patients will be sensitized in the coming years because of the reduced longevity of these kidneys and lower levels of HLA matching, thus potentially increasing the need for HLAi transplantation. Therefore, it becomes important to determine the benefits or detriment of such transplantations so that we can use this appropriately to optimize patient care.
The graft rejection remains a major obstacle in achieving more successful long-term outcomes in HLAi renal transplantations, which is further compounded by the lack of effective treatment for antibody-mediated rejection (AMR). There is, however, a lack of published on long-term (10 or more y) outcome data for HLAi kidney transplantation. We now have completed suficient cases to be able to show 10-y patient and graft survival data and identify key factors that determine long-term outcomes.
MATERIALS AND METHODS
Patients
Patients who underwent HLAi renal transplantation between 2003 and 2018 were included. Patients sensitized to HLA antigens were selected for antibody incompatible transplantation if they had reactivity with donor HLA antigens measured by cytotoxic-dependent crossmatch (CDC), flow cytometry crossmatches (FC), or microbead assay (Bead). Pretransplant patients were typically treated with 5 alternate day sessions of double filtration plasmapheresis (DFPP) with the aim of achieving negative flow crossmatch at the time of surgery. In some cases, depending on the starting levels of DSA, fewer or more sessions of DFPP were administered and the transplant was performed in the presence of FC-positive crossmatch.
Patients who had ABO incompatibility or had combined HLAi and ABOi transplants were excluded.
Immunosuppression Protocols, Treatment of Rejection and HLA Antibody Testing were standardized.
DATA ANALYSIS
Overall, patient survival and death-censored graft survival were analyzed. Graft failure was de!ned as a return to requiring renal replacement therapy as indicated in the clinical records of the patients.
Patients were divided into 3 groups: CDC, FC, and Bead based on the crossmatch assay on the pretreatment/pretransplant serum samples. If the patients underwent the first double filtration plasmapheresis (DFPP) before transplant, pretreatment samples before the start of DFPP session were used. One-, 5, and 10-y graft and patient survival were analyzed, and outcomes were compared between the groups.
The study subjects were categorized based on their donor specifc antibody (DSA) status (class I, class II, class I+II antibody groups).
Patients were classified as those who had rejection and those who did not based on renal biopsy as described previously. Each case was confirmed by independent review, and all cases reported as “suspicious rejection” were included as rejection, and comparative 1-, 5-, and 10-y graft survival were analyzed.
Statistical analysis of comparison between groups was performed with nonparametric testing for interdependent groups using IBM SPSS Version 25.0 (SPSS Institute, Chicago, IL). Kaplan-Meier death-censored survival analysis was used to calculate all survival estimates. Chi-square (Log Rank [Mantel-Cox]) was used to determine statistical significance in the survival analysis between groups. A probability of values (P value) < 0.05 was considered statistically significant.
RESULTS Graft survival
Graft survival was also analyzed with respect to DSA specificity. The transplants were divided on the basis of antibody specificity for donor HLA class I, class II, or both. Although there appeared to be poor early graft survival in the group with both class I and II DSAs, overall, there is no signi!cant difference between these 3 groups.
Graft survival was analyzed in term of baseline (immediately pretreatment) DSA levels characterized by Bead positive only, FC positive (Bead+, CDC–), and CDC positive (FC+, Bead+). The graft survival for CDC positive group was 83%, 64%, and 40% at 1, 5, and 10 y, respectively, which is significantly lower than the other 2 groups.
CDC titer was also seen to influence graft survival. As a group, those with a cytotoxic titer >1 in 2 did significantly worse than those with a titer at 1 in 2 or below. The 1-, 5-, and 10-y graft survival for those with CDC+ titer of 1 in 2 or below was 100%, 92%, and 70%, which is similar to the CDC negative group and not statistically different. However, the group with a CDC+ titer of >1 in 2 have significantly worse outcomes with 1-, 5-, and 10-y survival of 60%, 30%, and 10% (P<0.001).
Patiente survival
There was no difference in patient survival between the 3 groups based on DSA levels characterized by Bead positive (FC–, CDC–), FC positive (Bead+, CDC–), and CDC positive (FC+, Bead+).
Rejection on Graft Survival Outcomes
The 1-, 5-, and 10-y graft survival for patients who had rejection was 93%, 77%, and 54% when compared with those who did not have rejection which was 97%, 91%, and 82%. This was statistically significant, P=0.002. There was no increased rejection based on flow crossmatch positivity in this group (P=0.26, Fisher Exact 2-tailed test). However, higher relative median frequency on flow cytometry was associated with increased rates of rejection (Mann-Whitney analysis P=0.024).
Fifty-seven patients had any type of rejection diagnosed by biopsy, including “suspicious” (Table 3). Of these, 47 had AMR with 1-, 5-, and 10-y graft survival of 91%, 77%, and 49%, which is significantly lower than those with no rejection, P <0,001. The graft survival of patients with TCMR no significant difference in overall graft survival when compared with patients who had no rejection, P=0.97.
As the number of rejection episodes increases, the graft survival decreases. This is significantly lower compared with patients who had a single episode (P=0.003) and those who had no rejection (P<0.001).
Rejection occurring only within the first 2 wk of transplantation did not cause any significant decline in the long-term graft survival when compared with rejection-free patients. In contrast, graft survival was signi!cantly lower in those with rejection occurring for the !rst time after 2 wk (P<0.001).
DISCUSSION
The patient and graft survival estimates of our HLAi cohort for 1, 5, and 10 y is 95%, 90%, and 81% and 95%, 85%, and 70%, respectively.
We have looked in detail at 2 factors that signi!cantly affect outcome: measurements of baseline sensitization and the nature of the rejection responses. Graft survival for the group with a positive baseline CDC crossmatch is significantly lower when compared with the FC- and Bead-positive groups. However, in our experience, it is only the higher levels of cytotoxic reactivity, that is CDC titer >1 in 2 that determine reduced graft survival.
AMR was the only rejection type that significantly reduced graft survival in comparison to TCMR or no rejection in our study. And the timing of an early rejection episode, either side of 2 wk posttransplant, is significant in terms of short and long-term graft survival. No significant difference was observed in graft survival probability between patients who only had rejection within the first 2 wk following transplantation and those who had no rejection at all. However, there was a significant impact on graft survival if rejection occurred after the first 2 wk of transplantation or within and after the first 2 wk of transplantation. In addition, experiencing >1 rejection episode caused a signi!cant reduction in graft survival rates in our study.
CONCLUSION
Long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation. There are certain subgroups, in particular those with a crossmatch CDC titer of >1 in 2, antibody-positive female patients, and unresolving or recurrence of AMR, which are associated with a poor prognosis.
What is type of this study?
This is a primary study, a retrospective cohort.
What is the level of evidence?
It has a leves 3 of evidence
Abdulrahman Ishag
3 years ago
Type of the study ;
A retrospective cohort study.
What is the level of evidence?
Level 3
The aim of the study;
Was to compare the overall patient and graft survival data of the HLAi study cohort with (i) first- time deceased donor renal transplant, UK cohort, (ii) first-time deceased donor transplant, (iii) UHCW (our center) cohort, and (iv) the standard live donor transplant of UHCW cohort.
Study area ;
Study was conducted at the University Hospitals Coventry and Warwickshire (UHCW) NHS Trust, which is a UK tertiary international referral center for HLAi transplants.
Ethical approval ;
The study was approved by the Coventry University Ethical committee and the UHCW Research and Development.
Populations;
Patients who underwent HLAi renal transplantation between 2003 and 2018 were included.
Inclusion criteria ;
Patients sensitized to HLA antigens were selected for anti- body incompatible transplantation if they had reactivity with donor HLA antigens measured by cytotoxic-dependent crossmatch (CDC), flow cytometry crossmatches (FC), or micro -bead assay (Bead).
Exclusion criteria ;
Patients who had ABO incompatibility or had combined HLAi and ABOi transplants were excluded.
Immunosuppression protocols;
Consisted of methylprednisolone 500 mg was given as a single intravenous dose intraoperatively and two doses of basiliximab 20 mg were given, at days 0 and 4 as induction therapy . Mcophenolate mofetil, tacrolimus, and prednisolone as maintenance therapy .
Treatment of Rejection;
During the initial few years of our AiT program, rejection was treated with high dose of methyl- prednisolone for 3 d and with OKT3 (muromomab-CD3) if the rejection was steroid resistant. After 2007, antithymocyte globulin (ATG, Genzyme) replaced OKT3.
HLA Antibody Testing ;
Post transplant serum samples for antibody analysis were taken daily for the first 2 wk and then 3 times a week for the next 2 wk .
Data Analysis;
1-Patient Survival and Graft Survival;
Overall, patient survival and death-censored graft survival were analyzed. Patient survival was calculated from the date of renal transplantation to date of death or last follow-up. Death- censored graft survival was calculated from the date of transplantation to the date of graft failure or last follow-up. Graft failure was defined as a return to requiring renal replacement therapy as indicated in the clinical records of the patients.
2- Cross match Status;
Patients were divided into 3 groups: CDC, FC, and Bead based on the cross match assay on the pretreatment/pretransplant serum samples. One-, 5-, and 10-y graft and patient survival were analyzed, and outcomes were compared between the groups.
3- HLA Antibodies ;
The study subjects were categorized based on their donor-specific antibody (DSA) status (class I, class II, class I + II antibody groups). One-, 5-, and 10-y graft survival outcomes between the groups were analyzed.
4- Rejection;
The patients who had rejection were regrouped based on the timing of rejection as rejection occurring within the first 2 wk after transplantation and after the first 2 wk of transplantation. The 1-, 5-, and 10-y graft survivals were compared between the 2 groups.
Statistical analysis ;
Statistical analysis of comparison between groups was performed with nonparametric testing for interdependent groups using IBM SPSS . Kaplan-Meier death-censored survival analysis was used to calculate all survival estimates.Chi-square (Log Rank [Mantel-Cox]) was used to determine statistical significance in the survival analysis between groups.
The result of the study;
Long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation.
Strength of the study ;
This is a study from a tertiary international referral center for HLAi renal transplantation in the United Kingdom. Which has a considerable experience in such transplantations.
limitations of the study;
1-The number of cases is limited given the constraints of a single center.
2-Protocols were not standardized, which could have resulted in
a bias in the outcomes.
3-Exclusion of the highest immunologic risk cases .
Weam Elnazer
3 years ago
Due to improved matching and expanded opportunities to locate a suitable donor, the number of HLA incompatible transplants has reduced around the world, whether through paired kidney donation or exchange in live donors or a kidney allocation system in deceased donors.
However, certain highly sensitized receivers who have been on the waiting list for an interminable period of time without being admitted are at risk of receiving an HLA incompatible donation (after certain desensitization protocols).
Although the result of such instances compared to a continuation of dialysis is questionable, some believe it may be better in some circumstances.
The purpose of this study was to compare the result of a living donor transplant with that of a deceased donor transplant.
The presence of preformed DSA was determined using a variety of methods, including CDC, flow cytometry, and Luminex SAB.
Recipients with simultaneous ABO incompatibility were barred from participating in the study.
In this study, outcomes were compared across groups based on their baseline crossmatch status as well as the kind and timing of rejection events.
The patient and graft survival estimates from this HLAi research cohort were compared to those from the following studies:
I First-time dead donor kidney transplantation
transplantation in the United Kingdom
-Transplantation from a deceased donor for the first time
A cohort of UHCW students
-The standard live donor transplantation procedure consists of Cohort of UHCW
From the same start date of January 1, 2003, to the same end date of December 31, 2018,
In terms of overall patient survival, the results were comparable to those of the first-time dead donor transplant cohort.
Compared to the other groups (microbead assay and flow cytometry crossmatch), the graft survival for the pretreatment cytotoxic-dependent cross matches (CDC) positive crossmatch group was considerably lower.
According to pretreatment crossmatch, female patients had inferior overall results in terms of both patient and graft survival in each of the three groups studied, however, this did not achieve statistical significance in any of them.
When compared to no rejection, antibody-mediated rejection was the most common kind of rejection, and it was associated with a substantial decrease in graft survival after 10 years.
When rejection happened or continues to occur after the first two weeks of pregnancy,
It was shown that transplantation resulted in a considerable reduction in graft survival, whereas those who experienced a single early rejection event had favourable results.
CONCLUSIONS
Patient and graft survival after HLAi renal transplantation are comparable to those after deceased donor transplantation. It is important to note that there are specific populations, including those with an antigen crossmatch CDC titer of >1 in 2, antibody-positive female patients, and patients who have persistent or recurrent AMR, that have a bad prognosis. Given the fact that the need for HLAi transplantation exists and is anticipated to rise in the future, despite the existence of PKE programs, more major studies investigating risk stratification, early diagnosis, and treatment of rejection are required.
-a retrospective cohort study.
-level of evidence3
Reem Younis
3 years ago
-There is a global decrease in HLAi kidney transplantation due to an increase in the paired kidney exchange (PKE) programs and the changes in the local allocation policies, but there is an ongoing requirement for HLAi transplantation in patients wherein finding a compatible donor through PKE is difficult.
-Highly sensitized patients, desensitization could be considered via a combined approach wherein the recipients are offered a lower immunologic risk donor through the PKE or directly from their potential donors after risk stratification.
– Several studies have reported an increase in patient survival with HLAi renal transplantation in comparison to patients remaining on the waiting list or dialysis.
– Many studies have also shown reasonable success in short- and medium-term outcomes in graft survival in HLAi renal transplantation.
– Graft rejection remains a major obstacle in achieving more successful long-term outcomes in HLAi renal transplantations, which is further compounded by the lack of effective treatment for antibody-mediated rejection (AMR).
-This retrospective study was conducted at the University Hospitals Coventry and Warwickshire (UHCW) NHS Trust, which is a UK tertiary international referral center for HLAi transplants.
-134 HLA incompatible renal transplantation patients from 2003 to 2018 were involved in this study.
-The patient and graft survival estimates of HLAi cohort for 1, 5, and 10 y is 95%, 90%, and 81% and 95%, 85%, and 70%, respectively that similar to the outcomes seen for the first time, deceased brain dead donor transplants in the United Kingdom and at this study for the same period.
-There was a significant difference in overall patient and graft survival between the HLAi study cohort and the standard live donor transplant cohort at same center.
-More than half of the recipients had repeat transplants.
-Graft survival for the group with a positive baseline CDC crossmatch is significantly lower when compared with the FC- and Bead-positive groups.
-The graft survival of the CDC low titer group was similar to the CDC negative group.
– Patients with complement-fixing HLA class I DSAs had inferior graft survival compared with HLA class II DSAs.
-Female recipients with DSAs had poorer graft and patient survival compared with male recipients.
– proinflammatory state postpartum in general and increased sensitivity to pregnancy induced antigens speci!cally, could result in decreased graft
and patient survival.
-AMR was the only rejection type that significantly reduced graft survival in comparison to TCMR or no rejection in this study.
-The timing of an early rejection episode, either side of 2 wk posttransplant,
is significant in terms of short and long-term graft survival. No significant difference was observed in graft survival probability between patients who only had rejection within the first 2 wk following transplantation and those who had no rejection at all.
-However, there was a significant impact on graft survival if rejection occurred after the first 2 wk of transplantation.
-Intensive monitoring of patients during the first few wk following transplantation,
could detect rejection early, resulting in prompt and efficient management. Whereas, rejection occurring, later on, is often diagnosed when patients present with overt symptoms or upon routine checkups.
-AMR is considered to be a disease process with a continuum of severity,
beginning at any time after transplantation and developing at varying levels of intensity, progressively leading to the development of chronic allograft damage, dysfunction, and loss.
-There are significantly better outcomes in those with the earlier, compared with those with later rejection episodes.
– This is a retrospective study, the protocols were not standardized, which could have resulted in a bias in the outcomes.
-This is the first long-term study of a relatively large cohort of HLAi transplants that shows equivalent graft and patient survival to deceased donor transplantation. CONCLUSIONS
-Long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation.
-There are certain subgroups, in particular, those with a crossmatch CDC titer of >1 in 2, antibody-positive female patients, and unresolving or recurrence of AMR, which are associated with a poor prognosis. What is type of this study?
Retrospective study What is the level of evidence?
III
Mohamed Mohamed
3 years ago
II. HLA Antibody Incompatible Renal Transplantation: Long-term Outcomes Similar to Deceased Donor Transplantation Please summarise this article Introduction There is a universal decrease in HLAi kidney transplantation due to accompanying increase in the PKE programs & the changes in the allocation policies. However there is still a need for HLAi transplantation in highly sensitized patients who fail to find a compatible donor through PKE programs. Data show that HLAi transplantation has a better survival compared to patients who remain on the waiting list or on dialysis. A recent study from UK however did not show any such survival benefit. The study This retrospective study looked into graft survival of the HLAi transplant compared to deceased donor & the standard live donor transplants. Recipients with anti-HLA DSAs (CDC-XM,FCM-XM or SAB) underwent incompatible transplantation. ABOi or combined HLAi & ABOi transplants were excluded. PP sessions were given pre-transplant to achieve -ve FCM-XM. In some patients the transplant was done in the presence of FCM +ve. The IS protocol consisted of MMF, tacrolimus, & prednisolone.Methylprednisolone (500 mg IV) was given intra-op. Basiliximab 20 mg was given at days 0 & 4. DSA was followed post-transplant daily for 2 weeks & 3 times a week for the next 2 weeks. Rejection was treated with high dose of MP for 3 d plus OKT3 which was replaced by ATG after 2007. The patient & graft survival outcomes of HLAi cohort for 1, 5, & 10 y were similar to that of the 1st time, deceased BDD transplants in the UK & at the study center for the same time period. There was a significant difference in patient & graft survival between the HLAi study cohort & the standard live donor transplant cohort at the center. This study showed that HLAi transplantation offers good long-term results for highly sensitized patients with low chances for a compatible donor. Graft survival for those with a positive baseline CDC-XM was significantly lower compared to FCM- & SAB-positive groups. There was no differences in death-censored graft survival in relation to HLA class DSA. Recipients with complement fixing HLA class I DSAs had inferior graft survival compared with HLA class II DSAs. Combined class I & II DSAs was prevalent in patients with a positive CDC-XM. 12 graft losses occurred in CDC-XM positive group. The earliest (within 1 y) losses seen among those with combined class I & II DSAs. Females with DSAs had poorer graft & patient survival compared with male patients. AMR significantly reduced graft survival compared to TCMR or no rejection. TCMR HLAi transplantation was more likely to respond to treatment. The timing of early rejection episode was significant in terms of short & long-term graft survival. No difference in graft survival between those who only had rejection within the 1st 2 weeks postransplant & those who had no rejection at all. There was a significant impact on graft survival if rejection occurred after the 1st 2 week or within & after the 1st 2 week of transplantation. Having >1 rejection episode caused negatively impacted graft survival. The majority of recipients with >1 rejection episode had an event both within & after 2 week post-transplant. Intensive monitoring during the 1st few weeks post-transplant can detect rejection early & allow prompt treatment. Late rejections, on the other hand, are often diagnosed when patients present with overt symptoms or upon routine checkup. Among those with => 2 rejection episodes, the majority were those with rejections occurring within & after the 1st 2 weeks post-transplant & was therefore associated with non-resolution of the 1st episode. The outcomes were significantly better in those with the earlier rejection episodes, which seem to be more effectively treated. The study identified 2 key points which allow very good outcomes in high-risk transplantation: (i) Exclusion of the highest immunologic risk cases(CDC titer of >1 in 2) gives a 10-y graft survival estimates of nearly 75%. (ii) AMR or TCMR diagnosed & treated within the 1st 2 week post-transplant have a good chance of long-term transplant survival. ================================================ What is type of this study? Retrospective cohort study ================================================ What is the level of evidence? Level III
Wael Jebur
3 years ago
As it’s continued to be a major impediment for kidney transplantation, HLA incompatible( HLAi) renal transplantation still considered the best option for highly sensitized and difficult to match patients.However,the long term outcome of the patient and graft is disputed.It was shown that post desensitization transplant of HLAi patients ,associated with high risk and worse outcome. Furthermore the transplantation for HLAi patient featured downward trend all over the world because of growing trend of adopting kidney paired donation (KPD) program.
Nevertheless, HLAi transplantation still considered for those patients failed to find an HLA matched donor in KPD. Furthermore ,desensitization can be offered to those highly sensitized patient via a combined approach wherein lower HLAi profile donor is considered by KPD program.
Experience with HLAi transplantation:
1) Studies have reported an increase in patients survival after HLAi transplantation, in comparison to those on regular hemodialysis.
2) A recent study from UK failed to show any survival benefit for HLAi transplantation over hemodialysis.
3) It was demonstrated in many studies ,a successful short and medium term survival benefits.
4) Graft rejection ,remain the major obstacle for a successful long term HLAi transplantation outcome. That could be compounded by the lack of effective treatment of AMR.
Therefore,this study was conducted to invetigate the long term patient and graft survival in comparison to HLA matched transplantation.
Study Design:
A retrospective study assessed 134 patients had HLA incompatible renal transplantation from 2003 to 2018 with median follow up period of 6.9 years, for graft and patient survival.
The outcomes compared with groups defind by:
1) Baseline cross match status .
2) Type and timing of rejection episodes.
Material and methods:
1)134 patients with positive DSAs were categorized into bead positive,FC positive and CDC positive accordingly,
2) 5 DFPP were performed prior to transplantation, to have negative CDC pre transplant.
3) These patients followed for 6.9 years for patient and graft survival.
4) Acute rejection was diagnosed by allograft biopsy and reported against timing of rejection.
5)Those HLAi patients and graft survival were compared to 3 groups of patients
a) first time deceased donor transplant in UK
b) first time deceased donor in UHCW
c) Life donor transplant
6) Basiliximab was considered for induction,and Tac based protocol for maintenance.
7) Daily assessment of DSAs for first 2 weeks post transplant,then 3 times weekly .
8) 1,5 and 10 years graft and patient survival were compared between the groups.
9) Similarly, survival was assessed according to DSAs phenotype ( anti HLA I,II,and I+II).
10) Before 2 weeks rejection group vs after 2 weeks post transplant rejection group were assessed for its effect on long term survival 1,5 and 10 years.
11) No.of rejection episodes ,3 groups categorized ,no rejection, 1 episode and 2 or more,assessing 1,5 and 10 year survival in each.
Results:
1) graft and patient survival was comparable in HLAi and first deceased in UK and UHCW,and inferior to life donor transplant.
2) There was no difference between class I and class II DSAs on long term outcome
3) Those with CDC positive DSAs showed inferior outcome in comparison to FC or bead positive assay.
4) CDC positivity depend on DSAs titer not mere positivity.
5) Rejection before 2 weeks post transplant has no effect vs after 2 weeks on long term.
6) Similarly,more than one rejection episodes is associated with poor long term outcome in comparison to one or no rejection.
7) AMR is associated with adverse outcome in comparison to CMR.
8) females with DSAs associated with adverse outcome in comparison to male patients.
It’s Retrospective study with evidence level 3.
Nasrin Esfandiar
3 years ago
For highly sensitized patients who can’t find a matched donor HLA in compatible (HLAi) TX is one of the options if compatible.
PKE is not possible or in combination with PKE program.
This article studies 10-year patient and graft survival and its key factors.
A retrospective study was performed in a tertiary referral centers for HLAi TX in UK. Patients with HLAi TX during 2003-2018 were included and their outcome was compared to first DDRT from UK cohort and standard LDRT of UHCW cohort
Highly sensitized patients underwent HLAi TX if they had reactivity with donor HLA Ags by CDC, flow cytometry XM or microbeads assay excluding ABOi TX.
They were treated with 5 alternate day DFPP to achieve negative flow-XM at surgery.
Few patients were transplanted with positive flow-XM.
They received induction therapy with basiliximab and methylprednisolone and maintenance.
The triple therapy with tacrolimus, MMF and prednisolone HLA-abs were monitored using microbeads assay.
XM was performed at baseline and within 24 h pre-transplant patient and graft survival XM were analyzed for three group based on results of CDC flow XM AND microbeads F/W of 6.93 years.
There was no difference between these patients in other cohorts regarding patient and graft survival.
The graft survival for CDC+ group was significantly lower than the other groups and was worse for females in all groups.
Graft survival for patients who had rejection especially AMR was significantly for lower than those without rejection.
Higher RMF (relate MFI) was seen in patients with rejection.
Graft survival was significantly lower in patients with repeated rejection.
Rejections occurring after 2 weeks were significantly associated with lower graft survival.
Earlier completely treated rejection were associated with better outcome.
So in conclusion, long –term graft and patient survival for HLAi TX were similar to DDTXs.
This is retrospective study.
The level of evidence is 3.
HLA antibodies are the major barrier to transplantation and associated with inferior outcomes.
HLA-incompatible transplantation are now declining due to increase in PKD programs but highly sensitization may required combined approach ; desensitization + PKD[4,5]
HLA incompatible transplantation offers better patient survival compared to remaining on waiting list or dialysis[8,9]
Allograft rejection & absence of effective treatment for AMR are the main obsctacle to HLA-incompatible transplantation[14]
This retrospective study of 134 HLA-incompatible transplantation patients between 2003 to 2018 aimed to estimate both patient and graft survival
Materials & Methods ;
patients ;
Retrospective between 2003 & 2018 study at the university hospitals Coventry and Warwickshire(UHCW) NHS Trust ; tertiary referral hospital for HLA-incompatible transplants
Patients came from different centers in UK & Ireland and were send back after stabilization
Immunologic and HLA data were obtained from NHS blood and Transplant Center, Birmingham
Overall patient and graft survival were compared to ; 1. first time deceased donor renal Tx, UK cohort 2.first time deceased donor transplant,UHCW cohort 3. Standard live donor transplant, UHCW cohort
HLA-incompatiblity was defected by ; CDCXM, FCXM, & Micro-bead assay
Pretransplant treatment by Double filtration plasma pheresis was carried out for 5 alternative days to achieved FCXM negative results[12,15]
Immune-suppression protocol ;
MPA + Tacrolimus + Pred
Single dose methyl pred intra-operative 500 mg IV
Rituximab 20 mg day 0 & day 4
Post-Tx DSA daily for 2 weeks then 3 times weekly for the another 2 weeks
Treatment of rejection ; Defined by biopsy or clinically if raising Cr, DSA , & oligouria
Methyl pred for 3 days, if resistant OKT3
After 2007 ATG replaced OKT3
HLA antibody testing ;
Mirobead assay, CDCXM, FCXM
Data Analysis ;
Patient survival ; Calculated from the date of Tx to the date of death or last follow up
Graft survival ; Date of Tx to the date of graft failure or last follow up
Graft failure ; Return to dialysis
Cross-match status ;
3 groups ; CDCXM, FCXM, Beads
In CDCXM group evaluation was based on CDC titer level
1,5,10 y patient and graft survival were compared between the 3 groups
HLA Antibodies ;
Class I, Class II or both I &II
1,5,10y graft survival were compared between groups
Rejection
Based on biopsy ; rejection VS no rejection
Type of rejection ; AMR, TCMR, or Mixed
Number of rejection episodes ;no rejection, 1, or >=2
Timing of rejection ; first 2 weeks after Tx or after 2 weeks post-Tx
1,5,10 y graft survival were compared between groups
Statistical analysis
Non-parametric test = comparison between groups
Kaplan-Meier = survival estimate
Chi-square = statistical significant
P value < 0.05 = statistically significant
Results ;
134 patients in the final analysis after exclusion of patients without concerns with median follow of 6.93+/-3.33
Significant patient survival was notice between UHCW live donor cohort, UHCW HLAi cohort, UK deceased cohort, and UHCW deceased cohort
Antibody Variables Relating to Outcome
Graft Survival ;
The graft survival for CDC+ve group was 83%,64%,and 40% at 1,5,10y respectively which is significantly lower than the other group(Bead vs CDC, CDCvs FCXM, Bead vs FCXM)
The graft survival for FCXM +ve was 100%,93%,77% and for bead +ve was 95%,86%,and 82% at 1,5,10y respectively
CDC titer > 1 in 2 had worst outcome than those with a CDC titer at 1 in 2
1,5,10y graft survival for CDC +ve titer was 100%,92%,70% (= similar to CDC-ve group)while 1,5,10 years graft survival for CDC+ve < 1 in 2 was 60%,30%,and 10%
Patient Survival ;
There was no difference in patient survival the 3 groups based on DSA levels, CDC titer, or antibody specificity to HLA(I,II, or I + II)
Rejection on Graft Survival Outcomes ;
The 1,5,10 y graft survival for those with rejection was 93%,77%,54% compared with to those with no rejection 97%, 91%, 82%
Type of Rejection ;
The 1,5,10 yr graft survival for ABMR was 91%, 77%, 45% which is significantly lower than those with no rejection
The graft survival for TCMR is not different from those with no rejection(87% at 1,5,10 y)
Number of rejection ;
Single episode of rejection was associated better graft survival compared to 2 or more episode of rejections(p<0.001)
Timing of rejection ;
Graft survival was better in those with rejection < 2 weeks compared to those with rejection occurring after 2 weeks(p< 0.001)
Discussion ;
This study address the problem of no long-term studies for HLAi transplantation.
This study demonstrated that HLAi transplantation offers long-term survival for highly sensitized patients
Those with +ve CDC had lower graft survival than those with FCXM & Bead positive groups
High CDC titer >1 in 2 was associated with reduced graft survival compared to those with low CDC titer < 1 in 2 (similar to CDC -ve groups)
Although not statistically significant female recipient with DSAs had poorer graft outcomes compared with the males
Rejection less than 2 weeks was associate with better survival than rejections after 2 weeks
Two or more episodes of rejections was associated with inferior graft survival compared to those with single or no rejection
Strength ; This study identified 2 areas that allows very good outcomes of HLAi transplantation
Those with high titer CDC>1 in 2 should be excluded from HLAi transplantation due clearly poor outcomes
Early diagnosis & treatment of rejection < 2 weeks is expected to be associated with very good graft survival
Limitation ;
Findings of this study may not be applicable in other settings
Limited number of participants
Retrospective analysis
Conclusion ;
Long-term graft & patient survival for HLAi transplantation is similar to deceased donor Tx
Risk factors for poor prognosis are ; High CDC titer > 1 in 2, female gender, & continues or recurrent episodes of rejections
Further studies focusing on risk stratification, early diagnosis, & management of rejection are required
HLA Antibody Incompatible Renal Transplantation: Long-term Outcomes Similar to Deceased Donor Transplantation. Retrospective study to revealed long-term outcomes of HLAi transplantation. Level evidence III. Introduction:
Transplantation is considered the best modality of RRT, but still HLA incompatibility is an obstacle for successful transplantation and led to increase of waiting list time.
Paired kidney exchange program decreases the number of HLAi transplantation but still we need to proceed to HLAi transplantation to decrease number on waiting list specially many studies revealed that increase in patient survival with HLAi renal transplantation in comparison to patients remaining on the waiting list or on dialysis and other shown reasonable success in short- and medium-term outcomes in graft survival in HLAi renal transplantation. MATERIALS AND METHODS:
-134 patients who underwent HLAi renal transplantation between 2003 and 2018 were included and treated with 5 alternate day sessions of double filtration plasmapheresis (DFPP) with the aim of achieving negative cross match at the time of surgery.
HLA antigens measured by cytotoxic-dependent cross-match (CDC), flow cytometry cross-matches (FC), or microbeads assay (Bead).
Immunosuppression Protocols:
Methylprednisolone 500mg was given as a single intravenous dose intraoperatively and two doses of basiliximab 20mg were given, at days 0 and 4.
Tacrolimus based triple therapy given and HLA ab analysis were taken daily for the first 2 week and then 3 times a week for the next 2 wk.
Rejection treated early by I.V steroid with OKT3 then the later changed by ATG. RESULTS:
Patient survival was 95%, 90%, and 81%; and graft survival was 95%, 85%, and 70% at 1, 5, and 10 y, respectively. This was similar to the first-time deceased donor transplant cohort.
One-, 5-, and 10-y patient and graft survival estimates of the different comparative cohorts revealed a significant difference in patient survival between the UHCW live donor cohort versus others, However, there were no significant differences between other pairs in both patient and graft survival.
Graft survival was analyzed in term of baseline DSA level Bead positive only, FC positive (Bead+, CDC–), and CDC positive (FC+, Bead+)showed significantly reduced graph survival when the baseline cross-match was CDC positive.
The group with a CDC+ titer of >1 in 2 have significantly worse outcome compared with the low titer group.
No difference in graft survival based on class of donor-specific antibodies.
There was also no difference in patient survival based on CDC titer or antibody specificity to HLA class (I, II, or I+II).
The 1-, 5-, and 10-y graft survival for patients who had rejection was 93%, 77%, and 54% when compared with those who did not have rejection which was 97%, 91%, and 82%.
Antibody-mediated rejection was the most frequent type of rejection with significant decline in graft survival by 10 y .
Rejection that occurred after the first 2 week of transplantation caused a significant reduction in graft survivals and who developed single attack of rejection has a good outcome. Discussion:
Still the standard live donor transplant has the best graft and patient survival but HLAi transplantation can, overall, offer good long-term outcomes for highly sensitized patients with a low prospect of a compatible donor.
AMR was the only rejection type that significantly reduced graft survival in comparison to TCMR or no rejection in our study.
The timing of an early rejection episode, either side of 2 week post-transplant, is significant in terms of short and long-term graft survival and number of rejection attacks also affect graft survival. STRENGTHS AND LIMITATIONS:
Study from trusted specialized center in HLAi transplant, limited number of patients and it is a retrospective study, the protocols were not standardized, which could have resulted in a bias in the outcomes. CONCLUSIONS:
Long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation.
There is poor prognosis with special group who characterized by crossmatch CDC titer of >1 in 2, antibody-positive female patients, and un-resolving or recurrence of AMR.
Another studies needed to look at risk stratification, early diagnosis, and management of rejection and to increase HLAi transplantation in the future, despite PKE programs .
Asmaa Khudhur
3 years ago
The reason for the global decrease in HLAi kidney transplantation is the concomitant increase in the paired kidney exchange (PKE) programs and the changes in the local allocation policies. Nevertheless, there is an ongoing requirement for HLAi transplantation in patients wherein finding a compatible donor through PKE is difficult.
MATERIALS AND METHODS
Patients
A retrospective study was conducted
Patients who underwent HLAi renal transplantation between 2003 and 2018 were included.
Patient characteristics include :
Total number of patients Gender, n (%)
Female
Male
Mean age at time of transplantation, mean ± SD Median follow-up time in y, median ± SD Donor-specific antibodies, n (%)
Class I HLA Class II HLA Class I + II HLA
Crossmatch, n (%) Bead positive FC positive CDC positive
Transplantation type, n (%)
Living donor transplantation Deceased donor transplantation
Comorbidities Yes, n (%)
Hypertension, n Hypotension, n Obesity, n Diabetes, n Others, n
No, n (%)
Number of previous transplants, n (%)
0 1 2 3
aTreatment approach, n OKT3
ATG
IVIG Rituximab Campath
They compared the overall patient and graft survival data of the HLAi study cohort with
(i) first- time deceased donor renal transplant, UK cohort, (ii) first-time deceased donor transplant, (iii) UHCW cohort, and (iv) the standard live donor transplant of UHCW cohort.
Sensitization to HLA antigens measured by cytotoxic-dependent cross- match (CDC), flow cytometry crossmatches (FC), or micro- bead assay (Bead). Patients who had ABO incompatibility or had combined HLAi and ABOi transplants were excluded.
Pretransplant patients were typically treated with 5 alter- nate day sessions of double filtration plasmapheresis (DFPP) with the aim of achieving negative flow crossmatch at the time of surgery.
Immunosuppression Protocols:
mycophenolate mofetil, tacrolimus, and prednisolone
methylprednisolone 500 mg was given as a single intravenous dose intraoperatively. Two doses of basiliximab 20mg were given, at days 0 and 4. Posttransplant serum samples for anti- body analysis were taken daily for the first 2 wk and then 3 times a week for the next 2 wk.
Treatment of Rejection:
rejection was treated with high dose of methyl- prednisolone for 3 d and with OKT3 (muromomab-CD3) if the rejection was steroid resistant. After 2007, antithymocyte globulin (ATG, Genzyme) replaced OKT3.
HLA Antibody Testing:
microbead assay
was performed at baseline (pretreatment) and within 24 h pretransplant .
HLA Antibodies
The study subjects were categorized based on their donor- specific antibody (DSA) status (class I, class II, class I+II antibody groups). One-, 5-, and 10-y graft survival outcomes between the groups were analyzed.
Rejection
Patients were classified as those who had rejection and those who did not based on renal biopsy .Patients were further categorized based on biopsy- proven definitive evidence of the type of rejection—AMR, T-cell–mediated rejection (TCMR), or mixed rejection.
Further analyses were performed by grouping patients based on the number of rejection episodes,and the timing of rejection as rejection occurring within the first 2 wk after transplantation and after the first 2 wk of trans- plantation. The 1-, 5-, and 10-y graft survivals were compared between the 2 groups.
RESULTS:
A total of 165 antibody incompatible trans- plants were reviewed and a final of 134 was analyzed in this study. Thirty-one patients were exclude.
The median follow-up for the HLAi study cohort was 6.93 ± 3.33 y.
There was a significant difference in patient survival between patients in this study and the UHCW live donor cohort versus other deceased mentioned cohorts.
Similarly, there was a significant difference in graft survival between the UHCW live donor versus (i) UHCW HLAi , (ii) UK deceased donor ,and (iii) UHCW deceased donor .
The patient and graft survival estimates of this HLAi cohort for 1, 5, and 10 y is 95%, 90%, and 81% and 95%, 85%, and 70%, respectively.
Antibody Variables Relating to Outcome
1-Graft Survival
Graft survival was analyzed in term of baseline (immediately pretreatment) DSA levels characterized by Bead positive only, FC positive (Bead+, CDC–), and CDC positive (FC+, Bead+).
The graft survival for CDC positive group was 83%, 64%, and 40% at 1, 5, and 10 y, respectively, which is significantly lower than the other 2 groups
The graft survival for the 9 female CDC positive patients is 75%, 75%, and 30%, which is worse, although not signifi- cantly different than the 14 male CDC positive patients with survival of 87%, 59%, and 47% at 1, 5, and 10 y, respectively .
FC-positive and Bead-positive groups in which graft survival in females was lower than males, but this did not reach statistical significance.
CDC titer was also seen to influence graft survival .those with a cytotoxic titer >1 in 2 did significantly worse than those with a titer at 1 in 2 or below.
Graft survival was also analyzed with respect to DSA specificity for donor HLA class I, class II, or both. there is no significant difference between these 3 groups .
2-Patient Survival:
There was no difference in patient survival between the 3 groups based on DSA levels characterized by Bead positive (FC–, CDC–), FC positive (Bead+, CDC–), and CDC positive (FC+, Bead+). Patient survival for CDC positive females was lower but not statistically significant when compared with males .
There was a similar trend in the FC-positive and Bead-positive groups with lower survival in the females but not reaching statistical significance. There was also no difference in patient survival based on CDC titer or antibody specificity to HLA class (I, II, or I+II).
Rejection on Graft Survival Outcomes:
The 1-, 5-, and 10-y graft survival outcome for patients who had rejection was lower than those not have rejection .
Type of Rejection:
57 patients had any type of rejection diagnosed by biopsy, including “suspicious.
Of these, 47 had AMR with 1-, 5-, and 10-y graft survival significantly lower than those with no rejection.
AMR was the only rejection type that significantly reduced graft survival in comparison to TCMR or no rejection in this study.
Number of Rejection Episodes:
As the number of rejection episodes increases, the graft survival decreases.
Timing of Rejection:
Rejection occurring only within the first 2 wk of transplantation did not cause any significant decline in the long-term graft survival when compared with rejection-free patients.
In contrast, graft survival was significantly lower in those with rejection occurring for the first time after 2 wk or continuing to occur after the first 2 wk of transplantation compared with rejection-free patients.
There was a significant difference in the graft survival estimates for patients who had rejection in 1 in 2, gives us an estimated 10-y graft survival of almost 75%.
Similarly, those with AMR or TCMR diagnosed and treated within the first 2 wk posttransplantation can be expected to have a good chance of long-term transplant survival.
CONCLUSIONS:
Long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplanta- tion. There are certain subgroups, in particular those with a crossmatch CDC titer of >1 in 2, antibody-positive female patients, and unresolving or recurrence of AMR, which are associated with a poor prognosis. Given that the need for HLAi transplantation exists and is likely to increase in the future, despite PKE programs, further large studies looking at risk stratification, early diagnosis, and management of rejection are needed.
Retrospective study
Level 3
these results may not necessarily be extrapolated to other practices. Also, the number of cases is limited given the con- straints of a single center. As it is a retrospective study, the protocols were not standardized, which could have resulted in a bias in the outcomes.
2 key areas that allow very good outcomes in high-risk transplantation.
Exclusion of the highest immunologic risk cases, defined as those with a CDC titer of >1 in 2, gives us an estimated 10-y graft survival of almost 75%.
Similarly, those with AMR or TCMR diagnosed and treated within the first 2 wk posttransplantation can be expected to have a good chance of long-term transplant survival.
Huda Al-Taee
3 years ago
Retrospective study level of evidence 3
Aim: to estimate patient and graft survival in HLAi renal transplantation
Setting: University Hospital Conventry and Warwickshire NHS trust from 2003 to 2018
Inclusion criteria: patients who underwent HLAi renal transplantation
Exclusion criteria: patients who had ABOi or had combined ABOi & HLAi transplantation
Ethical approval: Conventry University Ethical Committee and the UHCW Research Development.
Patients:total of 134 patients included with median follow up of 6.9 years. sensitized patients were selected if they had either CDC, FCXM, or bead assay positive, desensitized using 5 alternate day sessions of double filtration plasmapheresis with aim of achieving negative FCXM.
IS protocol consist of Tac, MMF, and prednisolone. Intraoperative 500 mg MP single dose was given IV. 2 doses of basiliximab 20 mg were given at day 0 & 4. Post transplant antibody analysis was done daily for the first 2 weeks and then 3 times a week for the next 2 wks.
Rejection was diagnosed by biopsy and treated with high dose of MP for 3days and OKT3, after 2007, ATG replaced OKT3 for treating steroid resistant rejection. Anti-HLA antibodies were monitored by microbead assay, lymphocytes CXM was done pre treatment, and within 24 hr pre transplant.
Patient and graft survival were analyzed ( 1,5,10 year).
Patients were devided into 3 groups according to CXM assay. Also DSA status was used to caterogize the patients ( class 1, class 2, class 1 &2).
Patients were classified as having rejection or not based on biopsy results and the suspecious cases were considered as rejection.
Results:
At 1,5,10 year follow up:
Patient survival was 95%, 90%,85%
Graft survival was 95%, 85%, 70%
The results were similar to the first time deceased donor transplant cohort.
Graft survival for pretreatment CDC positive patients were lower at 1,5,10 year compared to other groups.
Low CDC titer has results similar to CDC negative patients.
Females showed lower patient and graft survival in the 3 groups
ABMR was the most frequent type of rejection with significant decline in graft survival by 10 years when compared to no rejection.
Limitations:
Non standardized protocols may result in biased outcomes
Single center retrospective study
Strength:
Long term study
Large cohort
Conclusion:
One, 5, 10 years HLAi graft and patient survival is comparable to deceased donor transplantation and can be further improved by excluding high CDC titer cases. Antibody positive female cases showed worse long term survival. Resolution of early rejection is associated with good long term graft survival.
Amit Sharma
3 years ago
Please summarise this article
Sensitized patients form a major portion of transplant wait-list. Paired kidney exchange program (PKE) is a boon for such patients, although many patients fail to find a donor in PKE. Highly sensitized patients difficult to match can undergo HLA incompatible (HLAi) transplant.
To know the long-term effects of these transplants, a retrospective study was conducted amongst patients with HLAi transplant between 2003 and 2018, comparing the results with first-time deceased donor (UK cohort and centre cohort), as well as live donor (centre cohort) transplant recipients. ABO incompatible transplants were excluded.
The patients were desensitized using plasmapheresis, given induction with Basiliximab and tacrolimus based triple drug maintenance immunosuppression. Post-transplant antibody levels were done daily for 2 weeks and then 3 times a week for next 2 weeks. Steroid resistant rejections were treated with OKT3 (till 2007) and ATG (after 2007).
Patients were divided into 3 groups: CDC, Flow cytometry and Bead based positive crossmatch. One-, five- and ten-year graft and patient survival were analysed.
A total of 134 patients were included in the study with a median follow-up of 6.93 years. The patient and graft survival in the live donor transplant group was significantly better than the deceased donor groups as well as the HLAi group. The patient and graft survival amongst the HLAi group and the deceased donor group (UK cohort and the centre cohort) was similar.
Among the HLAi transplants, patients with CDC positive group, especially the female recipients, had worse graft and patient survival, as compared to the flow cytometry and Bead positive groups. Amongst the CDC positive group, patients with titres ≤1:2 had graft survival rates similar to non-sensitized patients, while those with tires >1:2 had worst graft survival, being 10% at 10 years.
In all the 3 HLAi transplant groups, females had lower survival rates than males, although not significant.
Patients with rejections had significantly lower graft survival rates as compared to those without rejection. Regarding the type of rejection, the patients with AMR or mixed rejection had significantly lower graft survival than those with T cell mediated rejection, which in turn, had graft survival similar to those without rejection. Patients with 2 or more rejection episodes had very low graft survival rates, with 10-year graft survival at 15%.
Patients with rejection occurring within first 2 weeks had graft survival similar to those without any rejection while those with rejections after first 2 weeks or with rejection in first 2 weeks as well as later had significantly lower graft survival.
The study emphasizes that HLAi transplants have outcomes similar to deceased compatible transplants with poorer graft survival in CDC positive with high titre, those with AMR alone or with T cell mediated rejection, having 2 or more rejections, especially after first 2 weeks post-transplant.
The limitations of the study include low number of cases, retrospective study and, being a tertiary centre, results may not be similar in other transplant centres.
The study identifies 3 subsets of HLAi transplant recipients with poor prognosis: namely CDC crossmatch tire >1:2, female patients with DSA and unresolved or recurring AMR.
What is type of this study?
A retrospective cohort study.
What is the level of evidence?
Level 3.
Zahid Nabi
3 years ago
Kidney transplant remains the best possible solution for patients on dialysis.Finding a suitable donor remains a challenge and organ shortage adds on to this dilemma.HLAi transplant is one way of overcoming this challenge.
Studies have reported an increase in patient survival with HLAi renal transplantation in comparison to patients remaining on the waiting list or on dialysis. Many studies have also shown reasonable success in short- and medium-term outcomes in graft survival in HLAi renal transplantation.Advances in antibodies detection and screening, HLA typing, and desensitization of patients have aided in curtailing the risk associated with HLAi renal transplants.
To address this issue a retrospective study was conducted at the University Hospitals Coventry and Warwickshire (UHCW) NHS Trust, which is a UK tertiary international referral center for HLAi transplants.
Patients who underwent HLAi renal transplantation between 2003 and 2018 were included.
They also compared the overall patient and graft survival data of the HLAi study cohort with (i) first- time deceased donor renal transplant,
UK cohort, (ii)
first-time deceased donor transplant,
(iii) UHCW (our center) cohort, and
(iv) the standard live donor transplant of UHCW cohort.
Patients sensitized to HLA antigens were selected for anti- body incompatible transplantation if they had reactivity with donor HLA antigens measured by cytotoxic-dependent cross- match (CDC), flow cytometry crossmatches (FC), or micro- bead assay (Bead). Patients who had ABO incompatibility or had combined HLAi and ABOi transplants were excluded.
Pretransplant patients were typically treated with 5 alternate day sessions of double filtration plasmapheresis (DFPP) with the aim of achieving negative flow crossmatch at the time of surgery. In some cases, depending on the starting levels of DSA, fewer or more sessions of DFPP were administered and the transplant was performed in the presence of FC- positive cross match.
Immunosuppression consisted of mycophenolate mofetil, tacrolimus, and prednisolone methylprednisolone 500 mg was given as a single intravenous dose intraoperatively. Two doses of basiliximab 20mg were given, at days 0 and 4. Posttransplant serum samples for antibody analysis were taken daily for the first 2 wk and then 3 times a week for the next 2 weeks.
RESULTS
A total of 165 consecutive antibody incompatible transplants performed were reviewed and a final of 134 was analyzed in this study. The median follow-up for the HLAi study cohort was 6.93 ± 3.33 y.
The overall patient survival was 95%, 90%, and 81%; and graft survival was 95%, 85%, and 70% at 1, 5, and 10 y, respectively. This was similar to the first-time deceased donor transplant cohort. The graft survival for pretreatment cytotoxic-dependent crossmatch (CDC) positive crossmatch group was significantly low at 83%, 64%, and 40% at 1, 5, and 10 y, respectively, compared with other groups (Bead/CDC, P = 0.007; CDC/Flow, P=0.001; and microbead assay/flow cytometry crossmatch, P=0.837), although those with a low CDC titer (<1 in 2) have comparable outcomes to the CDC negative group. Female patients in general fared worse in both patient and graft survival outcomes in each of the 3 groups based on pretreatment crossmatch, although this did not reach statistical significance. Antibody-mediated rejection was the most frequent type of rejection with significant decline in graft survival by 10 y when compared with no rejection (P<0.001). Rejection that occurred or continued to occur after the first 2 wk of transplantation caused a significant reduction in graft survivals (P < 0.001), whereas good outcomes were seen in those with a single early rejection episode.
Conclusions. One-, 5-, and 10-y HLA incompatible graft and patient survival is comparable to deceased donor transplantation and can be further improved by excluding high-CDC titer cases. Antibody-positive female patients show worse long-term survival. Resolution of early rejection is associated with good long-term graft survival.
Shereen Yousef
3 years ago
INTRODUCTION
-HLA-specific antibodies have been considered a significant barrier to successful kidney transplantation
-desensitization could be considered via a combined approach wherein the recipients are offered a lower immunologic risk donor through the PKE or directly from their potential donors after risk stratification.
-The increase in number of patients and increase in number of sensitized patients together with shortage of doner increased the need for HLAi transplantation.
-Transplantation even of incompatible donor is associated with improved patient’s survival as compared with patients on dialysis although some studies found no difference.
Methods:
This is a retrospective study included 134 renal transplant recipients with HLAi transplants between 2003 and 2018 with follow-up for 6.93 years .
They also compared the overall patient and graft survival data of the HLAi study cohort with (i) fist-time deceased donor renal transplant, UK cohort,
(ii) first time deceased donor transplant.
(iii) UHCW (their center) cohort, and (iv) the standard live donor transplant of UHCW cohort.
Sensitized patients with positive CDC, FCXM or microbead assay were selected, treated with plasmapheresis till achieve negative FCXM before transplant
Patients who had ABO incompatibility or had combined HLAi and ABOi transplants were excluded.
*Desensitization by
alternate day sessions of double filtration plasmapheresis (DFPP) till they become negative FCXM .
In some cases, transplant was performed in the presence of FC-positive crossmatch.
•Immunosuppression Protocols
-methylprednisolone 500mg ,single intravenous dose intraoperatively.
-Triple immunosuppression with mycophenolate mofetil, tacrolimus, and prednisolone.
– Two doses of basiliximab 20mg were given, at days 0 and 4.
-rejection episodes treated by high dose of methyl-prednisolone for 3 days with ATG replaced OKT3 after 2007 .
•Results :
-The patient and graft survival estimates for HLAi cohort for 1, 5, and 10 y is 95%, 90%, and 81% and 95%, 85%, and 70%, respectively.
-results were similar to the outcomes for first time, deceased donor transplants .
– significant difference in overall patient and graft survival between the HLAi study cohort and the standard live donor transplant cohort .
-Graft survival with a positive baseline CDC crossmatch is significantly lower than compared with the FC- and Bead-positive groups.
-graft survival of the CDC low titer group was similar to the CDC negative group.
-no statistical differences in death-censored graft survival when comparing cases with either HLA class I DSA, class II, or both.
**this report provides reassurance that HLAi transplantation can, overall, offer good long-term outcomes for highly sensitized patients with a low prospect of a compatible donor.
-female recipients with DSAs had poorer graft and patient survival compared with male recipients but no significant.
-AMR was the only rejection type that significantly reduced graft survival in comparison to TCMR or no rejection.
-No significant difference in graft survival between patients who had rejection within the 2 wk following transplantation and those who had no rejection at all.
-there was a signifiantly better outcomes in patients with the earlier, compared with those with later rejection episodes .
•STRENGTHS AND LIMITATIONS :
-first long-term study of a relatively large cohort of HLAi transplants that shows equivalent graft and patient survival to deceased donor transplantation.
– Exclusion of the highest immunologic risk cases, those with a CDC titer of >1 in 2, gives us an estimated 10-y graft survival of almost 75%. Similarly, those with AMR or TCMR diagnosed and treated within the 2 wk posttransplantation.
-retrospective study, the protocols were not standardized,
It is retrospective study level of evidence III.
Mohamad Habli
3 years ago
The paired kidney exchange programs and the changes in the local allocation policies have led to a global decrease in HLAi kidney transplantation.
But with the use of extended criteria donors, retransplantation, reduced longevity of renal allografts, it is likely that more patients will be sensitized with potential increasing in the need for HLAi transplantation.
A retrospective study was conducted in UK at the University Hospitals Coventry and Warwickshire (UHCW) NHS Trust to evaluate the long terms outcomes of transplantation in HLA incompatible patients. Patients who underwent HLAi renal transplantation between 2003 and 2018 were included in the analysis.
The overall patient and graft survival data of the HLAi study cohort were compared to:
1- first-time deceased donor renal transplant, UK cohort,
2- first-time deceased donor transplant,
3- UHCW cohort
4- The standard live donor transplant of UHCW cohort.
Immunosuppression consisted of MMF, TAC, and prednisolone.
A total of 134 antibody incompatible transplants was analyzed in this study. The median follow-up for the HLAi study cohort was 6.93±3.33 y.
Results
Patient survival at 1,5 and 10 years was 95%, 90%, & 81%, whereas graft survival was 95%, 85% & 70%.
Graft survival in patients with positive CDC was lower than for positive FCXM and beads assay. This only occur when CDC titer >1in 2.
There was no impact on graft survival among different types of DSA (class I, II or both).
Recipient sex was shown to be of significance, because female patients had worse graft and patient survival.
AMR was strongly liked to graft outcome in terms of reduce survival, comparing to TCMR. Timing of rejection was important for short and long term graft survival.
Conclusion
Long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation. Whereas living donor kidney was associated with better graft and patient survival in the short and long term.
Abdul Rahim Khan
3 years ago
This article highlights the outcome of HLA incompatible (HLAi ) renal transplantation on long term outcomes. Kidney transplantation in patients who are HLA incompatible is risky and carries poor outcome . With the development of paired kidney donation and kidney allocation system it is possible to do renal transplants using living and deceased donors . For some patients who are HLA incompatible and cannot find a suitable donor through paired kidney donation or KAS, the only option is HLA incompatible kidney transplants which can have a poor outcome. The pain main problem here remains a positive cross match due to preformed antibodies. However with the development of newer methods to deals with DSA has made it possible to do kidney transplants in such HLAi patients. In spite the fact that there is high risk ABMR but early detection can improve prognosis. Different studies have shown different outcomes in HLAi transplants when compared to no transplant and dialysis. Some studies have shown improved outcomes while other have shown no benefit.
In this study 134 HLAi transplants were assessed between 2003-2008 for long term graft outcome. All patients had 5 sessions of PLEX, and transplanted with positive FXCM. Induction with Basiliximab and maintenance with Tacrolimus, MMF and steroids.
Outcome of study
Patient survival at 1, 5 and 10 years was 95%, 90% and 81%( similar to deceased donor) while graft survival at 1, 5 and 10 years was 95%,85% and 70 % respectively. Graft survival was poor in females s compared to males.
CDC negative and low titre DSA patients had better outcomes. Patients with compliment fixing DSA against class1 antigens had poor outcomes as compared to DSA against class 11 antigens.
In this study TCMR was mild responded well to treatment. ABMR was associated with graft loss. early rejection had better outcome as compared to late rejection.
Exclusion of those with CDC titre of >1 in 2 may give 10 year graft survival of 75%
ABMR and TCMR diagnosed and treated in first 2weeks post transplantation may have better outcome
Need for HLAi may increase in future even with the presence of PKE
Further studies looking at risk stratification, early diagnosis and management are required
What is this type of study
A retrospective Study
Level of evidence
Level 111
Heba Wagdy
3 years ago
HLA incompatible (HLAi) transplants are associated with high immunological risk.
Although paired exchange programs provided an alternative to HLAi transplants, highly sensitized patients still have difficulties to find compatible donors.
Number of sensitized patients is increasing due to increase in extended criteria donors and lower levels of matching leading to the decreased longevity of these kidneys which increases the need for HLAi transplant.
Studies showed that HLAi transplant is associated with better patient survival than remaining on dialysis or remaining on the waiting list. However, a recent study failed to find any survival benefit in patients with HLAi transplant compared to those remaining on dialysis.
This study aimed to investigate the long-term outcome of HLAi transplant in highly sensitized patients. Materials and methods:
A retrospective study included 134 patients with HLAi transplants.
Patient and graft survival of study cohort were compared with first deceased donor transplant in UK cohort and in UHCW cohort and with standard live donor transplant of UHCW cohort.
Sensitized patients with positive CDC, FCXM or microbead assay were selected, treated with plasmapheresis till achieve negative FCXM before transplant, however, some cases had positive FCXM before transplantation
ABO incompatible transplants were excluded. Results:
Patient and graft survival estimates of HLAi cohort were similar to those seen in first time deceased donor transplant and were significantly worse when compared with standard live donor transplant.
Positive baseline CDC crossmatch (with high titer) was associated with significantly lower graft survival compared to flowcytometry and bead positive groups.
Death censored graft survival was the same when comparing cases with DSAs against either class I, II or both.
Female recipients with DSA had poorer graft and patient survival than male recipients.
Antibody mediated rejection (AMR) significantly reduced graft survival in comparison with TCMR or no rejection.
Early rejection episodes (after 2 weeks post transplant) significantly affect short and long-term graft survival.
>1 rejection episode significantly decreased graft survival. Limitations:
Retrospective study, small number of cases, single center and used non-standardized protocols. Strengths:
Long-term study
Determined points to improve graft outcome in highly sensitized patients as exclusion of cases with highest immunological risk whose CDC titer>1 in 2 and early diagnosis and treatment of AMR and TCMR. Conclusion:
Long-term graft and patient survival in HLAi transplant are the same as deceased donor transplant and worse when compared with standard live donor transplant.
Subgroups associated with poor prognosis are those with positive CDC crossmatch>1 in 2, female patients with antibodies and unresolving or recurring AMR. Type of study: Retrospective study Level of evidence: 3
fakhriya Alalawi
3 years ago
Please summarise this article
Type of this study: A retrospective study
The level of evidence is Level 3
Summary:
This study was conducted at the University Hospitals Coventry, UK where 134 HLA incompatible renal transplantation patients from 2003 to 2018 with a median follow of 6.93 year were analysed retrospectively to estimate patient and graft survivals. Patients who had ABO incompatibility or had combined HLAi and ABOi transplants were excluded. Pre-transplant patients were typically treated with 5 alternate day sessions of double filtration plasmapheresis (DFPP) with the aim of achieving negative or low crossmatch at the time of surgery. Immunosuppression consisted of mycophenolate mofetil, tacrolimus, and prednisolone. Two doses of basiliximab 20mg were given, on days 0 and 4. Post-transplant serum samples for antibody analysis were taken daily for the first 2 wk and then 3 times a week for the next 2 wk.
Outcomes were compared with groups defined by baseline crossmatch status and the type and timings of rejection episodes. Patient survival and death-censored graft survival were analysed. Crossmatch Status Patients were divided into 3 groups: CDC, FC, and Bead-based on the crossmatch assay on the pretreatment/pretransplant serum samples. One-, 5-, and 10-y graft and patient survival were analyzed, and outcomes were compared between the groups. A further subgroup analysis based on gender was also performed in each of the groups. Patients were further categorized based on biopsy-proven definitive evidence of the type of rejection
Results:
· The overall patient survival of this HLAi cohort was 95%, 90%, and 81%; and graft survival was 95%, 85%, and 70% at 1, 5, and 10 y, respectively. This was similar to the first-time deceased donor transplant cohort in the United Kingdom. However, there was a significant difference in overall patient and graft survival between the HLAi study cohort and the standard live donor transplant cohort at the same center.
· The graft survival for pre-treatment cytotoxic-dependent crossmatch (CDC) positive crossmatch group was significantly low at 83%, 64%, and 40% at 1, 5, and 10 y, respectively, which is significantly lower than the other 2 groups (Bead versus CDC, P=0.007, CDC versus Flow, P=0.001, and Bead versus Flow, P=0.837).
· The graft survival for the 9 female CDC positive patients is 75%, 75%, and 30%, which is worse, although not significantly different than the 14 male CDC positive patients with survival of 87%, 59%, and 47% at 1, 5, and 10 y, respectively (P=0.572).
· CDC titer was also seen to influence graft survival. As a group, those with a cytotoxic titer >1 in 2 did significantly worse than those with a titer at 1 in 2 or below. The 1-, 5-, and 10-y graft survival for those with CDC+ titer of 1 in 2 or below was 100%, 92%, and 70%, which is similar to the CDC negative group and not statistically different. However, the group with a CDC+ titer of >1 in 2 have significantly worse outcomes with 1-, 5-, and 10-y survival of 60%, 30%, and 10%.
· The graft survival of the CDC low titer group was similar to the CDC negative group.
· No significant difference was observed in graft survival probability between patients who only had rejection within the first 2 wk following transplantation and those who had no rejection at all. However, there was a significant impact on graft survival if rejection occurred after the first 2 wk of transplantation.
· Experiencing >1 rejection episode caused a significant reduction in graft survival rates in our study.
In conclusion: HLA incompatible renal transplantation remains better therapeutic options for a subgroup of patients who are highly sensitized and difficult to match.
Mohammed Sobair
3 years ago
Please summarise this article:
HLA Antibody Incompatible Renal Transplantation: Long-term Outcomes Similar to Deceased Donor Transplantation:
INTRODUCTION:
Downward trend of HLA antibody incompatible (HLAi) renal transplantation worldwide.
There is an ongoing requirement for HLAi transplantation in patients wherein finding a
compatible donor through PKE is difficult.
For these highly sensitized patients, desensitization could be considered via a combined
approach wherein the recipients are offered a lower immunologic risk donor through the
PKE or directly from their potential donors after risk stratification.
Important to determine the benefit or detriment of HLA incompatible transplantation such
transplantations so that we can use this appropriately to optimize patient care.
MATERIALS AND METHODS:
A retrospective study was conducted at the University Hospitals Coventry and
Warwickshire (UHCW) NHS Trust.
Time of study:
Patients who underwent HLAi renal transplantation between 2003 and 2018 were
included.
Patients sensitized to HLA antigens were selected for antibody incompatible
transplantation if they had reactivity with donor HLA antigens measured by CDC, FC), or
microbead assay (Bead).
Patients who had ABO incompatibility or had combined HLAi and ABOi transplants were
excluded.
Pretransplant patients were typically treated with 5 alternate day sessions of double
filtration plasmapheresis (DFPP) with the aim of achieving negative #ow crossmatch at
the time of surgery.
Immunosuppression Protocols:
Mycophenolate mofetil, tacrolimus, and prednisolone.
Methylprednisolone 500mg was given as a single intravenous dose intraoperatively.
Two doses of basiliximab 20mg were given, at days 0 and 4.
Posttransplant serum samples for antibody analysis were taken daily for the first 2 wk
and then 3 times a week for the next 2 wk.
Treatment of Rejection:
antithymocyte globulin..
Data Analysis:
Patient Survival and Graft Survival:
Patient survival and death-censored graft survival were analyzed.
Crossmatch Status:
Patients were divided into 3 groups:
CDC, FC, and Bead based on the crossmatch assay on the pretreatment/Pretransplant
serum samples.
HLA Antibodies:
The study subjects were categorized based on their donor specific antibody (DSA) status
(class I, class II, class I+II antibody groups). One-, 5-, and 10-y.
Rejection:
Patients were classified as those who had rejection and those who did not based on
renal biopsy as described previously.
RESULTS:
Antibody Variables Relating to Outcome Graft Survival:
Immediately pretreatment DSA levels characterized by Bead positive only, FC positive
(Bead+, CDC–), and CDC positive (FC+, Bead+).
The graft survival for CDC positive group was 83%, 64%, and 40% at 1, 5, and 10 y,
respectively, which is significantly lower than the other 2 groups (Bead versus CDC,
P=0.007, CDC versus Flow, P=0.001, and Bead versus Flow, P=0.837.
The graft survival for FC-positive patient group was 100%, 93%, and 77%, and Bead
positive patient group was 95%, 86%, and 82% at 1, 5, and 10 y, respectively.
Patient Survival:
There was no difference in patient survival between the 3 groups based on DSA levels
characterize.
Rejection on Graft Survival Outcomes:
The 1-, 5-, and 10-y graft survival for patients who had rejection was 93%, 77%, and
54% when compared with those who did not have rejection which was 97%, 91%, and
82%. This was statistically significant.
DISCUSSION:
There has been a lack of published, long-term outcome data for HLAi renal
transplantation and we have addressed this.
The patient and graft survival estimates of this HLAi cohort for 1, 5, and 10 y is 95%,
90%, and 81% and 95%, 85%, and 70%, respectively.
This is similar to the outcomes seen for first time, deceased brain dead donor
transplants in the United Kingdom.
However, there was a significant difference in overall patient and graft survival between
the HLAi study cohort and the standard live donor transplant cohort at our center.
Given the higher risk nature of our cases, more than half of whom had repeat
transplants, this report provides reassurance that HLAi transplantation can, overall, offer
good long-term outcomes for highly sensitized patients with a low prospect of
CONCLUSIONS:
Long-term graft and patient survival for HLAi renal transplantation is similar to deceased
donor transplantation.
mai shawky
3 years ago
· Q1. Summary:
· HLA incompatible transplantation has decreased allover the world due to better matching and increased opportunity to find suitable donor either through: paired kidney donation or exchange in living donor or kidney allocation system in deceased ones.
· However, some of highly sensitized recipients who have been on waiting list for unaccepted long time are prone to HLA incompatible transplant (after certain desensitization protocols).
· The outcome of those cases compared to stay on dialysis may be doubtful, some suggest that it may better.
· This study was carried out to compare outcome with deceased transplant.
· Presence of preformed DSA were measured by either CDC, Flow cytometry or Luminex SAB.
· Recipients with concomitant ABO incompatibility were excluded.
· All cases received 5 sessions of PEX prior to transplant.
· All received tacrolimus based triple immunosuppressive therapy.
· As a conclusion:
o Positive cross match by CDC has worse prognosis( as it means that high titer of preformed DSA to be detectable by such insensitive method) .
o Most important complication was ABMR but advances in early diagnosis and treatment of ABMR the long term survival was acceptable
o Survival benefit wascomparable to deceased donor transplantation
o Females had worse prognosis.
o Preformed DSA against HLA class I has worse graft outcome when compared to DSA against class II.
o ABMR especially if occur after the first 2 weeks of transplantation was was worse than early ABMR.
o TCMR was less frequent, less severe and respond well to treatment
Q2. type of this study? Retrospective cohort Q3. level of evidence? Level III
Tahani Ashmaig
3 years ago
☆HLA Antibody Incompatible Renal Transplantation: Long-term Outcomes
Similar to Deceased Donor Transplantation
¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤
☆INTRODUCTION
______________
▪︎ One of the significant barrier to successful kidney transplantation is anti HLA antibodies.
▪︎ Pretransplant antibody removal, or desensitization, was pioneered to
overcome this barrier.
▪︎There is a decrease of HLA antibody incompatible (HLAi) renal transplantation worldwide with concomitant increase in the paired kidney exchange (PKE) programs. Nevertheless, there is an ongoing requirement for HLAi transplantation in patients with difficult PKE.
▪︎Desensitization could be considered via a combined approach wherein the recipients are offered a lower immunologic risk donor through the PKE or directly from their potential donors after risk stratification.
☆MATERIALS AND METHODS:
______________________________
▪︎A retrospective study which was conducted at the University Hospitals Coventry and Warwickshire (UHCW) NHS Trust,
▪︎One hundred thirty-four HLA incompatible renal transplantation patients from 2003 to 2018 with a median follow of 6.93 y were analyzed retrospectively to estimate patient and graft survivals.
▪︎ These patients were referred from various centers in the United Kingdom and Ireland and all relevant clinical data, immunologic and histocompatibility related data were collated.
▪︎ Patients sensitized to HLA antigens were selected for antibody incompatible transplantation if they had reactivity with donor HLA antigens measured by cytotoxic-dependent crossmatch (CDC), Flow cytometry crossmatches (FC), or microbead assay (Bead).
▪︎Patients who had ABO incompatibility or had combined HLAi and ABOi transplants were excluded. Pretransplant patients were typically treated with 5 alternate day sessions of double filtration plasmapheresis (DFPP).
▪︎ Immunosuppression consisted of mycophenolate mofetil, tacrolimus, and prednisolone
▪︎ The study subjects were categorized based on their DSA status
▪︎Patients with suspicious rejection based on biopsy were included and further categorized into AMR, T-cell–mediated rejection (TCMR), or mixed rejection,
▪︎Further analyses were performed by grouping patients based on the number of rejection episodes
☆RESULTS:
_____________
▪︎ The median follow-up for the HLAi study cohort was 6.93±3.33 y.
▪︎ Outcomes were compared with groups defined by baseline crossmatch status and the type and timings of rejection episodes.
▪︎The patient and graft survival estimates of this HLAi study cohort were compared with:
(i) First-time deceased donor renal
transplant, UK cohort
(ii) First-time deceased donor transplant,
UHCW cohort,
(iii) The standard live donor transplant of
UHCW cohort
Fom the same time period of January 1, 2003 to December 31, 2018
▪︎The overall patient survival was similar to the first-time deceased donor transplant cohort.
▪︎ The graft survival for pretreatment cytotoxic-dependent crossmatch (CDC) positive crossmatch group was significantly low compared with other groups (microbead assay& flow cytometry crossmatch.
▪︎Female patients in general fared worse in both patient and graft survival outcomes in each of the 3 groups based on pretreatment crossmatch, although this did not reach statistical significance.
▪︎Antibody-mediated rejection was the most frequent type of rejection with significant decline in graft survival by 10 y when compared with no rejection.
▪︎ Rejection that occurred or continued to occur after the first 2 wk of
transplantation caused a significant reduction in graft survivals, whereas good outcomes were seen in those with a single early rejection episode.
☆STRENGTHS AND LIMITATIONS:
▪︎ This is a study from a tertiary international referral center for HLAi renal transplantation in the United Kingdom. So, it is not necessarily be extrapolated to other practices.
▪︎ The cases is limited given the constraints of a single center.
▪︎The protocols were not standardized, which could have resulted in a bias in the outcomes.
▪︎ It is the first long-term study of a relatively large cohort of HLAi transplants that shows equivalent graft and patient survival to deceased donor transplantation.
▪︎It identified 2 key areas that allow very good outcomes in what is considered high-risk transplantation. Exclusion of the highest immunologic risk cases, gives an estimated 10-y graft survival of almost 75%. Similarly, those with AMR or TCMR diagnosed and treated within the First 2 wk posttransplantation can be expected to
have a good chance of long-term transplant survival.
☆CONCLUSIONS:
__________________
▪︎Long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation and can be further improved by excluding high-CDC titer cases.
▪︎Antibody-positive female patients show worse long-term survival.
▪︎Resolution of early rejection is associated with good long-term graft survival
◇What is type of this study? Retrospective cohort study
◇What is the level of evidence? Level III
Manal Malik
3 years ago
SUMMARY OF HLA ANTIDODY HLA INCOMPAITABLE TRANSPLAANTATION LONG TERNM OUTCOME SIMLAR DECEASESD TRANSPLA Introduction
HLA specific antibodies is a major barrier for successful therapy transplant, to over come this barrier pretransplant Abs removal can be carry on (desensitization) but still high risk transplant result in unfavrable graft out come.
The reason for the global decrease in HLAi kidney transplantation is:
a) Paired kidney transplant exchange increasing in number
b) The change in the local allocation policies
Combined approach of designation for sensitized patients:
Recipient offer low immunological risk donor through paired exchange
Direct for their optional donor through the PKE
Studies have reported an increase in patients survival with HLAi renal transplantation incomputable to patients remain on the waiting list ,kingdom did not show a survival benefit in patient under go HLAi to those remain on dialysis
Risk associated HLAi renal transplant to over come by
Advances in antibodies detection and screening
HLA typing
Desensitization
Despite all these above graft rejection still obstacle for successful long term outcome in HLAi renal transplant which is more complicated by lacking of effector treatment for AMCR.
MATERIAL AND METHOD PATIENTS
Retrospective study was conducted at the (UHCW) NHS—for patients who under went HLAi renal transplant between2003 and 2018 were included:
All immunological and histocompatibility related data were collated from NHS blood and transplant centre ,Birmingham.
Compared the all patients and graft survival data of HLAi study cohort with:
First time deceased donor renal transplant ,UK cohort
First time deceased donor transplant
UHCW(this study centre) cohort
The standard live donor transplant of UHCW cohort
group of patients selected patients sensitized to HLA Ags for antibodies incompaitabe transplant Alloreactive antibody to donor HLA antigens measured by:
CDC,
Flowcy tometry crossmatch(FC)
micro bead assays bead
Patients excluded from the study:
ABO incompatibility
Combined ABO and HLA incompatible.
Pretransplant patients treated with 5 alternative day session of double filtration plasmapheresis(DFFPP) to achieve negative flow cross matching at the time of surgery although can be done with +ve flow cytometry Immunosuppression Protocols:
Immunosuppression protocol consist of:
MMF
Tacrolimus
Prednisolone
Interoperative single I.Vmethylprednisolone
2 doses of basilixmab 20 mg given at day 0,4.
Posttransplant serum sample for antibodies analysis more taken daily for the first 2 wk and 3 time /wk for the next 2wk. Treatment of rejection
Rejection diagnosis clinically or by renal biopsy
Increase dose of methylprednisolone for 3 days to treat rejection
ATG for steroid resistant HLA antibodies testing
Using microbead assay for characterize and monitoring HLA antibodies
Using serum sample taken in the 24 h preferment to perform lymphocytic crossmatching.
Data Analysis
Patients survival and graft survival:
Patients survival was calculated from the date of renal transplant to date of death or last or last follow up .
Death censored graft survival was calculated from the date of transplant to the date of graft failure or last follow up.
Defined of graft failure as retain to requiring RRT.
Crossmatch Status:
Patients were 3 groups based on crossmatch assays(CDC,FC and Bead) on pretransplant serum sample.
Patients underwent to used pretransplant sample before start DFPP.
Further subgroups analysis based on gender .
CDC group analysis done based on CDC titer level
1-,5-,10-y graft and patients survival urine analgised and out come compared between the groups
HLA Antibody Testing
Study subjects were categorized based on donor specific antibodies status(HLA 1,HLA11 and HLA1+11class) antibody group.
1,5,10 graft survival outcome between the group were analyse.
Rejection
Patients who had rejection compared 1-,5-,10- group survival were analysed .
Based on biopsy and type of rejection categorize:
AMCR
TCMR
Mixed rejection
Data analysed retaining only definitive diagnosis of rejection.
Another analysis performed by group patients based on the number of rejection:
No rejection
One episode of rejection
2or more episode of rejection
The 1,5,10 y graft survival were compared between the 3 group based on the timing of rejection:
Rejection occurring within the first 2wk after transplantation.
After 2wk of transplant
1-,5-,10-y group survival compared between 2 group. Statistical Analysis
Statical analysis of comparison between groups was performed with nonparametric testing for interdependent groups using IBM SPSS Version 25.0 (SPSS Institute, Chicago, IL). RESULTS
134 antibody incompatible transplants finalize from 165 Abs incompatible transplants:
31 excluded for the these reason:
Patent did not provide consent
23 patients had ABO incomputable or both HLA and ABO incomputable
7 patient did not proceed to transplantation.
The median follow up for this study was 6.93+or_3.33y
Patients and graft survival estimate of HLAi study cohort were compared with
first time deceased donor renal transplant cohort.
First-time deceased donor TX UHCW cohort.
The standard live donor transplant of UHCW cohort from the same time period of ja1/ 2003 to dece31/2018.
There was signifint difference with patents and graft survival between the UHCW live donor cohort and deceased donor (UK+UHCW) cohort. Antibody Variables Relating to Outcome Graft Survival
Graft survival was analysed based on immediate pretransplant DSA level detected by CDC,FC and Bead positive test.
Graft survival in CDC +ve group is significs lower than 2 group.
Graft survival for the 9 female CDC +ve patients which is worse although not signified different than 14 male CDC+ve influence the graft survival.
Graft survival analyse based on DSA specify for donor HLA class1,11 or both
Poor graft survival in group with both class1 and 2 DSA overall there was no different between 3 group. Patient Survival
There was no difference in patients survival between 3 group based on DSA level.
Patients survival for CDC+ve and Bead positive group female lower survival but not statical signifince
No difference in patients survival based on CDC titter or Abs specificity to HLA class1,2,or 1+2. Rejection on Graft Survival Outcomes
The 1-,5-,10-y graft survival for patients who had rejection was 93%,77% and 54% when compared with those who did not have rejection was 97%,91% and 82% , there was statically signifince.
P=0.002. Type of Rejection
ABMR signifies lower graft survival than no rejection ,but graft survival of patents with TCMR was no signifying difference in graft survival compared with patients who had no rejection. Number of Rejection Episodes
Graft survival decrease when the number of rejection episodes increase. Timing of rejection
Graft survival was signific lower in those with occurring for the first time after 2wk in contrast to those have rejection with first 2wk,the graft survival did not signified decline. DISCUSSION
HLAi renal transplant have been addressed as there is no publish long term outcome data for HLAi.
2factors affect outcome of HLAi renal transplant:
Measurement of baseline senzatation.
Nature of rejection response.
Graft survival for the group positive based CDC crossmatch is signify lower than FC and Bead positive groups.
No any statical difference in death censored graft survival when comparing cases with either HLAclass1,class2 or both1and 2.
The relationship between pregnancy and subsequent HLAi transplant need further study because
The consequence seem sever.
ABMR was the only rejection type that signify graft survival in compare to TCMR or no rejection in the study
TCMR in HLAi transplant decrease number in the study, seem to be more amenable to successful treatment and does not precipice graft loss.
This extended study show that lower 5 y graft survival in patients with ABMR.
Significant important on graft impact on survival if rejection occurred after the first 2wk of transplant or within and after 2wk of transplant. STRENGTHS AND LIMITATIONS
Limitation of this study:
Study from tertiary internal referral centre so these result may not necessary be extrapolated to other practices.
Limited number of cases..
Retrospective study, the protocol were not standardized ,which could have resulted in a bias in the outcome.
Strength of study:
Long term study
Long cohort of HLAi transplantation shows equivocal graft and patients survival to deceased donor transplant
. Exclusion of the highest immunologic risk cases, defined as those with a CDC titre of >1 in 2. CONCLUSIONS
Long term graft and patients survival for HLAi renal transplant is similar to deceased donor transplant.
Subgroup in the study include :
1- Cross match CDC titter >1 in 2
2-,antibody-positive female patients.
3-Unresolving or recurrence of AMR.
2-type of study
is retrospective cohort study.
3-level 3 evidence.
nawaf yehia
3 years ago
Aricle summary
Although HLA incompatible ( HLAi) renal transplantation still remains one of best therapeutic options for highly sensitized patients ; not much is known about its long-term ( i,e 10 years and above ) graft and patient survival .
This retrospective study was conducted to assess the the overall patient and graft survival data at 1 ,5 & 10 years taking into account the following characteristics :
gender
DSA status ( class I HLA , Class II HLA , Class I+II HLA)
#) Type ( AMR vs TCMR and MIxed)
#) timing ( first 2 w postTx vs after 2w postTx or continuing)
#) treatment
it was shown that :
females had poorer outcomes
No significant difference in DSA specificity groups ( although combined I+II DSA had poorer early graft survival ) .
XM with CDC + ( FC + , Bead + ) had lower graft survival as compared to the other 2 groups :Bead + ( FC – , CDC – ) & FC + ( Bead + , CDC – ) but no differnce in patient survival ( although non statistically significant lower female survival) .
HLAi Tx has similar outcomes to those seen for first time, deceased brain dead donor transplants in the United Kingdom ( where the study was conducted )
having 2 or more frejections has poorer oucome than 1 or no episodes .
AMR ( pure or mixed ) is associated with poorer outcomes
rejection occuring after first 2 weeks of Tx or within the first 2 w and continuing beyond has poorer outcomes .
It is important to note that in CDC+ cases , the higher cytotoxic reactivity ( i.e. CDC titre > 1 in 2 ) matters in determining reduced graft survival. The graft survival of the CDC low titer group was similar to the CDC negative group. This observation therefore should widen access to transplantation to almost half of cases referred with a positive CDC crossmatch who might otherwise be declined.
although no statistical differences in death-censored graft survival was found when comparing cases with either HLA class I, class II, or both class I and II DSAs. It has been shown that patients with complement !xing HLA class I DSAs had inferior graft survival compared with HLA class II DSAs .
CONCLUSIONS
1)Long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation.
2)There are certain subgroups, in particular those with a XM CDC titer of >1 in 2, antibody-positive female patients, and unresolving or recurrence of AMR, which are
associated with a poor prognosis.
Given that the need for HLAi transplantation exists and is likely to increase in the
future, despite PKE programs, further large studies looking at risk strati!cation, early diagnosis, and management of
rejection are needed.
Type of study : Retrospective cohort study Level of evidence : Level III
Batool Butt
3 years ago
SUMMARY:
HLA incompatible renal transplantation is still a reasonable option for highly sensitized renal transplant candidates in which PKE failed, due to improved long term survival to those who remained on dialysis.
This retrospective study conducted from 2003-2018 analyzed 134 patients from a single tertiary center with positive crossmatch( CDC, FCXM & microbes assay) and excluded combined HLAi and ABOi transplant patients or ABO incompatible patients.All patients were followed up for a median of 6.9 years , patient and graft survivals were estimated at the end .Patients were treated pre transplantation with 5 alternate day sessions of double filtration plasmapheresis. Immunosuppression protocol included mycophenolate mofetil, tacrolimus, and prednisolone.Induction with Basiliximab was prescribed on day 0 and 4 with single dose of methylprednisolone(500mg) intraoperatively. Rejection was diagnosed by renal biopsy or clinically and treated with high dose of methylprednisolone and with OKT3 and ATG in resistant cases. RESULTS:
Graft survival at 1, 5 and 10 years was 95%, 85%, and 70% , and the patient survival was 95%, 90%, and 81% which is comparable to deceased donor transplantation.
Graft survival for patients with positive CDC was lower than for positive FCXM& microbes assay. This only occur when CDC titer >1in 2 (low titer CDC show similar survival for negative CDC patients).
Graft survival was worse in females with DSA when compared to male recipients
No difference in death-censored graft survival with either HLA class I, class II, or both class I and II DSAs
The graft survival of patients with AMR at 1-, 5-, and 10-y was significantly lower than those without rejection while graft survival for cases with TMR did not significantly different than cases without rejection.
Early ABMR was associated with better graft outcomes when compared to late rejection CONCLUSION:
Long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation What is type of this study? Retrospective cohort study What is the level of evidence? Level III
Doaa Elwasly
3 years ago
–Summary
Studies demonstrated an increase in patient survival with HLA incompatible renal transplantation in comparison to those on the waiting list or on dialysis
The combination of desensitisation with Paired kidney programs provide to highly sensitised cases a less immunological risk transplantation.
Meanwhile the extended criteria donors render more patients sensitized because of the reduced graft survival and lower levels of HLA matching, therfore increasing the need for HLA incompatible transplantation. Patients and methods
They compared the patient and graft survival data of the HLA incompatible study cohort with the first time deceased donor renal transplant, UK cohort, the first-time deceased donor transplant in their center cohort, and the standard live donor transplant of their center cohort.
Patients were treated pre transplantation with 5 alternate day sessions of double filtration plasmapheresis
Immunosuppression protocol included mycophenolate mofetil, tacrolimus, and prednisolone
Basiliximab was given on day 0 and 4 and methylprednisolone was given 500 mg intraoperatively.
Rejection was diagnosed by renal biopsy or clinically and treated with high dose of methylprednisolone and with OKT3 if it was steroid resistant then ATG replaced OKT3. Results
There was a significant difference in patient survival and graft survival between their center live donor cohort versus their center HLAi cohort and the UK deceased donor cohort versus their center deceased donor cohort .
The graft survival for CDC positive group was lower than FC and Bead positive groups
CDC titre influences graft survival
There was no difference in patient survival between the CDC ,FC and Bead positive groups
The 1-, 5-, and 10-y graft survival for patients who had rejection was lower than those who did not have rejection.
higher relative median frequency on flow cytometry was associated with increased rates of rejection
The graft survival of patients with AMR at 1-, 5-, and 10-y was significantly lower than those without rejection while graft survival for cases with TMR did not significantly differ than cases without rejection.
As the number of rejection episodes increases, the graft survival decreases.
Rejection occurring in the first 2 weeks post transolanation did not significantly lower the graft survival on the other hand rejection occurring primarily after the first 2 weeks post trasnplanation was associated with significantly lower the graft survival. Discussion
HLAi transplantation can provide good long-term outcomes for highly sensitized patients with a low possibility of having a compatible donor.
2 factors that significantly affect the outcome are measurements of sensitization and the nature of the rejection responses.
The graft survival of the CDC low titer group was similar to the CDC negative group increasing the availability of transplantation to some cases with a positive CDC crossmatch who are declined.
Recipients with complement fixing HLA class I DSAs had worse graft survival compared with HLA class II DSAs.
There was a clear bias towards combined class I and II DSAs in the patients with a positive CDC crossmatch this could be rendered to the reaction complexity of the sera facilitating complement activation on donor cells.
Female recipients with DSAs had worse graft and patient survival in comparison to male recipients.
It can be explained by the possibility of proinflammatory state in the postpartum period and increased sensitivity to pregnancy induced antigens resulting in decreased graft and patient survival.
AMR reduced graft survival significantly in comparison to TCMR , indicating that TCMR is more responsive to treatment.
Rejection episode recurrence lead to a significant reduction in graft survival rates
Rejection occurring after the first 2 wk of transplantation are associated with poorer graft survival than those cases suffering from rejection in the first 2 weeks of trasnplanation could be due to intensive monitoring during the first post transplantation period
There were some limitations as being a single centre retrospective study Conclusion
Long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation
–Type of the study is retrospective cohort study
– Level of evidence is level III
Sherif Yusuf
3 years ago
Most of transplant centers try to avoid HLA incompatible transplantation (constitutes 1.5% of transplantation in 2016) due to expected poor outcome and the development of good kidney allocation system (KAS) and national kidney paired donation (KPD) which facilitates deceased and living kidney transplantation and decrease the need for HLA incompatible transplantation.
But actually HLA i kidney transplantation may be the only solution for some transplant recipients who are highly sensitized and cannot find suitable donor through KAS or KPD.
An important barrier in HLA incompatible transplantation is the positive cross match due to preformed DSA, advances in antibody detection and in techniques of desensitization has decreased the risk associated with this type of transplantation
Most important concern in HLA incompatible transplantation is the occurrence of ABMR but again due to advances in early diagnosis and treatment of ABMR the long term survival was acceptable
Survival benefit of incompatible kidney transplantation in comparison with maintaning the patient on dialysis was addressed by several studies and was debatable, some found better and other found no survival benefit
The current study addresses the effect of transplanting HLA incompatible donor graft on long term outcome,
134 HLA incompatible renal transplantation patients with positive CDC or FCM cross match transplanted between 2003, 2018 were followed retrospectively, patients and graft survival were assessed
All patients received around 5 sessions of plasmapheresis to remove preformed DSA, and transplanted with positive FCM cross match, induction received in the form of basiliximab and maintenance tacrolimus based triple therapy
Conclusion
1. Graft survival at 1, 5 and 10 years was 95%, 85%, and 70% , and the patient survival was 95%, 90%, and 81% which is comparable to deseased donor transplantation
2. The worst graft survival was noticed in females with DSA when compared to male recipients
3. Patients with CDC negative or low titer positive cross match have better prognosis CDC titer of >1 in 2 is associated with the worst outcome
4. Patients with preformed complement fixing DSA against HLA class I has inferior graft survival when compared to patients with DSA against class II
5. ABMR especially if occur after the first 2 weeks of transplantation was strongly linked to graft loss, early ABMR were associated with better graft outcome when compared to late rejection
6. TCMR episodes in the current study was less frequent, less severe and respond well to treatment
7. Early successful treatment of ABMR was associated with better outcome
This is a Retrospective study, Level of evidence III
Ibrahim Omar
3 years ago
Please summarise this article :
HLA incompatible renal transplantation is still a reasonable option for highly sensitized renal transplant candidates. however, the long-term graft and patient survivals are still largely unknown.
this article was for a retrospective study for evaluation of the long-term outcome of HLA-incompatible renal transplantation.
this study included 134 highly-sensitized ESRD patients who were transplanted between 2003 and 2018. they were followed up for a median of 6.9 years. the outcome was estimation of patient and graft survivals.
the results were as following :
1- the overall patient survival was 95%, 90% and 81% at 1,5 and 10 years post-transplantation.
2- the overall graft survival was 95%, 85% and 70% at 1,5 and 10 years post-transplantation.
3- these results were similar to the outcome of 1st time deceased-related kidney transplantation.
4- graft survival for patients with pre-treatment CDC+ve crossmatch was 83%, 64% and 40% at 1, 5 and 10 years post-transplantation. these rates of graft survivals were low as compared with other forms of crossmatch as microbead assay and flow cytometry. the outcome of patients with low CDC titre was comparable to that of CDC-ve crossmatch.
5- female patients generally have worse patient and graft survivals although this was statistically insignificant.
6- antibody mediated rejection (AMR) was the most frequent type of rejection with significant decline in graft survival by 10 years
the conclusion was the following :
1- the long-term graft and patient survival of highly sensitized recipients is comparable to deceased donor transplantation.
2-this outcome can be improved by excluding high CDC-titre cases.
3- antibody +ve female patients have worse long-term survival.
What is type of this study?
retrospective study
What is the level of evidence?
III
Ban Mezher
3 years ago
Retrospective study, level 3.
In 1969, DSA were identified & considered as a barrier to successful transplantation. But since introduction of recent desensitization protocoling mid 1980s, transplantation became feasible for sensitized patients, but still had high risk of complications with lower graft outcome. Transplantation of HLAi patients was reduced due to increasing use of PKE & changes in allocation polices. But the need for HLAi transplantation is increased due to failure of PKE to provide good chance for patients with high cPRA.
Several studies show that HLAi transplantation was associated with improvement in patient survival when compared to patients remain on dialysis. Improvement in DSA detection, HLA typing, and desensitization protocol associated with reduce the risk associated with HLAi transplantation.
This study is retrospective include all patients (134) receive HLAi transplantation in single tertiary center from 2003-2018. The study include only patient with positive crossmatch( CDC, FCXM & microbes assay) & exclude patient with ABO incompatible patients & positive crossmatch in ABO incompatible patients.
Enrolled patient receive 5 session of DFPP on alternating day to achieve negative FCXM at time of surgery.
Induction was with 2 doses of basiliximab. All patient maintained on triple ( MMF, Tac & steroids) immunosuppressants. DSA monitored daily in first 2 weeks & 3times/week for second 2 weeks.
Diagnosis of rejection based on finding of graft biopsy & DSA positivity. treatment of rejection was with OKT3 for those who had transplantation before 2007 & with ATG for those who receive transplantation after 2007.
Patient survival calculated from date of transplantation to patient death or last follow-up.
Graft survival calculated from date of transplantation to date of graft loss or last follow-up.
Graft failure mean returns or need to dialysis.
1,5 & 10 year graft survival were analyzed with measurement of class I &II DSA.
Results & discussion:
patient survival for 1,5 & 10 years was 95%, 90%, & 81%, & graft survival was 95%, 85% & 70%. So HLAi transplantation can give good long term outcome for highly sensitized patients.
graft survival for patients with positive CDC was lower than for positive FCXM& microbes assay. This only occur when CDC titer >1in 2 ( low titer CDC show similar survival for negative CDC patients).
Type of DSA ( class I, II or both) had no effect on graft survival.
female patients had worse survival ( graft & patients).
AMR is the only type of rejection that can affect graft outcome ( reduce survival) comparing to TCMR.
timing of rejection was important for short & long term graft survival.
Strength of the study:
tertiary international study
long term study
Limitation of the study:
single center study with limited number of patients.
non standardized protocols.
Conclusion:
long term graft & patients survival was similar to deceased donor transplantation
poor prognostic factors for HLAi transplantation include high CDC titer, Ab positive female patients & un resolving or recurrent AMR
In this study there was a significant difference in patient & graft outcome between HLAi transplant & standard living donor transplantation
Filipe prohaska Batista
3 years ago
Please summarise this article
Paid kidney exchange programs have been decreasing the number of HLA-incompatible kidney transplants (HLAi) and changing local allocation policies. But studies show that HLAi patients have longer survival compared to those who remain on dialysis. Other precautions such as advances in detection and screening of antibody detection, HLA typing, and patient desensitization have improved the outcome of HLAi transplants.
It is a single-center retrospective cohort study from 2003 to 2018.
In pre-transplant protocols, patients with positive FCXM performed five sessions on alternate days of plasmapheresis in an attempt to turn negative antibodies for surgery. Some cases underwent extra sessions and others underwent transplantation in the presence of low titers and weakly positive FCXM.
Basiliximab 20mg on D0 and D4, methylprednisolone 500mg in surgery, and maintenance with tacrolimus, MMF, and prednisone were the most used protocol.
Antibody dosage in the first two weeks was collected daily and then three-time a week.
Patients were divided into three groups based on Crossmatch: CDC, FC, and bead
Rejection was diagnosed by biopsy or clinically (serum creatinine and DSA levels).
Patients with FCXM and beads had better results than those who were CDC-positive. Even titers greater than 1 had significant clinical worsening and graft loss.
There was no difference in mortality in the three groups based on DSA values. However, the higher number of rejections was an important predictor for graft loss. The later rejection time (greater than two weeks) decreased graft survival.
AMR was the only rejection type that significantly reduced graft survival in comparison to TCMR or no rejection in this study. Apparently, earlier rejections were treated more effectively probably by an earlier diagnosis or optimization of the patient’s early immune status.
What is the type of this study?
It is a single-center retrospective cohort study from 2003 to 2018.
Professor, there is no doubt that a transplant between the living is better for the recipient, although when the desensitization process is started, there is no statistical difference in graft survival in the first few years. However, the higher risk of ABMR, de novo lesions, transplant glomerulopathy should be considered in overall graft survival, closely monitoring renal function, biopsies, monitoring of immunosuppressants and DSA levels.
Sahar elkharraz
3 years ago
HLA Antibody Incompatible Renal Transplantation: Long-term Outcomes Similar to Deceased Donor Transplantation
HLAi transplant remain the problem of kidney disease but the best option rather than staying for long time on dialysis.
it’s retrospective study done from 2003 to 2018 where data collected from tertiary center and all patients with HLAi transplant included and patients with ABO incompatible or mixed ABO & HLAi excluded from study.
sensitised patients underwent plasma exchange alternative day before transplant in aim to remove DSA at time of surgery.
Induction therapy started with pulse therapy of steroid intraoperative and basiliximab at day 0 / day 4 post transplant and monitoring of DSA level daily for 2week and 3times /week for 3 weeks
Maintenance therapy by MFF tacrolimus and low dose steroid.
treatment of rejection:
if diagnostic clinical by oliguria and increase renal parameters and increase level of DSA or diagnostic by renal biopsy; it’s treated by steroid and Iv ATG.
Results:
There’s no significant difference between patients survival and graft outcome in HLAi in living donor than deceased transplant patients.
Graft survival worse in patients with CDC positive and in patients with DSA class I.
Graft survival decrease when numbers of rejection episodes increase.
Graft survival decrease when rejection occur after first 2week from transplant rather than patients with early rejection (before 2 weeks).
There’s 2 factors important for graft outcome
first: measuring of baseline sensitisation
second: natural of rejection response.
AMR may worse graft survival in comparison with TCMR.
This study give reassurance patients with HLAI can safely had good outcome of graft survival in sensitised patients same as deceased donor transplant.
A compatible living donor transplant outcome is the best in terms of patient and allograft survival.
This study evaluated the outcome of HLAi transplant as a solution for recipients who are highly sensitized with no other transplantation options. The results showed that transplantation of HLAi allografts has a similar outcome to deceased donor allografts. Therefore, it may be a reasonable option for highly sensitised recipients to proceed for HLAi transplantation (after proper preparation) than to wait on the deceased donor waiting list.
Summary of the article:
This article, retrospectively reviewed performed HLAi-rTX in the UK(UHCW) between 2003 to 2018. Out of 165 patients, 134 patients were analyzed in this study after exclusion of 31 patients for the followings:
· No consent(1 patient).
· Presence of ABOi or combined HLAi and ABOi(23 patients).
· Didn’t proceed to transplant(7 patients).
Patient’s selection was based on the status of crossmatch, and the reactivity to donor HLA antigens was measured by:
· CDCXM.
· FCXM.
· Microbead assay(Bead).
Baseline crossmatch status pretransplant were categorized as follows:
· Bead positive only(FC-ve, CDC-ve).
· Positive FCXM(Bead+ve, CDC-ve).
· CDC+ve (FCXM+ve and Bead+ve).
The used immunosuppression protocol was as follows:
· DFPP on alternate days for 5 sessions.
· Basiliximab 20 mg; 2 doses were given at day 0 and day 4.
· Intra-operative IV dose of 500 mg of Methylprednisolone.
· The triple of TAC, MMF and Prednisolone.
Post-transplant serum sample for antibody analysis were taken daily for the first 2 weeks and then 3 times a week for the next 2 weeks.
For treatment of rejection episodes, the followings were used:
· Combination of 3 doses of Methylprednisolone and OKT-3(before 2007).
· ATG replaced OKT-3 after 2007.
HLAi-rTX outcome
Graft Survival at 1, 5 and 10 y:
· The graft survival for CDC positive group was 83%, 64%, and 40% at 1, 5, and 10 y, respectively. CDC positive group is associated with the worst graft survival in comparison to FCXM+ve and Bead+ve. CDC positive female patients were lower in graft survival than male patients although statistically insignificant.
· The graft survival for FC-positive patient group was 100%, 93%, and 77% at 1, 5, and 10 y, respectively.
· Bead positive patient group was 95%, 86%, and 82% at 1, 5, and 10 y, respectively.
· In respect to DSA specificity(HLA class I,II or both) there there is no significant difference between these 3 groups.
Patient Survival
· no difference in patient survival rate between the 3 groups based on DSA level.
· There was also no difference in patient survival based on CDC titer or antibody specificity to HLA class (I, II, or I+II).
· lower survival in the females but not reaching statistical significance.
Rejection and Graft Survival Outcomes
· The 1-, 5-, and 10-y graft survival for patients who had rejection was 93%, 77%, and 54% when compared with those who did not have rejection which was 97%, 91%, and 82%.
· In patients diagnosed with AMR(including suspicious diagnosis of AMR), the 1, 5, and 10 ygraft survival rate was 91%, 77%, and 49% respectively which was significantly lower than those without rejection.
· The 10-y graft survival of BPAR(AMR) was lower at 39% which was statistically significant.
· The graft survival of patients with TCMR was 87% at 1, 5, and 10 y with no significant difference in overall graft survival when compared with patients who had no rejection.
· The estimated graft survival of patients with mixed rejection is comparable to AMR.( as the numbers were low this did not reach statistical significance).
· The graft survival decreases with increasing number of rejection episodes. With single rejection episode the graft survival rates were 95%, 82%, and 67% and with 2 or more rejection episodes it was 85%, 61%, and 15% at 1, 5, and 10 y, respectively.
· No significant decline in the long-term graft survival when rejection occurs in the first 2 weeks post-transplant with rates of 97%, 91%, and 82% at 1, 5, and 10 y.
· Significantly, lower graft survival in those with rejection episodes after 2 weeks post-transplant with rates of 84%, 49%, and 27%. The rates of graft survival for those with episodes before and after the 2 weeks were 89%, 78%, and 31%. Results were similar when BPAR cases were only analyzed.
Study conclusion
The long-term graft survival and patient survival in HLAi transplant is similar and equivalent to deceased donor transplant.
HLAi transplantation is associated with poor outcome in the followings:
· CDC titer of >1 in 2.
· Antibody-positive female patients.
· Unresolving or recurrence of AMR.
Limitations of the study:
· Single center study. Results may not necessarily be national or extrapolated.
· Limited number of cases.
· Protocols were not standardized(retrospective study).
Strength of the study:
· The first long-term study of a relatively large cohort of HLAi transplants that shows equivalent graft and patient survival to deceased donor transplantation.
Study type: retrospective cohort study
Level of evidence: 2 a
Summary
HLA incompatible renal transplant appears to one of the better options for sensitized patients. This article focuses on long term survival rates of patient and graft in comparison with deceased donor transplant.
Finding compatible donors for highly sensitized patients are a challenge. Desensitization can be considered for these patients however outcome may to always be as expected. With the increase in sensitized patients, then requirement for understanding HLAi transplants increase.
Female patients with DSA could have potential for poorer graft and patient survival in comparison with male patients.
AMR in these patients can have serious graft survival consequences in comparison with TCMR.
Exclusion of highest immunological risk cases, defined as CDC titer of >1 in 2 can give 10 yr graft survival of 75%. AMR or TCMR occurring in the first few weeks post transplant has better chances of survival.
Type of study
Retrospective cohort study
Level of evidence is 3
HLA Antibody Incompatible Renal Transplantation: Long-term Outcomes Similar to Deceased Donor Transplantation
Please summarize this article
HLAi KT has been decreasing in trend as increasing in PKE program and changes in local allocation policies. However, there is need for HLAi KT when there is difficulties in compatible donor through Aim of the study: to determine the long-term outcome in HLA I- transplant including both graft and patient survival over 10 years Follow up and recognize the main factors that affect the long-term outcome.
PKE is difficult. Studies have reported that increased survival with HLAi compared to patient remaining inn dialysis. Although there is advancement in antibodies detection and screening, HLA typing and desensitisation, graft rejection remains a major obstacle in achieving more successful long-term outcome. There is lack of 10-year outcome data for HLAi KT, so this study done to show 10-year patient outcome and graft survival data and determine the key factors that determining long te
Methods and materials:
Retrospective cohort of sensitised patients from UHCW, single tertiary international referring centre with good experience in HLAi kidney transplant , they included total of 134 HLAi KT from 2003-2018, with long follow up period of 10 years (median of 6.9 years). Data including patient clinical characteristics and immunological and histocompatibility data are collected from the NHS and national records from the referring local centres and compare these data to three groups
1 – first time DCD UK cohort group
2-First-time DD transplant UHCW cohort (local centre)
3-standard living donor transplant of UHCW. they include sensitised patients with HLA
AB – by CDCX, FXCM and SAB, they exclude the combined HLAi, ABOi KT
All patients have similar maintenance triple IS with tacrolimus, MMF, prednisolone and induction with basiliximab D0, D4. Antibody measurements were taken daily for 2 weeks then 3 times a week for next 2weeks
All patients have similar maintenance triple IS with tacrolimus, MMF, prednisolone and induction with basiliximab D0, D4
Discussion:
Generally, Long-term graft survival and patients’ survival in this cohort for HLAi transplantation was comparable to DCD cohort but significant difference of graft and patient survival compared to living donor cohort. The centre was high-risk cohort and more than half of cases they had previous transplantation, so the result was encouraging.
Patients with baseline positive CDC XM (CDC titer > 1 in 2) associated with lower graft survival.the graft survival for low CDC titre similar to CDC negative KT.
Female KTR with DSAs had lower graft survival compared to males.pregnancy stimulated DSAs rebound more aggressively . studies in pregnancy showed anti-inflammatory state in pregnancy with increased in the T helper 2 cytokines and immune modulatory proteins with a shift postpartum.
AMR was the only rejection type that significantly reduced graft survival when compared to TCMR or no rejection. Graft survival about 49% at 10 year if there was AMR compared 82.4% if no rejection.
When the acute rejection happens within 2 weeks, the graft survival comparable to those did not had rejection. However when the rejection happens after 2 weeks , it has significant impact on graft survival. More than 1 rejection episode cause significant reduction in graft survival.
Limitations of the study:
Retrospective design from local centre, small sample size with risk of bias
Protocols not standardised
Strength of the study:
Long- term follow up and large cohort of HLAi transplant
What is type of this study?
Retrospective large cohort study
What is the level of evidence?
Level of evidence 3
Level 3 evidence
Retrospective study
Summary :
Studies have reported an increase in patient survival with HLAi renal transplantation in comparison to patients remaining on the waiting list or on dialysis
graft rejection remains a major obstacle in achieving more successful long-term outcomes in HLAi renal transplantations, which is further compounded by the lack of effective treatment for antibody-mediated rejection (AMR).
this report provides reassurance that HLAi transplantation can, overall, offer good long-term outcomes for highly sensitized patients with a low prospect of a compatible donor.
Graft survival for the group with a positive baseline CDC crossmatch is signicantly lower when compared with the FC- and Bead-positive groups.
The graft survival of the CDC low titer group was similar to the CDC negative group
patients with complement xing HLA class I DSAs had inferior graft survival compared with HLA class II DSAs
female recipients with DSAs had poorer graft and patient survival compared with male recipients.
proinammatory state postpartum in general and increased sensitivity to pregnancy induced antigens specically, could result in decreased graft and patient survival.
AMR is considered to be a disease process with a continuum of severity, beginning at any time after transplantation and developing at varying levels of intensity, progressively leading to the development of chronic allograft damage, dysfunction, and loss.
the earlier rejections seem to be more effectively treated, for operational reasons, as above, or perhaps because of fundamental immunologic reasons, thereby limiting AMR progression.
INTRODUCTION
HLA-specific antibodies have been considered a significant barrier to successful kidney transplantation. In the mid-1980s, pretransplant antibody removal, or desensitization, was pioneered to overcome this barrier, but these have tended to be high risk transplants with inferior outcomes. Moreover, in recent years, there has been a downward trend of HLA antibody incompatible (HLAi) renal transplantation worldwide. However; The reason for the global decrease in HLAi kidney transplantation is the concomitant increase in the paired kidney exchange (PKE) programs and the changes in the local allocation policies.
Moreover, with the increase in fast track and extended criteria donors, it is likely that more patients will be sensitized in the coming years because of the reduced
longevity of these kidneys and lower levels of HLA matching,7 thus potentially increasing the need for HLAi transplantation. Therefore, it becomes important to determine the benefits or detriment of such transplantations so that we can use this appropriately to optimize patient care.
Studies have reported an increase in patient survival with HLAi renal transplantation in comparison to patients remaining on the waiting list or on dialysis.
MATERIALS AND METHODS
Patients
A retrospective study was conducted at the University Hospitals Coventry and Warwickshire (UHCW) NHS Trust, which is a UK tertiary international referral center for HLAi transplants.
Patients sensitized to HLA antigens were selected for antibody incompatible transplantation if they had reactivity with donor HLA antigens measured by cytotoxic-dependent crossmatch (CDC), #ow cytometry crossmatches (FC), or microbead assay (Bead). Patients who had ABO incompatibility or had combined HLAi and ABOi transplants were excluded.
Pretransplant patients were typically treated with 5 alternate day sessions of double filtration plasmapheresis (DFPP) with the aim of achieving negative #ow crossmatch at the time of surgery. In some cases, depending on the starting levels of DSA, fewer or more sessions of DFPP were administered and the transplant was performed in the presence of FC-positive crossmatch.
Immunosuppression Protocols
Immunosuppression consisted of mycophenolate mofetil, tacrolimus, and prednisolone. methylprednisolone 500mg was given as a single intravenous dose intraoperatively. Two doses of basiliximab 20mg were given, at days 0 and 4. Posttransplant serum samples for antibody analysis were taken daily for the !rst 2 wk and then 3 times a week for the next 2 wk
Treatment of Rejection
Rejection was diagnosed by renal biopsy or clinically if there was rapid onset of oliguria with a rise in both serum creatinine and in DSA levels. During the initial few years of our AiT program, rejection was treated with high dose of methylprednisolone for 3 d and with OKT3 (muromomab-CD3) if the rejection was steroid resistant. After 2007, antithymocyte globulin (ATG, Genzyme) replaced OKT3
HLA Antibody Testing
Lymphocyte crossmatching was performed at baseline (pretreatment) and using a serum sample taken within 24h pretransplant according to our previous description
Data Analysis
Patient Survival and Graft Survival
Overall, patient survival and death-censored graft survival were analyzed.
Crossmatch Status
Patients were divided into 3 groups: CDC, FC, and Bead based on the crossmatch assay on the pretreatment/pretransplant serum samples. If the patients underwent DFPP before transplant, pretreatment samples before the start of the first DFPP session were used. If not, the pretransplantation serum sample was used. One-, 5-, and 10-y graft and patient survival were analyzed, and outcomes were compared between the groups.
HLA Antibodies
The study subjects were categorized based on their donorspeci!c antibody (DSA) status (class I, class II, class I+II antibody groups). One-, 5-, and 10-y graft survival outcomes between the groups were analyzed.
Rejection
Patients were classified as those who had rejection and those who did not based on renal biopsy.
Each case was confirmed by independent review, and all cases reported as “suspicious rejection” were included as rejection, and comparative 1-, 5-, and 10-y graft survival were analyzed.
Statistical Analysis
Statistical analysis of comparison between groups was performed with nonparametric testing for interdependent groups using IBM SPSS Version 25.0.
CONCLUSIONS
Long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation. There are certain subgroups, in particular those with a crossmatch CDC titer of >1 in 2, antibody-positive female patients, and unresolving or recurrence of AMR, which are
associated with a poor prognosis. Given that the need for HLAi transplantation exists and is likely to increase in the future, despite PKE programs, further large studies looking at risk stratification, early diagnosis, and management of rejection are needed.
Retrospective study to revealed long-term outcomes of HLAi transplantation.
Level evidence III.
Paid kidney exchange programs have been decreasing the number of HLA-incompatible kidney transplants and modifying local allocation policies. It was shown that HLA i patients have better survival in comparison with those who remain on dialysis. Other measures such as advances in detection and screening of antibody detection, HLA typing, and patient desensitization have improved the outcome of HLA i transplants.
This is a single-center retrospective cohort study from 2003 to 2018.
Pre-transplant protocols included that patients with positive FCXM underwent five sessions on alternate days of plasmapheresis aiming at turn to negative antibodies. Some cases underwent extra sessions and others underwent transplantation with low titers and weakly positive FCXM.
Basiliximab 20mg on D0 and D4, methylprednisolone 500mg intraoperatively ,and maintenance with TAC ,MMF, and prednisone were the most commonly used protocol.
Antibody dosage in the first two weeks was evaluated daily and then three-time a week.
Patients were divided into three groups based on XM: CDC, FC, and Luminex.
Rejection was diagnosed by biopsy or clinically ; by serum creatinine and DSA levels.
Patients with FCXM and beads had better results than those who were CDC-positive. Titers greater than 1 had significant clinical worsening and graft loss.
No difference was found in mortality in the three groups based on DSA values but the higher number of rejections was an important predictor for graft loss. The later rejection time ;greater than two weeks ,the decreased graft survival.
AMR was the only rejection pattern which significantly reduced graft survival in comparison with TCMR or no rejection in this study. Earlier rejections were treated more effectively.
Level of evidence: III
1.This article actually describes the outcome of HLAi tx ,where pts with either CDC+/FCXM +/DSA+ included and treated with dfpp mostly 5 sessions and transplanted with crossmatch negative with basiliximab, steroid,tac,mmf triple immunesuppression.
The outcome at 1,5,10yr-
Patient survival 95%,90%,85% respectively
Graft survival 95%,85%,70% respectively
Which was simillar to 1st time deceased donor transplant.
Some groups like-
Female with ab positive
Patient with cdc ag positive >1 out of 2
Recurrent or persistant abmr have prognosis.
This is a retrospective study
Level of evidence 3
This a review with expert opinion reflecting results of previous data so it is with level evidence of IV
This paper draws attention to the importance of sensitization as a rock on the way to successful transplantation stressing the importance of preventing sensitization as a better option.
In our practice, we prefer kidney paired donation in case of very highly sensitized recipients with no mismatch but some centers perform desensitization with IVIG plus plasmapheresis.
summary of the paper:
sensitization is still a big problem. factors contributing are multiple pregnancies, blood transfusions, and prior transplant history. highly sensitized (PRA>85-100%) are at risk of hyperacute rejection.
HLA is extremely polymorphic. since the immune system is not educated for any other HLA molecule than self, the immune response is expected and antibody formation maybe even formed against paternal HLA antigens inherited from the father during the gestational period. sensitization by blood transfusion is less wide than immunization by pregnancy. since Luminex advented the term unacceptable antigens is more dominant than pure PRA measured with CDC. MFI measured by SAB immunoassays should be interpreted carefully due to many factors. prozone effect, antibody titers, and binding capacity are important.
the new kidney allocation system increased the rate of transplantation of highly sensitized patients. Highly sensitized patients (i.E PRA>98%) are given priority to those with 99% or 100%.
the travel of organs through this policy may lead to an increase in cold ischemia in case of long distances. the 6-month graft survival may not be affected but longer graft survival needs to be determined.
Within eurotransplant program, the acceptable mismatch (AM) program reduced the waiting time of highly sensitized patients dramatically.
Kidney paired donation is still superior to transplanting highly sensitized patients. in KPD programs HLA and or AMO incompatible patient-donor couples are entered into dedicated match rounds to find the highest matching possible chances. still transplanting highly sensitized patients through this program is not well utilized. Sill we need to expand the program overseas to maximize benefit.
Desensitization
even after KDP still, there are patients highly sensitized but maybe to less extent. for these and other acceptable sensitized cases, desensitization is a chance for transplantation. very high levels of DSA are still resistant so we need to define suitable criteria for desensitization. high dose IVIG or low dose IVIG plus plasmapheresis are utilized. Novel drugs are now available like bortezomib and streptococcus pyogenes derived IgG- degrading enzyme.
This is a retrospective study of class 3 evidence
HLA incompatible transplants are associated with high immunological risk.
Studies showed that HLAi transplant is associated with better patient survival than dialysis or remaining on the waiting list.
This study aimed to investigate the long-term outcome of HLAi transplant in highly sensitized patients.
Patients and methods:
A retrospective study included 134 patients with HLAi transplants.
Sensitized patients with positive CDC, FCXM or microbead assay were selected, treated with plasmapheresis till achieve negative FCXM before transplant, however, some cases had positive FCXM before transplantation
ABO incompatible transplants were excluded.
Results:
Patient and graft survival estimates of HLAi cohort were similar to those seen in first time deceased donor transplant and were significantly worse when compared with standard live donor transplant.
Positive baseline CDC crossmatch (with high titer) was associated with significantly lower graft survival compared to FCXM and bead positive groups.
Conclusion:
Long-term graft and patient survival in HLAi transplant are worse when compared with standard live donor transplantation but the same as deceased donor transplant .
retrospective cohort study
level IIIB evidence
HLA Antibody Incompatible Renal Transplantation: Long-term Outcomes Similar to Deceased DonorTransplantation
HLA compatible transplantation is the best available option for ESRD patients. With increasing the number of sensitizing patients on the waiting list, this option becomes scantly available. Desensitization has been developed to remove the immunological (DSA) barrier to transplantation. with this still, there is a need for more offers to transplant these patients. Recently, HLA antibody incompatible (HLAi) renal transplant has decreased worldwide. Ultimately; a study of the benefits and risks of HLAi transplantation is needed to optimize patient care. Many studies have shown short and long term benefits of HLAi transplants. Long term outcome is still scanty.
Methodology
A retrospective study includes patients with HLAi renal transplantation between 2003 and 2018. At “UHCW” which is UK tertiary international referral centre for HLAi transplants.
After the collection of the data. Comparison of the overall patient and graft survival data of the HLAi study cohort with (i) first-time deceased donor renal transplant, UK cohort, (ii) first-time deceased donor transplant, (iii) UHCW (their centre) cohort, (iv) the standard live donor transplant of UHCW cohort. Sensitized patients were selected for antibody incompatible transplantation if they had reactivity with donor HLA antigens assessed by CDC, FCXM, or microbead assay. Pretransplant patients underwent double filtration plasmapheresis (DFPP) for about 5 sessions with aim of achieving a negative flow crossmatch at the time of surgery. Some cases depend on DSA level the transplant was performed in presence of positive FCXM. Patients who had ABO incompatibility or had combined HLAi and ABOi transplants were excluded.
Immunosuppression protocol
Induction with methylprednisolone 500 mg single dose and basiliximab two doses. Maintenance with MMF, tacrolimus, and prednisolone.
Postoperatively DSA was monitored daily in the 1st 2wks the on alternate days for the next 2 wks.
The rejection has been diagnosed by the biopsy or clinically in the presence of oliguria with both raise in creatinine and in DSA levels.
It was treated with high dose methylprednisolone for 3 days and OKT3 or ATG if steroid resistance.
HLA Antibody Testing
HLA Abs were analyzed by microbead assay. Lymphocyte crossmatch was performed at baseline (pretreatmaet) and within 24 hrs pretransplant.
Data Analysis:
Classified according to; patient and graft survival, cross-match status, HLA antibodies and rejection (the timing of rejection as rejection occurring within the first 2 weeks after transplantation or after the first 2 weeks post-transplantation.
Result:
Overall, the patient’s survival was 95%, 90%, and 81%. And the graft survival was 95%. 85%, and 70% at 1, 5, and 10 years respectively. This was similar to the first-time deceased donor transplant cohort.
For the pretreatment CDC positive crossmatch group the graft survival was significantly low at 83%. 64%. And 40% at 1, 5, 10 years respectively. Female patients had a worse outcome in both patient and graft survival, although it did not reach significance. This may be due to increased sensitization during pregnancy. those who develop single early rejection episode has a good outcome whereas, those who develop rejection after the first 2 weeks or recurrent rejections have worse outcome.
Conclusion:
In conclusion the long term patient and graft survival outcomes for HLAi transplants similar to deceased donor transplant
Level 3 B evidence.
SUMMARY
The presence of HLA-specific antibodies in a recipient is considered a barrier to transplantation, and the measures that have been used to reduce this antibody load before transplantation, eg, desensitization, have ended up with inferior outcomes. The incidence of HLA-incompatible [HLAi] transplants greatly reduced with the introduction of Paired Kidney Exchange programs and other allocation programs that aid tranaplantation. However, with the increase of these programs, including the Extended Criteria donors and fast track programs that tend to end up with reduced logevity of the grafts, there is going to be ain increase insensitization. Also for the highly sensitized patients who are unable to get donors with the new allocation prgrams HLAi transplants wil have to be done. Hence the need to study the outcomes of HLAi transplants on the graft and patient survival.
Materials and Methods: This is a retrospective study done in University Hospitals Coventry and Warwikshire NHS Trust on patients who underwent HLAi between 2003 and 2018.The overall patient and graft survival data of the cholrt was compared with [i]first time deceased donor renal tramnsplanmt UK cohort, [ii] first time deceased donor transplant, [iii]UHCW cohort and [iv] standard live donor transplant of UHCW cohort. The patients for the HLAi- transplant were selected if they had antibodies detected by CDC, FCXM or Microbead assay. Exclused wer those who had ABO-incompatibiltiy and those who had both ABO-i and HLA-i. The patients were treated with Double Filtration Plasmapheresis [DFPP] with the aim of achieveing a negative FCXM at the time of surgery; the sessions of DFPP varied with the starting levels of DSA.
Immunosuppresion was done with MMF, Tacrolimus and Prednisolone. Methylprednisolone was given as a single Intravenous dose intaroperatively: 500mg. Basiliximab was given 20mg on days 0 and 4. Post transplant serym samples for antibodies count was taken daily for the first 2 weeks and then 3 times a week for the next 2 weeks.
Rejection was diagnosed clinically [oliguria and rising serum creatinine levels] or with a renal biosy. Treatment of rejection was done with high doses of M<ethyprednisolone for 3 days and OKT3 if the rejection was steroid resistant; and after 2007 ATG replaced OKT3.
RESULTS
The median follow up for the HLAi cohort was 6.93 years. On comparingh this HLAi cohort with the 4 listed cohorts, there was
TYPE OF STUDY: Retrospective study
LEVEL OF EVIDENCE: Level 3
Summary:
Introduction :
HLA-I kidney transplant limited to highly sensitization recipients that failed to be involved in KPD and improved in allocation programs with prioritizing the sensitized patients in KAS which helped in improving the better allocation for matched donor and reduce waiting list ,so HLAI transplantation have been reduced its use limited to < 1.5% in UK, but on the other hand there is ongoing increase need for HLAI transplantation due to increasing numbers of highly sensitized kidney transplant especially with the use of fast path of extended criteria donor kidney transplantation with lower graft survival , so we need to assess the benefit of HLAI transplantation as many studies shows conflicting results in short and intermediate FU regarding patient outcome with HLAI transplant compared to stay on long-term dialysis.
Aim of the study: to determine the long-term outcome in HLA I- transplant including both graft and patient survival over 10 years FU and recognize the main factors that affect the long-term outcome.
Methods and martials:
In this retrospective cohort of sensitized patients from single tertiary international referring center with good experience in HLAi kidney transplant , they included total of 134 HLA I kidney transplantation from the period of 2003-2018, with long FU period of 10 years with a median of 6.9 years all data including patient clinical characteristics and immunological and histocompatibility data are collected from the NHS and national records from the referring local centers and compare these data to three groups ,1 – first time DD UK cohort group , 2-Firsttime DD transplant UHCWUHCW cohort ( local centre) , 3-standrard living donor transplant of UHCW. they include sensitized patients with HLA AB – by CDCX, FXCM and SAB, they exclude the combined HALI, ABOI kidney transplant.
All patients have homogenous maintenance triple IS with tacrolimus, MMF, prednisolone and induction with basiliximab D0, D4
Frequent DSA monitoring immediate post transplantation period with daily DSA for the first two then three times /week for two weeks by using SAB assay
Diagnosis of acute rejection based on biopsy proven plus circulatory DSA, they included suspicious cases of rejection and treated as AR.
Factors that associated with long-term outcome including baseline degree of sensitization and rejection form and response to treatment.
Discussion:
Over all long-term graft survival and patients’ survival in this cohort for HLAI transplantation was similar to DD cohort but significant difference of graft and patient survival compared to living donor transplant cohort give the fact that in high-risk cohort more than half of cases they had previous transplantation.
Patients with baseline positive CDCXM The higher level of the CDCXM positivity with titer > 1 in 2 associated with lower graft survival.
Female recipients with DSAs have lower graft survival compared to males, this may be explained in part due to pregnancy associated proinflammatory status with the risk of DSA rebound
AMR which occurs > 2weeks post-transplantation with frequent rejections episodes all associated with lower graft survival compared to no rejection or TCMR.
Lower rate of TCMR in this cohort with comparable graft survival while AMR associated with significantly lower graft survival of 49% compared to > 81% in nonrejection cases.
Limitations of the study:
Retrospective design from local center, small sample size with risk of bias
Protocols not standardized
Strength of the study:
Long- term fu for large cohort of HLA I transplant with compared groups Identify the importance of early diagnosis of AMR before two weeks will improve and impact the long-term grafts survival
What is type of this study?
Retrospective large cohort from single international tertiary with long follow up time that allow for proper assessment of secondary outcome
What is the level of evidence?
Level of evidence 111B
summary
INTRODUCTION
HLA incompatible Tx is preferred when finding a suitable donor for highly sensitized patients is difficult.
Desensitization can be considered. Patients’ with HLA incompatible renal Tx have better survival compared to those who remained on dialysis waiting for compatible donor.
The whole main barrier was graft rejection and lack of effective treatment of ABMR.
MATERIALS AND METHODS
Patients
A retrospective study, Patients who underwent HLAi renal transplantation between .2003 and 2018 were included .They compared the overall patient and graft survival data of the HLAi study cohort with deceased donor renal transplant.
Patients sensitized to HLA antigens were selected for antibody incompatible transplantation if they had reactivity with donor HLA antigens assessed by cytotoxic-dependent cross match (CDC), flow cytometry cross matches (FC), or micro bead assay (Bead).
Pretransplant patients were typically treated with 5 plasmapheresis sessions.
Immunosuppression Protocols
Protocol included mycophenolate mofetil, tacrolimus, and prednisolone.
Methylprednisolone 500 mg was given as a single intravenous dose intraoperative. Two doses of basiliximab 20 mg were administered at days 0 and 4.
Treatment of Rejection
High dose of methylprednisolone for 3 d and with OKT3 (muromomab-CD3) or antithymocyte globulin (ATG, Genzyme) if the rejection was steroid resistant.
HLA Antibody Testing
Lymphocyte cross matching was performed at baseline (pretreatment) and another serum sample taken within 24 h pretransplant.
Data Analysis
Classified according to; patient survival and graft survival, cross match status, HLA antibodies and rejection (the timing of rejection as rejection occurring within the first 2 wk. after transplantation and after the first 2 wk. of transplantation).
RESULTS
HLA incompatible recipients were similar to deceased donor graft recipients about 95%patient survival and 95% graft survival on first year post renal tx.
CDC positive cross match recipients were of lower values (83%) regarding patient survival and graft survival when compared to those of CDC negative cross matches.
Female patients were worse in general regarding patient and graft survival.
ABMR is the most frequent type of rejection associated with decline in graft survival by 10 years when compared to those who had no rejection episodes.
Rejection episodes that occurred early postoperative and lasted for 2 weeks caused significant reduction in graft compared to those of single early rejection treated episode.
CONCLUSIONS
HLA incompatible graft and patient survival is comparable to deceased donor Tx and can achieve more improvement by avoiding high CDC titer cases.
Antibody positive female recipients have worse long term survival.
Resolution of early rejection episode is associated with good long term survival.
Type of study:
Retrospective cohort single center study.
Level of evidence:
level 3.
HLA Antibody incompatible Renal Transplantation.
This is a retrospective cohort single center study at UHCW with level 3 evidence.
The objective is to study the long term outcome for HLA antibody incompatible ( HLAi ) renal transplantation in term of patients and graft survival factors. The study subjects were classified based on their donor specific antibody (DSA) status (class I, class II, class I+II antibody groups). Outcomes were compared with groups defined by baseline crossmatch status and the type and timings of rejection episodes.
A total of 134 HLAi renal transplant recipients were successfully recruited and analyzed from 2003 until 2018 with median follow up of 6.93 years. 82 % were female with mean age of 42.93 years old. The living donor transplant constituted 88.1% and 12% were deceased donor transplant. 45.5% of study population had medical comorbidities before transplantation. 61.9% of study population had previous history of transplantation. Immunosuppressant protocol included mycophenolate mofetil, tacrolimus, and prednisolone. Single dose IV methylprednisolone 500mg was given as a single intravenous dose intraoperatively. Two doses of basiliximab 20mg were given, at days 0 and 4. In the event of rejection, high dose IV methylprednisolone was given for 3 days along with OKT3 (muromomab-CD3) if steroid resistant. Antithymocyte globulin (ATG, Genzyme) replaced OKT3 after 2007. The overall patient survival was 95%, 90%, and 81%; and graft survival was 95%, 85%, and 70% at 1, 5, and 10 years, respectively. The graft survival for pretreatment cytotoxic-dependent crossmatch (CDC) positive crossmatch group was significantly low compared to Bead/CDC, P=0.007 and CDC/Flow, P=0.001 which were statistically significant. Antibody-mediated rejection significantly reduced graft survival. Single early rejection episode has good graft and patient survival. Female had poor graft and patient survival, however it was not statistically significant.
Limitation of this study include retrospective single center study without standardisation of protocol which lead to bias in the outcomes. On the other hand, this is the pilot study that involved long duration with relatively large cohort of HLAi transplants which serve as the strength of this paper.
In summary, long term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation.
Retrospective cohort study and the level of evidence is level 3
Highly sensitized patients are known to be waiting on HD and they have an overall inferior survival as compared to transplanted patients. Paired kidney exchange and HLA i renal transplants are the way forward for these patients who have high level of HLA antibodies. HLA incompatible renal transplantation still remains one of best therapeutic options for a subgroup of patients who are highly sensitized. Not many studies have addressed the long-term graft and patient survival.
This was a retrospective cohort study conducted at UHCW NHS trust. This a center for approved HLAi renal transplants. 134 HLA incompatible renal transplantation patients from 2003 to 2018 with a median follow of 6.93 years were analyzed to estimate patient and graft survivals. Outcomes were compared with groups defined by baseline crossmatch status and the type and timings of rejection episodes. They had also compared the outcome between the first time deceased donor transplant at their center and with the entire cohort. They also compared the results of the HLAi renal transplants with the live transplant cohort at UK and their center.
The overall patient survival was 95%, 90%, and 81%; and graft survival was 95%, 85%, and 70% at 1, 5, and 10 y, respectively. This was similar to the first-time deceased donor transplant cohort. CDC positive cross match transplants fared worse. The graft survival for pretreatment cytotoxic-dependent crossmatch (CDC) positive crossmatch group was significantly low at 83%, 64%, and 40% at 1, 5, and 10 y, respectively. Female patients in general fared worse in both patient and graft survival outcomes in each of the 3 groups based on pretreatment crossmatch, although this did not reach statistical significance. This is probably due to increased sensitization in pregnancy. Antibody-mediated rejection was the most frequent type of rejection with significant decline in graft survival by 10 y when compared with no rejection. Rejection that occurred or continued to occur after the first 2 weeks of transplantation caused a significant reduction in graft survivals whereas good outcomes were seen in those with a single early rejection episode.
so in conclusions the 1, 5, and 10 year HLA incompatible graft and patient survival is comparable to deceased donor transplantation and can be further improved by excluding high-CDC titer cases. Antibody-positive female patients show worse long-term survival. Resolution of early rejection is associated with good long-term graft survival.
Surprising thing in this study why they use baciliximab induction although patients higher immunological risk and should use ATG instead ???
Please summaries this article:
In the United Kingdom, although approximately 40% of patients on the transplant waiting list are sensitized with HLA – specific antibodies, only 1.5% of the kidney transplantations performed last year were HLA i renal transplantations. the reason for the global decrease in HLA i kidney transplantation is the concomitant increase in the paired kidney exchange (PKE) programs and the changes in the local allocation policies.
Studies have reported an increase in patient survival with HLA i renal transplantation in comparison to patients remaining on the waiting list.
a recent study from the United Kingdom did not show any survival benefit in patients undergoing HLA i in comparison to those who remain on dialysis.
graft rejection remains a major obstacle in achieving more successful long-term outcomes in HLA i renal transplantations, which is further compounded by the lack of effective treatment for antibody-mediated rejection (AMR).
MATERIALS AND METHODS
Patients A retrospective study was conducted at the University Hospitals Coventry and Warwickshire (UHCW) NHS Trust, which is a UK tertiary international referral center for HLA i transplants between 2003 and 2018.
Patients sensitized to HLA antigens were selected for antibody incompatible transplantation if they had reactivity with donor HLA antigens measured by cytotoxic-dependent crossmatch (CDC), #ow cytometry crossmatches (FC), or microbead assay (Bead). Patients who had ABO incompatibility or had combined HLAi and ABOi transplants were excluded.
Immunosuppression consisted of mycophenolate mofetil, tacrolimus, and prednisolone as previously described12 and methylprednisolone 500mg was given as a single intravenous dose intraoperatively. two doses of basiliximab 20mg were given, at days 0 and 4. Posttransplant serum samples for antibody analysis were taken daily for the first 2 w k and then 3 times a week for the next 2 wk.
RESULTS:
A total of 165 consecutive antibody incompatible transplants performed at our unit were reviewed and a final of 134 was analyzed in this study. Thirty-one patients were excluded for the following reasons, patient did not provide consent, 23 patients had blood group (ABO) incompatibility, or both HLA and ABO incompatibility, and 7 did not proceed to transplant .
Graft survival was also analyzed with respect to DSA specificity. The transplants were divided on the basis of antibody specificity for donor HLA class I, class II, or both. Although there appeared to be poor early graft survival in the group with both class I and II DSAs, overall, there is no significant difference between these 3 groups .
CONCLUSION
There was no difference in patient survival between the 3 groups based on DSA levels characterized by Bead positive (FC–, CDC–), FC positive (Bead+, CDC–), and CDC positive (FC+, Bead+).
As the number of rejection episodes increases, the graft survival decreases, rejection occurring only within the first 2 wk of transplantation did not cause any significant decline in the long-term graft survival when compared with rejection-free patients with rates of 97%, 91%, and 82% at 1, 5, and 10 y, P=0.95. In contrast, graft survival was significantly lower in those with rejection occurring for the first time after 2 wk .
there was a significant difference in overall patient and graft survival between the HLAi study cohort and the standard live donor transplant cohort at our center. Given the higher risk nature of our cases, more than half of whom had repeat transplants, this report provides reassurance that HLAi transplantation can, overall, offer good long-term outcomes for highly sensitized patients with a low prospect of a compatible donor.
We did not find any statistical differences in death-censored graft survival when comparing cases with either HLA class I, class II, or both class I and II DSAs.
We also saw a trend in which female recipients with DSAs had poorer graft and patient survival compared with male recipients, this does not reach statistical significance.
AMR was the only rejection type that significantly reduced graft survival in comparison to TCMR or no rejection in our study. our analysis extends the time frame and is consistent with findings from similar studies showing significantly lower 5-y graft survival in patients who had AMR.
No signi!cant difference was observed in graft survival probability between patients who only had rejection within the first 2 wk following transplantation and those who had no rejection at all. However, there was a significant impact on graft survival if rejection occurred after the first 2 wk of transplantation.
What is type of this study?
retrospective study
What is the level of evidence?
level 3
This is a retrospective study conducted at at the University Hospitals Coventry and Warwickshire (UHCW) NHS Trust, a UK tertiary international referral center for HLA incompatible transplants. It included 134 HLA incompatible renal transplantation patients from 2003 to 2018.
The patient and graft survival estimates were compared with
1. first-time deceased donor renal transplant, UK cohort
2. first-time deceased donor transplant, UHCW cohort
3. the standard live donor transplant of UHCW cohort from the same time period
There was a significant difference in patient survival between these cohorts between the live UHCW donor and all other donor types .The patient survival was 95% at 1 year, 90% at 5 year, and 81% at 10 years. the graft survival was 95%, 85%, and 70% at 1, 5, and 10 y, respectively.
Graft survival was analyzed in term of baseline (immediately pretreatment) DSA levels characterized by Bead positive only, FC positive (Bead+, CDC–), and CDC positive (FC+, Bead+). The graft survival for CDC positive group was 83%, 64%, and 40% at 1, 5, and 10 y, respectively, which is significantly lower than the other 2 groups. The graft survival for FC-positive patient group was 100%, 93%, and 77%, and Bead positive patient group was 95%, 86%, and 82% at 1, 5, and 10 irrespectively. Within the CDC+ group, overall outcome is poorer for the female recipients, although not statistically significant. In those with a CDC+ titer of 1 in 2 or below, graph survival matches the CDC negative group. The group with a CDC+ titer of >1 in 2 have significantly worse outcome compared with the low titer group .there was difference in graft survival based on class of donor-specific antibodies. The graft survival in antibody-mediated rejection was 91%, 77%, and 49% when compared with rejection-free patients with survival of 97%, 91%, and 82% at 1, 5, and 10 y. Number of rejection episodes if > 2, the graft survival rate were significantly lower. If rejection occurred or continued to occur after 2 wk, the graft survival was significantly lower.
So, long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation.
this is a retrospective cohort so the level of evidence is 3
RETROSPECTIVE STUDY LEVEL OF EVIDENCE 3
INTRODUCTION
MATERILAS AND METHODS
PATIENTS,
IMMUNOSUPPRESION USED,
TREATMENT OF REJECTION,
HLA ANTIBODY TESTING,
DATA ANALYSIS,
HLA ANTIBODIES ,
Rejection
Statistical analysis
RESULTS,
1-Patient survival was 95%, 90%,85%
2-Graft survival was 95%, 85%, 70%
3-The results were similar to the first time deceased donor transplant cohort.
4-Graft survival for pretreatment CDC positive patients were lower at 1,5,10 year compared to other groups.
5-Low CDC titer has results similar to CDC negative patients.
6-Females showed lower patient and graft survival in the 3 groups
7-ABMR was the most frequent type of rejection with significant decline in graft survival by 10 years when compared to no rejection
INTRODUCTION
In the United Kingdom, although approximately 40% of patients on the transplant waiting list are sensitized with HLA-specifc antibodies, only 1.5% of the kidney transplantations performed last year were HLA incompatible (HLAi) renal transplantations. The reason for the global decrease in HLAi kidney transplantation is the concomitant increase in the paired kidney exchange (PKE) programs and the changes in the local allocation policies, allied to desensitization via a combined approach wherein the recipients are offered a lower immunologic risk donor.
Moreover, with the increase in fast track and extended criteria donors, it is likely that more patients will be sensitized in the coming years because of the reduced longevity of these kidneys and lower levels of HLA matching, thus potentially increasing the need for HLAi transplantation. Therefore, it becomes important to determine the benefits or detriment of such transplantations so that we can use this appropriately to optimize patient care.
The graft rejection remains a major obstacle in achieving more successful long-term outcomes in HLAi renal transplantations, which is further compounded by the lack of effective treatment for antibody-mediated rejection (AMR). There is, however, a lack of published on long-term (10 or more y) outcome data for HLAi kidney transplantation. We now have completed suficient cases to be able to show 10-y patient and graft survival data and identify key factors that determine long-term outcomes.
MATERIALS AND METHODS
Patients
Patients who underwent HLAi renal transplantation between 2003 and 2018 were included. Patients sensitized to HLA antigens were selected for antibody incompatible transplantation if they had reactivity with donor HLA antigens measured by cytotoxic-dependent crossmatch (CDC), flow cytometry crossmatches (FC), or microbead assay (Bead). Pretransplant patients were typically treated with 5 alternate day sessions of double filtration plasmapheresis (DFPP) with the aim of achieving negative flow crossmatch at the time of surgery. In some cases, depending on the starting levels of DSA, fewer or more sessions of DFPP were administered and the transplant was performed in the presence of FC-positive crossmatch.
Patients who had ABO incompatibility or had combined HLAi and ABOi transplants were excluded.
Immunosuppression Protocols, Treatment of Rejection and HLA Antibody Testing were standardized.
DATA ANALYSIS
Overall, patient survival and death-censored graft survival were analyzed. Graft failure was de!ned as a return to requiring renal replacement therapy as indicated in the clinical records of the patients.
Patients were divided into 3 groups: CDC, FC, and Bead based on the crossmatch assay on the pretreatment/pretransplant serum samples. If the patients underwent the first double filtration plasmapheresis (DFPP) before transplant, pretreatment samples before the start of DFPP session were used. One-, 5, and 10-y graft and patient survival were analyzed, and outcomes were compared between the groups.
The study subjects were categorized based on their donor specifc antibody (DSA) status (class I, class II, class I+II antibody groups).
Patients were classified as those who had rejection and those who did not based on renal biopsy as described previously. Each case was confirmed by independent review, and all cases reported as “suspicious rejection” were included as rejection, and comparative 1-, 5-, and 10-y graft survival were analyzed.
Statistical analysis of comparison between groups was performed with nonparametric testing for interdependent groups using IBM SPSS Version 25.0 (SPSS Institute, Chicago, IL). Kaplan-Meier death-censored survival analysis was used to calculate all survival estimates. Chi-square (Log Rank [Mantel-Cox]) was used to determine statistical significance in the survival analysis between groups. A probability of values (P value) < 0.05 was considered statistically significant.
RESULTS
Graft survival
Graft survival was also analyzed with respect to DSA specificity. The transplants were divided on the basis of antibody specificity for donor HLA class I, class II, or both. Although there appeared to be poor early graft survival in the group with both class I and II DSAs, overall, there is no signi!cant difference between these 3 groups.
Graft survival was analyzed in term of baseline (immediately pretreatment) DSA levels characterized by Bead positive only, FC positive (Bead+, CDC–), and CDC positive (FC+, Bead+). The graft survival for CDC positive group was 83%, 64%, and 40% at 1, 5, and 10 y, respectively, which is significantly lower than the other 2 groups.
CDC titer was also seen to influence graft survival. As a group, those with a cytotoxic titer >1 in 2 did significantly worse than those with a titer at 1 in 2 or below. The 1-, 5-, and 10-y graft survival for those with CDC+ titer of 1 in 2 or below was 100%, 92%, and 70%, which is similar to the CDC negative group and not statistically different. However, the group with a CDC+ titer of >1 in 2 have significantly worse outcomes with 1-, 5-, and 10-y survival of 60%, 30%, and 10% (P<0.001).
Patiente survival
There was no difference in patient survival between the 3 groups based on DSA levels characterized by Bead positive (FC–, CDC–), FC positive (Bead+, CDC–), and CDC positive (FC+, Bead+).
Rejection on Graft Survival Outcomes
The 1-, 5-, and 10-y graft survival for patients who had rejection was 93%, 77%, and 54% when compared with those who did not have rejection which was 97%, 91%, and 82%. This was statistically significant, P=0.002. There was no increased rejection based on flow crossmatch positivity in this group (P=0.26, Fisher Exact 2-tailed test). However, higher relative median frequency on flow cytometry was associated with increased rates of rejection (Mann-Whitney analysis P=0.024).
Fifty-seven patients had any type of rejection diagnosed by biopsy, including “suspicious” (Table 3). Of these, 47 had AMR with 1-, 5-, and 10-y graft survival of 91%, 77%, and 49%, which is significantly lower than those with no rejection, P <0,001. The graft survival of patients with TCMR no significant difference in overall graft survival when compared with patients who had no rejection, P=0.97.
As the number of rejection episodes increases, the graft survival decreases. This is significantly lower compared with patients who had a single episode (P=0.003) and those who had no rejection (P<0.001).
Rejection occurring only within the first 2 wk of transplantation did not cause any significant decline in the long-term graft survival when compared with rejection-free patients. In contrast, graft survival was signi!cantly lower in those with rejection occurring for the !rst time after 2 wk (P<0.001).
DISCUSSION
The patient and graft survival estimates of our HLAi cohort for 1, 5, and 10 y is 95%, 90%, and 81% and 95%, 85%, and 70%, respectively.
We have looked in detail at 2 factors that signi!cantly affect outcome: measurements of baseline sensitization and the nature of the rejection responses. Graft survival for the group with a positive baseline CDC crossmatch is significantly lower when compared with the FC- and Bead-positive groups. However, in our experience, it is only the higher levels of cytotoxic reactivity, that is CDC titer >1 in 2 that determine reduced graft survival.
AMR was the only rejection type that significantly reduced graft survival in comparison to TCMR or no rejection in our study. And the timing of an early rejection episode, either side of 2 wk posttransplant, is significant in terms of short and long-term graft survival. No significant difference was observed in graft survival probability between patients who only had rejection within the first 2 wk following transplantation and those who had no rejection at all. However, there was a significant impact on graft survival if rejection occurred after the first 2 wk of transplantation or within and after the first 2 wk of transplantation. In addition, experiencing >1 rejection episode caused a signi!cant reduction in graft survival rates in our study.
CONCLUSION
Long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation. There are certain subgroups, in particular those with a crossmatch CDC titer of >1 in 2, antibody-positive female patients, and unresolving or recurrence of AMR, which are associated with a poor prognosis.
This is a primary study, a retrospective cohort.
It has a leves 3 of evidence
Type of the study ;
A retrospective cohort study.
What is the level of evidence?
Level 3
The aim of the study;
Was to compare the overall patient and graft survival data of the HLAi study cohort with (i) first- time deceased donor renal transplant, UK cohort, (ii) first-time deceased donor transplant, (iii) UHCW (our center) cohort, and (iv) the standard live donor transplant of UHCW cohort.
Study area ;
Study was conducted at the University Hospitals Coventry and Warwickshire (UHCW) NHS Trust, which is a UK tertiary international referral center for HLAi transplants.
Ethical approval ;
The study was approved by the Coventry University Ethical committee and the UHCW Research and Development.
Populations;
Patients who underwent HLAi renal transplantation between 2003 and 2018 were included.
Inclusion criteria ;
Patients sensitized to HLA antigens were selected for anti- body incompatible transplantation if they had reactivity with donor HLA antigens measured by cytotoxic-dependent crossmatch (CDC), flow cytometry crossmatches (FC), or micro -bead assay (Bead).
Exclusion criteria ;
Patients who had ABO incompatibility or had combined HLAi and ABOi transplants were excluded.
Immunosuppression protocols;
Consisted of methylprednisolone 500 mg was given as a single intravenous dose intraoperatively and two doses of basiliximab 20 mg were given, at days 0 and 4 as induction therapy . Mcophenolate mofetil, tacrolimus, and prednisolone as maintenance therapy .
Treatment of Rejection;
During the initial few years of our AiT program, rejection was treated with high dose of methyl- prednisolone for 3 d and with OKT3 (muromomab-CD3) if the rejection was steroid resistant. After 2007, antithymocyte globulin (ATG, Genzyme) replaced OKT3.
HLA Antibody Testing ;
Post transplant serum samples for antibody analysis were taken daily for the first 2 wk and then 3 times a week for the next 2 wk .
Data Analysis;
1-Patient Survival and Graft Survival;
Overall, patient survival and death-censored graft survival were analyzed. Patient survival was calculated from the date of renal transplantation to date of death or last follow-up. Death- censored graft survival was calculated from the date of transplantation to the date of graft failure or last follow-up. Graft failure was defined as a return to requiring renal replacement therapy as indicated in the clinical records of the patients.
2- Cross match Status;
Patients were divided into 3 groups: CDC, FC, and Bead based on the cross match assay on the pretreatment/pretransplant serum samples. One-, 5-, and 10-y graft and patient survival were analyzed, and outcomes were compared between the groups.
3- HLA Antibodies ;
The study subjects were categorized based on their donor-specific antibody (DSA) status (class I, class II, class I + II antibody groups). One-, 5-, and 10-y graft survival outcomes between the groups were analyzed.
4- Rejection;
The patients who had rejection were regrouped based on the timing of rejection as rejection occurring within the first 2 wk after transplantation and after the first 2 wk of transplantation. The 1-, 5-, and 10-y graft survivals were compared between the 2 groups.
Statistical analysis ;
Statistical analysis of comparison between groups was performed with nonparametric testing for interdependent groups using IBM SPSS . Kaplan-Meier death-censored survival analysis was used to calculate all survival estimates.Chi-square (Log Rank [Mantel-Cox]) was used to determine statistical significance in the survival analysis between groups.
The result of the study;
Long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation.
Strength of the study ;
This is a study from a tertiary international referral center for HLAi renal transplantation in the United Kingdom. Which has a considerable experience in such transplantations.
limitations of the study;
1-The number of cases is limited given the constraints of a single center.
2-Protocols were not standardized, which could have resulted in
a bias in the outcomes.
3-Exclusion of the highest immunologic risk cases .
Due to improved matching and expanded opportunities to locate a suitable donor, the number of HLA incompatible transplants has reduced around the world, whether through paired kidney donation or exchange in live donors or a kidney allocation system in deceased donors.
However, certain highly sensitized receivers who have been on the waiting list for an interminable period of time without being admitted are at risk of receiving an HLA incompatible donation (after certain desensitization protocols).
Although the result of such instances compared to a continuation of dialysis is questionable, some believe it may be better in some circumstances.
The purpose of this study was to compare the result of a living donor transplant with that of a deceased donor transplant.
The presence of preformed DSA was determined using a variety of methods, including CDC, flow cytometry, and Luminex SAB.
Recipients with simultaneous ABO incompatibility were barred from participating in the study.
In this study, outcomes were compared across groups based on their baseline crossmatch status as well as the kind and timing of rejection events.
The patient and graft survival estimates from this HLAi research cohort were compared to those from the following studies:
I First-time dead donor kidney transplantation
transplantation in the United Kingdom
-Transplantation from a deceased donor for the first time
A cohort of UHCW students
-The standard live donor transplantation procedure consists of Cohort of UHCW
From the same start date of January 1, 2003, to the same end date of December 31, 2018,
In terms of overall patient survival, the results were comparable to those of the first-time dead donor transplant cohort.
Compared to the other groups (microbead assay and flow cytometry crossmatch), the graft survival for the pretreatment cytotoxic-dependent cross matches (CDC) positive crossmatch group was considerably lower.
According to pretreatment crossmatch, female patients had inferior overall results in terms of both patient and graft survival in each of the three groups studied, however, this did not achieve statistical significance in any of them.
When compared to no rejection, antibody-mediated rejection was the most common kind of rejection, and it was associated with a substantial decrease in graft survival after 10 years.
When rejection happened or continues to occur after the first two weeks of pregnancy,
It was shown that transplantation resulted in a considerable reduction in graft survival, whereas those who experienced a single early rejection event had favourable results.
CONCLUSIONS
Patient and graft survival after HLAi renal transplantation are comparable to those after deceased donor transplantation. It is important to note that there are specific populations, including those with an antigen crossmatch CDC titer of >1 in 2, antibody-positive female patients, and patients who have persistent or recurrent AMR, that have a bad prognosis. Given the fact that the need for HLAi transplantation exists and is anticipated to rise in the future, despite the existence of PKE programs, more major studies investigating risk stratification, early diagnosis, and treatment of rejection are required.
-a retrospective cohort study.
-level of evidence3
-There is a global decrease in HLAi kidney transplantation due to an increase in the paired kidney exchange (PKE) programs and the changes in the local allocation policies, but there is an ongoing requirement for HLAi transplantation in patients wherein finding a compatible donor through PKE is difficult.
-Highly sensitized patients, desensitization could be considered via a combined approach wherein the recipients are offered a lower immunologic risk donor through the PKE or directly from their potential donors after risk stratification.
– Several studies have reported an increase in patient survival with HLAi renal transplantation in comparison to patients remaining on the waiting list or dialysis.
– Many studies have also shown reasonable success in short- and medium-term outcomes in graft survival in HLAi renal transplantation.
– Graft rejection remains a major obstacle in achieving more successful long-term outcomes in HLAi renal transplantations, which is further compounded by the lack of effective treatment for antibody-mediated rejection (AMR).
-This retrospective study was conducted at the University Hospitals Coventry and Warwickshire (UHCW) NHS Trust, which is a UK tertiary international referral center for HLAi transplants.
-134 HLA incompatible renal transplantation patients from 2003 to 2018 were involved in this study.
-The patient and graft survival estimates of HLAi cohort for 1, 5, and 10 y is 95%, 90%, and 81% and 95%, 85%, and 70%, respectively that similar to the outcomes seen for the first time, deceased brain dead donor transplants in the United Kingdom and at this study for the same period.
-There was a significant difference in overall patient and graft survival between the HLAi study cohort and the standard live donor transplant cohort at same center.
-More than half of the recipients had repeat transplants.
-Graft survival for the group with a positive baseline CDC crossmatch is significantly lower when compared with the FC- and Bead-positive groups.
-The graft survival of the CDC low titer group was similar to the CDC negative group.
– Patients with complement-fixing HLA class I DSAs had inferior graft survival compared with HLA class II DSAs.
-Female recipients with DSAs had poorer graft and patient survival compared with male recipients.
– proinflammatory state postpartum in general and increased sensitivity to pregnancy induced antigens speci!cally, could result in decreased graft
and patient survival.
-AMR was the only rejection type that significantly reduced graft survival in comparison to TCMR or no rejection in this study.
-The timing of an early rejection episode, either side of 2 wk posttransplant,
is significant in terms of short and long-term graft survival. No significant difference was observed in graft survival probability between patients who only had rejection within the first 2 wk following transplantation and those who had no rejection at all.
-However, there was a significant impact on graft survival if rejection occurred after the first 2 wk of transplantation.
-Intensive monitoring of patients during the first few wk following transplantation,
could detect rejection early, resulting in prompt and efficient management. Whereas, rejection occurring, later on, is often diagnosed when patients present with overt symptoms or upon routine checkups.
-AMR is considered to be a disease process with a continuum of severity,
beginning at any time after transplantation and developing at varying levels of intensity, progressively leading to the development of chronic allograft damage, dysfunction, and loss.
-There are significantly better outcomes in those with the earlier, compared with those with later rejection episodes.
– This is a retrospective study, the protocols were not standardized, which could have resulted in a bias in the outcomes.
-This is the first long-term study of a relatively large cohort of HLAi transplants that shows equivalent graft and patient survival to deceased donor transplantation.
CONCLUSIONS
-Long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation.
-There are certain subgroups, in particular, those with a crossmatch CDC titer of >1 in 2, antibody-positive female patients, and unresolving or recurrence of AMR, which are associated with a poor prognosis.
What is type of this study?
Retrospective study
What is the level of evidence?
III
II. HLA Antibody Incompatible Renal Transplantation: Long-term Outcomes Similar to Deceased Donor Transplantation
Please summarise this article
Introduction
There is a universal decrease in HLAi kidney transplantation due to accompanying increase in the PKE programs & the changes in the allocation policies.
However there is still a need for HLAi transplantation in highly sensitized patients who fail to find a compatible donor through PKE programs.
Data show that HLAi transplantation has a better survival compared to patients who remain on the waiting list or on dialysis.
A recent study from UK however did not show any such survival benefit.
The study
This retrospective study looked into graft survival of the HLAi transplant compared to deceased donor & the standard live donor transplants.
Recipients with anti-HLA DSAs (CDC-XM,FCM-XM or SAB) underwent incompatible transplantation.
ABOi or combined HLAi & ABOi transplants were excluded.
PP sessions were given pre-transplant to achieve -ve FCM-XM.
In some patients the transplant was done in the presence of FCM +ve.
The IS protocol consisted of MMF, tacrolimus, & prednisolone. Methylprednisolone (500 mg IV) was given intra-op. Basiliximab 20 mg was given at days 0 & 4.
DSA was followed post-transplant daily for 2 weeks & 3 times a week for the next 2 weeks.
Rejection was treated with high dose of MP for 3 d plus OKT3 which was replaced by ATG after 2007.
The patient & graft survival outcomes of HLAi cohort for 1, 5, & 10 y were similar to that of the 1st time, deceased BDD transplants in the UK & at the study center for the same time period.
There was a significant difference in patient & graft survival between the HLAi study cohort & the standard live donor transplant cohort at the center.
This study showed that HLAi transplantation offers good long-term results for highly sensitized patients with low chances for a compatible donor.
Graft survival for those with a positive baseline CDC-XM was significantly lower compared to FCM- & SAB-positive groups.
There was no differences in death-censored graft survival in relation to HLA class DSA.
Recipients with complement fixing HLA class I DSAs had inferior graft survival compared with HLA class II DSAs.
Combined class I & II DSAs was prevalent in patients with a positive CDC-XM.
12 graft losses occurred in CDC-XM positive group. The earliest (within 1 y) losses seen among those with combined class I & II DSAs.
Females with DSAs had poorer graft & patient survival compared with male patients.
AMR significantly reduced graft survival compared to TCMR or no rejection.
TCMR HLAi transplantation was more likely to respond to treatment.
The timing of early rejection episode was significant in terms of short & long-term graft survival.
No difference in graft survival between those who only had rejection within the 1st 2 weeks postransplant & those who had no rejection at all.
There was a significant impact on graft survival if rejection occurred after the 1st 2 week or within & after the 1st 2 week of transplantation.
Having >1 rejection episode caused negatively impacted graft survival.
The majority of recipients with >1 rejection episode had an event both within & after 2 week post-transplant.
Intensive monitoring during the 1st few weeks post-transplant can detect rejection early & allow prompt treatment.
Late rejections, on the other hand, are often diagnosed when patients present with overt symptoms or upon routine checkup.
Among those with => 2 rejection episodes, the majority were those with rejections occurring within & after the 1st 2 weeks post-transplant & was therefore associated
with non-resolution of the 1st episode.
The outcomes were significantly better in those with the earlier rejection episodes, which seem to be more effectively treated.
The study identified 2 key points which allow very good outcomes in high-risk transplantation:
(i) Exclusion of the highest immunologic risk cases(CDC titer of >1 in 2) gives a 10-y graft survival estimates of nearly 75%.
(ii) AMR or TCMR diagnosed & treated within the 1st 2 week post-transplant have a good chance of long-term transplant survival.
================================================
What is type of this study?
Retrospective cohort study
================================================
What is the level of evidence?
Level III
As it’s continued to be a major impediment for kidney transplantation, HLA incompatible( HLAi) renal transplantation still considered the best option for highly sensitized and difficult to match patients.However,the long term outcome of the patient and graft is disputed.It was shown that post desensitization transplant of HLAi patients ,associated with high risk and worse outcome. Furthermore the transplantation for HLAi patient featured downward trend all over the world because of growing trend of adopting kidney paired donation (KPD) program.
Nevertheless, HLAi transplantation still considered for those patients failed to find an HLA matched donor in KPD. Furthermore ,desensitization can be offered to those highly sensitized patient via a combined approach wherein lower HLAi profile donor is considered by KPD program.
Experience with HLAi transplantation:
1) Studies have reported an increase in patients survival after HLAi transplantation, in comparison to those on regular hemodialysis.
2) A recent study from UK failed to show any survival benefit for HLAi transplantation over hemodialysis.
3) It was demonstrated in many studies ,a successful short and medium term survival benefits.
4) Graft rejection ,remain the major obstacle for a successful long term HLAi transplantation outcome. That could be compounded by the lack of effective treatment of AMR.
Therefore,this study was conducted to invetigate the long term patient and graft survival in comparison to HLA matched transplantation.
Study Design:
A retrospective study assessed 134 patients had HLA incompatible renal transplantation from 2003 to 2018 with median follow up period of 6.9 years, for graft and patient survival.
The outcomes compared with groups defind by:
1) Baseline cross match status .
2) Type and timing of rejection episodes.
Material and methods:
1)134 patients with positive DSAs were categorized into bead positive,FC positive and CDC positive accordingly,
2) 5 DFPP were performed prior to transplantation, to have negative CDC pre transplant.
3) These patients followed for 6.9 years for patient and graft survival.
4) Acute rejection was diagnosed by allograft biopsy and reported against timing of rejection.
5)Those HLAi patients and graft survival were compared to 3 groups of patients
a) first time deceased donor transplant in UK
b) first time deceased donor in UHCW
c) Life donor transplant
6) Basiliximab was considered for induction,and Tac based protocol for maintenance.
7) Daily assessment of DSAs for first 2 weeks post transplant,then 3 times weekly .
8) 1,5 and 10 years graft and patient survival were compared between the groups.
9) Similarly, survival was assessed according to DSAs phenotype ( anti HLA I,II,and I+II).
10) Before 2 weeks rejection group vs after 2 weeks post transplant rejection group were assessed for its effect on long term survival 1,5 and 10 years.
11) No.of rejection episodes ,3 groups categorized ,no rejection, 1 episode and 2 or more,assessing 1,5 and 10 year survival in each.
Results:
1) graft and patient survival was comparable in HLAi and first deceased in UK and UHCW,and inferior to life donor transplant.
2) There was no difference between class I and class II DSAs on long term outcome
3) Those with CDC positive DSAs showed inferior outcome in comparison to FC or bead positive assay.
4) CDC positivity depend on DSAs titer not mere positivity.
5) Rejection before 2 weeks post transplant has no effect vs after 2 weeks on long term.
6) Similarly,more than one rejection episodes is associated with poor long term outcome in comparison to one or no rejection.
7) AMR is associated with adverse outcome in comparison to CMR.
8) females with DSAs associated with adverse outcome in comparison to male patients.
It’s Retrospective study with evidence level 3.
For highly sensitized patients who can’t find a matched donor HLA in compatible (HLAi) TX is one of the options if compatible.
PKE is not possible or in combination with PKE program.
This article studies 10-year patient and graft survival and its key factors.
A retrospective study was performed in a tertiary referral centers for HLAi TX in UK. Patients with HLAi TX during 2003-2018 were included and their outcome was compared to first DDRT from UK cohort and standard LDRT of UHCW cohort
Highly sensitized patients underwent HLAi TX if they had reactivity with donor HLA Ags by CDC, flow cytometry XM or microbeads assay excluding ABOi TX.
They were treated with 5 alternate day DFPP to achieve negative flow-XM at surgery.
Few patients were transplanted with positive flow-XM.
They received induction therapy with basiliximab and methylprednisolone and maintenance.
The triple therapy with tacrolimus, MMF and prednisolone HLA-abs were monitored using microbeads assay.
XM was performed at baseline and within 24 h pre-transplant patient and graft survival XM were analyzed for three group based on results of CDC flow XM AND microbeads F/W of 6.93 years.
There was no difference between these patients in other cohorts regarding patient and graft survival.
The graft survival for CDC+ group was significantly lower than the other groups and was worse for females in all groups.
Graft survival for patients who had rejection especially AMR was significantly for lower than those without rejection.
Higher RMF (relate MFI) was seen in patients with rejection.
Graft survival was significantly lower in patients with repeated rejection.
Rejections occurring after 2 weeks were significantly associated with lower graft survival.
Earlier completely treated rejection were associated with better outcome.
So in conclusion, long –term graft and patient survival for HLAi TX were similar to DDTXs.
This is retrospective study.
The level of evidence is 3.
Introduction ;
Materials & Methods ;
patients ;
Immune-suppression protocol ;
Treatment of rejection ; Defined by biopsy or clinically if raising Cr, DSA , & oligouria
HLA antibody testing ;
Data Analysis ;
Cross-match status ;
HLA Antibodies ;
Rejection
Statistical analysis
Results ;
Antibody Variables Relating to Outcome
Graft Survival ;
Patient Survival ;
Rejection on Graft Survival Outcomes ;
Type of Rejection ;
Number of rejection ;
Timing of rejection ;
Discussion ;
Strength ; This study identified 2 areas that allows very good outcomes of HLAi transplantation
Limitation ;
Conclusion ;
HLA Antibody Incompatible Renal Transplantation: Long-term Outcomes Similar to Deceased Donor Transplantation.
Retrospective study to revealed long-term outcomes of HLAi transplantation.
Level evidence III.
Introduction:
Transplantation is considered the best modality of RRT, but still HLA incompatibility is an obstacle for successful transplantation and led to increase of waiting list time.
Paired kidney exchange program decreases the number of HLAi transplantation but still we need to proceed to HLAi transplantation to decrease number on waiting list specially many studies revealed that increase in patient survival with HLAi renal transplantation in comparison to patients remaining on the waiting list or on dialysis and other shown reasonable success in short- and medium-term outcomes in graft survival in HLAi renal transplantation.
MATERIALS AND METHODS:
-134 patients who underwent HLAi renal transplantation between 2003 and 2018 were included and treated with 5 alternate day sessions of double filtration plasmapheresis (DFPP) with the aim of achieving negative cross match at the time of surgery.
HLA antigens measured by cytotoxic-dependent cross-match (CDC), flow cytometry cross-matches (FC), or microbeads assay (Bead).
Immunosuppression Protocols:
Methylprednisolone 500mg was given as a single intravenous dose intraoperatively and two doses of basiliximab 20mg were given, at days 0 and 4.
Tacrolimus based triple therapy given and HLA ab analysis were taken daily for the first 2 week and then 3 times a week for the next 2 wk.
Rejection treated early by I.V steroid with OKT3 then the later changed by ATG.
RESULTS:
Patient survival was 95%, 90%, and 81%; and graft survival was 95%, 85%, and 70% at 1, 5, and 10 y, respectively. This was similar to the first-time deceased donor transplant cohort.
One-, 5-, and 10-y patient and graft survival estimates of the different comparative cohorts revealed a significant difference in patient survival between the UHCW live donor cohort versus others, However, there were no significant differences between other pairs in both patient and graft survival.
Graft survival was analyzed in term of baseline DSA level Bead positive only, FC positive (Bead+, CDC–), and CDC positive (FC+, Bead+)showed significantly reduced graph survival when the baseline cross-match was CDC positive.
The group with a CDC+ titer of >1 in 2 have significantly worse outcome compared with the low titer group.
No difference in graft survival based on class of donor-specific antibodies.
There was also no difference in patient survival based on CDC titer or antibody specificity to HLA class (I, II, or I+II).
The 1-, 5-, and 10-y graft survival for patients who had rejection was 93%, 77%, and 54% when compared with those who did not have rejection which was 97%, 91%, and 82%.
Antibody-mediated rejection was the most frequent type of rejection with significant decline in graft survival by 10 y .
Rejection that occurred after the first 2 week of transplantation caused a significant reduction in graft survivals and who developed single attack of rejection has a good outcome.
Discussion:
Still the standard live donor transplant has the best graft and patient survival but HLAi transplantation can, overall, offer good long-term outcomes for highly sensitized patients with a low prospect of a compatible donor.
AMR was the only rejection type that significantly reduced graft survival in comparison to TCMR or no rejection in our study.
The timing of an early rejection episode, either side of 2 week post-transplant, is significant in terms of short and long-term graft survival and number of rejection attacks also affect graft survival.
STRENGTHS AND LIMITATIONS:
Study from trusted specialized center in HLAi transplant, limited number of patients and it is a retrospective study, the protocols were not standardized, which could have resulted in a bias in the outcomes.
CONCLUSIONS:
Long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation.
There is poor prognosis with special group who characterized by crossmatch CDC titer of >1 in 2, antibody-positive female patients, and un-resolving or recurrence of AMR.
Another studies needed to look at risk stratification, early diagnosis, and management of rejection and to increase HLAi transplantation in the future, despite PKE programs .
The reason for the global decrease in HLAi kidney transplantation is the concomitant increase in the paired kidney exchange (PKE) programs and the changes in the local allocation policies. Nevertheless, there is an ongoing requirement for HLAi transplantation in patients wherein finding a compatible donor through PKE is difficult.
MATERIALS AND METHODS
Patients
A retrospective study was conducted
Patients who underwent HLAi renal transplantation between 2003 and 2018 were included.
Patient characteristics include :
Total number of patients Gender, n (%)
Female
Male
Mean age at time of transplantation, mean ± SD Median follow-up time in y, median ± SD Donor-specific antibodies, n (%)
Class I HLA Class II HLA Class I + II HLA
Crossmatch, n (%) Bead positive FC positive CDC positive
Transplantation type, n (%)
Living donor transplantation Deceased donor transplantation
Comorbidities Yes, n (%)
Hypertension, n Hypotension, n Obesity, n Diabetes, n Others, n
No, n (%)
Number of previous transplants, n (%)
0 1 2 3
aTreatment approach, n OKT3
ATG
IVIG Rituximab Campath
They compared the overall patient and graft survival data of the HLAi study cohort with
(i) first- time deceased donor renal transplant, UK cohort, (ii) first-time deceased donor transplant, (iii) UHCW cohort, and (iv) the standard live donor transplant of UHCW cohort.
Sensitization to HLA antigens measured by cytotoxic-dependent cross- match (CDC), flow cytometry crossmatches (FC), or micro- bead assay (Bead). Patients who had ABO incompatibility or had combined HLAi and ABOi transplants were excluded.
Pretransplant patients were typically treated with 5 alter- nate day sessions of double filtration plasmapheresis (DFPP) with the aim of achieving negative flow crossmatch at the time of surgery.
Immunosuppression Protocols:
mycophenolate mofetil, tacrolimus, and prednisolone
methylprednisolone 500 mg was given as a single intravenous dose intraoperatively. Two doses of basiliximab 20mg were given, at days 0 and 4. Posttransplant serum samples for anti- body analysis were taken daily for the first 2 wk and then 3 times a week for the next 2 wk.
Treatment of Rejection:
rejection was treated with high dose of methyl- prednisolone for 3 d and with OKT3 (muromomab-CD3) if the rejection was steroid resistant. After 2007, antithymocyte globulin (ATG, Genzyme) replaced OKT3.
HLA Antibody Testing:
microbead assay
was performed at baseline (pretreatment) and within 24 h pretransplant .
HLA Antibodies
The study subjects were categorized based on their donor- specific antibody (DSA) status (class I, class II, class I+II antibody groups). One-, 5-, and 10-y graft survival outcomes between the groups were analyzed.
Rejection
Patients were classified as those who had rejection and those who did not based on renal biopsy .Patients were further categorized based on biopsy- proven definitive evidence of the type of rejection—AMR, T-cell–mediated rejection (TCMR), or mixed rejection.
Further analyses were performed by grouping patients based on the number of rejection episodes,and the timing of rejection as rejection occurring within the first 2 wk after transplantation and after the first 2 wk of trans- plantation. The 1-, 5-, and 10-y graft survivals were compared between the 2 groups.
RESULTS:
A total of 165 antibody incompatible trans- plants were reviewed and a final of 134 was analyzed in this study. Thirty-one patients were exclude.
The median follow-up for the HLAi study cohort was 6.93 ± 3.33 y.
There was a significant difference in patient survival between patients in this study and the UHCW live donor cohort versus other deceased mentioned cohorts.
Similarly, there was a significant difference in graft survival between the UHCW live donor versus (i) UHCW HLAi , (ii) UK deceased donor ,and (iii) UHCW deceased donor .
The patient and graft survival estimates of this HLAi cohort for 1, 5, and 10 y is 95%, 90%, and 81% and 95%, 85%, and 70%, respectively.
Antibody Variables Relating to Outcome
1-Graft Survival
Graft survival was analyzed in term of baseline (immediately pretreatment) DSA levels characterized by Bead positive only, FC positive (Bead+, CDC–), and CDC positive (FC+, Bead+).
The graft survival for CDC positive group was 83%, 64%, and 40% at 1, 5, and 10 y, respectively, which is significantly lower than the other 2 groups
The graft survival for the 9 female CDC positive patients is 75%, 75%, and 30%, which is worse, although not signifi- cantly different than the 14 male CDC positive patients with survival of 87%, 59%, and 47% at 1, 5, and 10 y, respectively .
FC-positive and Bead-positive groups in which graft survival in females was lower than males, but this did not reach statistical significance.
CDC titer was also seen to influence graft survival .those with a cytotoxic titer >1 in 2 did significantly worse than those with a titer at 1 in 2 or below.
Graft survival was also analyzed with respect to DSA specificity for donor HLA class I, class II, or both. there is no significant difference between these 3 groups .
2-Patient Survival:
There was no difference in patient survival between the 3 groups based on DSA levels characterized by Bead positive (FC–, CDC–), FC positive (Bead+, CDC–), and CDC positive (FC+, Bead+). Patient survival for CDC positive females was lower but not statistically significant when compared with males .
There was a similar trend in the FC-positive and Bead-positive groups with lower survival in the females but not reaching statistical significance. There was also no difference in patient survival based on CDC titer or antibody specificity to HLA class (I, II, or I+II).
Rejection on Graft Survival Outcomes:
The 1-, 5-, and 10-y graft survival outcome for patients who had rejection was lower than those not have rejection .
Type of Rejection:
57 patients had any type of rejection diagnosed by biopsy, including “suspicious.
Of these, 47 had AMR with 1-, 5-, and 10-y graft survival significantly lower than those with no rejection.
AMR was the only rejection type that significantly reduced graft survival in comparison to TCMR or no rejection in this study.
Number of Rejection Episodes:
As the number of rejection episodes increases, the graft survival decreases.
Timing of Rejection:
Rejection occurring only within the first 2 wk of transplantation did not cause any significant decline in the long-term graft survival when compared with rejection-free patients.
In contrast, graft survival was significantly lower in those with rejection occurring for the first time after 2 wk or continuing to occur after the first 2 wk of transplantation compared with rejection-free patients.
There was a significant difference in the graft survival estimates for patients who had rejection in 1 in 2, gives us an estimated 10-y graft survival of almost 75%.
Similarly, those with AMR or TCMR diagnosed and treated within the first 2 wk posttransplantation can be expected to have a good chance of long-term transplant survival.
CONCLUSIONS:
Long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplanta- tion. There are certain subgroups, in particular those with a crossmatch CDC titer of >1 in 2, antibody-positive female patients, and unresolving or recurrence of AMR, which are associated with a poor prognosis. Given that the need for HLAi transplantation exists and is likely to increase in the future, despite PKE programs, further large studies looking at risk stratification, early diagnosis, and management of rejection are needed.
Retrospective study
Level 3
STRENGTHS AND LIMITATIONS:
these results may not necessarily be extrapolated to other practices. Also, the number of cases is limited given the con- straints of a single center. As it is a retrospective study, the protocols were not standardized, which could have resulted in a bias in the outcomes.
2 key areas that allow very good outcomes in high-risk transplantation.
Exclusion of the highest immunologic risk cases, defined as those with a CDC titer of >1 in 2, gives us an estimated 10-y graft survival of almost 75%.
Similarly, those with AMR or TCMR diagnosed and treated within the first 2 wk posttransplantation can be expected to have a good chance of long-term transplant survival.
Retrospective study level of evidence 3
Aim: to estimate patient and graft survival in HLAi renal transplantation
Setting: University Hospital Conventry and Warwickshire NHS trust from 2003 to 2018
Inclusion criteria: patients who underwent HLAi renal transplantation
Exclusion criteria: patients who had ABOi or had combined ABOi & HLAi transplantation
Ethical approval: Conventry University Ethical Committee and the UHCW Research Development.
Patients:total of 134 patients included with median follow up of 6.9 years. sensitized patients were selected if they had either CDC, FCXM, or bead assay positive, desensitized using 5 alternate day sessions of double filtration plasmapheresis with aim of achieving negative FCXM.
IS protocol consist of Tac, MMF, and prednisolone. Intraoperative 500 mg MP single dose was given IV. 2 doses of basiliximab 20 mg were given at day 0 & 4. Post transplant antibody analysis was done daily for the first 2 weeks and then 3 times a week for the next 2 wks.
Rejection was diagnosed by biopsy and treated with high dose of MP for 3days and OKT3, after 2007, ATG replaced OKT3 for treating steroid resistant rejection. Anti-HLA antibodies were monitored by microbead assay, lymphocytes CXM was done pre treatment, and within 24 hr pre transplant.
Patient and graft survival were analyzed ( 1,5,10 year).
Patients were devided into 3 groups according to CXM assay. Also DSA status was used to caterogize the patients ( class 1, class 2, class 1 &2).
Patients were classified as having rejection or not based on biopsy results and the suspecious cases were considered as rejection.
Results:
At 1,5,10 year follow up:
Patient survival was 95%, 90%,85%
Graft survival was 95%, 85%, 70%
The results were similar to the first time deceased donor transplant cohort.
Graft survival for pretreatment CDC positive patients were lower at 1,5,10 year compared to other groups.
Low CDC titer has results similar to CDC negative patients.
Females showed lower patient and graft survival in the 3 groups
ABMR was the most frequent type of rejection with significant decline in graft survival by 10 years when compared to no rejection.
Limitations:
Non standardized protocols may result in biased outcomes
Single center retrospective study
Strength:
Long term study
Large cohort
Conclusion:
One, 5, 10 years HLAi graft and patient survival is comparable to deceased donor transplantation and can be further improved by excluding high CDC titer cases. Antibody positive female cases showed worse long term survival. Resolution of early rejection is associated with good long term graft survival.
Sensitized patients form a major portion of transplant wait-list. Paired kidney exchange program (PKE) is a boon for such patients, although many patients fail to find a donor in PKE. Highly sensitized patients difficult to match can undergo HLA incompatible (HLAi) transplant.
To know the long-term effects of these transplants, a retrospective study was conducted amongst patients with HLAi transplant between 2003 and 2018, comparing the results with first-time deceased donor (UK cohort and centre cohort), as well as live donor (centre cohort) transplant recipients. ABO incompatible transplants were excluded.
The patients were desensitized using plasmapheresis, given induction with Basiliximab and tacrolimus based triple drug maintenance immunosuppression. Post-transplant antibody levels were done daily for 2 weeks and then 3 times a week for next 2 weeks. Steroid resistant rejections were treated with OKT3 (till 2007) and ATG (after 2007).
Patients were divided into 3 groups: CDC, Flow cytometry and Bead based positive crossmatch. One-, five- and ten-year graft and patient survival were analysed.
A total of 134 patients were included in the study with a median follow-up of 6.93 years. The patient and graft survival in the live donor transplant group was significantly better than the deceased donor groups as well as the HLAi group. The patient and graft survival amongst the HLAi group and the deceased donor group (UK cohort and the centre cohort) was similar.
Among the HLAi transplants, patients with CDC positive group, especially the female recipients, had worse graft and patient survival, as compared to the flow cytometry and Bead positive groups. Amongst the CDC positive group, patients with titres ≤1:2 had graft survival rates similar to non-sensitized patients, while those with tires >1:2 had worst graft survival, being 10% at 10 years.
In all the 3 HLAi transplant groups, females had lower survival rates than males, although not significant.
Patients with rejections had significantly lower graft survival rates as compared to those without rejection. Regarding the type of rejection, the patients with AMR or mixed rejection had significantly lower graft survival than those with T cell mediated rejection, which in turn, had graft survival similar to those without rejection. Patients with 2 or more rejection episodes had very low graft survival rates, with 10-year graft survival at 15%.
Patients with rejection occurring within first 2 weeks had graft survival similar to those without any rejection while those with rejections after first 2 weeks or with rejection in first 2 weeks as well as later had significantly lower graft survival.
The study emphasizes that HLAi transplants have outcomes similar to deceased compatible transplants with poorer graft survival in CDC positive with high titre, those with AMR alone or with T cell mediated rejection, having 2 or more rejections, especially after first 2 weeks post-transplant.
The limitations of the study include low number of cases, retrospective study and, being a tertiary centre, results may not be similar in other transplant centres.
The study identifies 3 subsets of HLAi transplant recipients with poor prognosis: namely CDC crossmatch tire >1:2, female patients with DSA and unresolved or recurring AMR.
A retrospective cohort study.
Level 3.
Kidney transplant remains the best possible solution for patients on dialysis.Finding a suitable donor remains a challenge and organ shortage adds on to this dilemma.HLAi transplant is one way of overcoming this challenge.
Studies have reported an increase in patient survival with HLAi renal transplantation in comparison to patients remaining on the waiting list or on dialysis. Many studies have also shown reasonable success in short- and medium-term outcomes in graft survival in HLAi renal transplantation.Advances in antibodies detection and screening, HLA typing, and desensitization of patients have aided in curtailing the risk associated with HLAi renal transplants.
To address this issue a retrospective study was conducted at the University Hospitals Coventry and Warwickshire (UHCW) NHS Trust, which is a UK tertiary international referral center for HLAi transplants.
Patients who underwent HLAi renal transplantation between 2003 and 2018 were included.
They also compared the overall patient and graft survival data of the HLAi study cohort with (i) first- time deceased donor renal transplant,
UK cohort, (ii)
first-time deceased donor transplant,
(iii) UHCW (our center) cohort, and
(iv) the standard live donor transplant of UHCW cohort.
Patients sensitized to HLA antigens were selected for anti- body incompatible transplantation if they had reactivity with donor HLA antigens measured by cytotoxic-dependent cross- match (CDC), flow cytometry crossmatches (FC), or micro- bead assay (Bead). Patients who had ABO incompatibility or had combined HLAi and ABOi transplants were excluded.
Pretransplant patients were typically treated with 5 alternate day sessions of double filtration plasmapheresis (DFPP) with the aim of achieving negative flow crossmatch at the time of surgery. In some cases, depending on the starting levels of DSA, fewer or more sessions of DFPP were administered and the transplant was performed in the presence of FC- positive cross match.
Immunosuppression consisted of mycophenolate mofetil, tacrolimus, and prednisolone methylprednisolone 500 mg was given as a single intravenous dose intraoperatively. Two doses of basiliximab 20mg were given, at days 0 and 4. Posttransplant serum samples for antibody analysis were taken daily for the first 2 wk and then 3 times a week for the next 2 weeks.
RESULTS
A total of 165 consecutive antibody incompatible transplants performed were reviewed and a final of 134 was analyzed in this study. The median follow-up for the HLAi study cohort was 6.93 ± 3.33 y.
The overall patient survival was 95%, 90%, and 81%; and graft survival was 95%, 85%, and 70% at 1, 5, and 10 y, respectively. This was similar to the first-time deceased donor transplant cohort. The graft survival for pretreatment cytotoxic-dependent crossmatch (CDC) positive crossmatch group was significantly low at 83%, 64%, and 40% at 1, 5, and 10 y, respectively, compared with other groups (Bead/CDC, P = 0.007; CDC/Flow, P=0.001; and microbead assay/flow cytometry crossmatch, P=0.837), although those with a low CDC titer (<1 in 2) have comparable outcomes to the CDC negative group. Female patients in general fared worse in both patient and graft survival outcomes in each of the 3 groups based on pretreatment crossmatch, although this did not reach statistical significance. Antibody-mediated rejection was the most frequent type of rejection with significant decline in graft survival by 10 y when compared with no rejection (P<0.001). Rejection that occurred or continued to occur after the first 2 wk of transplantation caused a significant reduction in graft survivals (P < 0.001), whereas good outcomes were seen in those with a single early rejection episode.
Conclusions. One-, 5-, and 10-y HLA incompatible graft and patient survival is comparable to deceased donor transplantation and can be further improved by excluding high-CDC titer cases. Antibody-positive female patients show worse long-term survival. Resolution of early rejection is associated with good long-term graft survival.
INTRODUCTION
-HLA-specific antibodies have been considered a significant barrier to successful kidney transplantation
-desensitization could be considered via a combined approach wherein the recipients are offered a lower immunologic risk donor through the PKE or directly from their potential donors after risk stratification.
-The increase in number of patients and increase in number of sensitized patients together with shortage of doner increased the need for HLAi transplantation.
-Transplantation even of incompatible donor is associated with improved patient’s survival as compared with patients on dialysis although some studies found no difference.
Methods:
This is a retrospective study included 134 renal transplant recipients with HLAi transplants between 2003 and 2018 with follow-up for 6.93 years .
They also compared the overall patient and graft survival data of the HLAi study cohort with (i) fist-time deceased donor renal transplant, UK cohort,
(ii) first time deceased donor transplant.
(iii) UHCW (their center) cohort, and (iv) the standard live donor transplant of UHCW cohort.
Sensitized patients with positive CDC, FCXM or microbead assay were selected, treated with plasmapheresis till achieve negative FCXM before transplant
Patients who had ABO incompatibility or had combined HLAi and ABOi transplants were excluded.
*Desensitization by
alternate day sessions of double filtration plasmapheresis (DFPP) till they become negative FCXM .
In some cases, transplant was performed in the presence of FC-positive crossmatch.
•Immunosuppression Protocols
-methylprednisolone 500mg ,single intravenous dose intraoperatively.
-Triple immunosuppression with mycophenolate mofetil, tacrolimus, and prednisolone.
– Two doses of basiliximab 20mg were given, at days 0 and 4.
-rejection episodes treated by high dose of methyl-prednisolone for 3 days with ATG replaced OKT3 after 2007 .
•Results :
-The patient and graft survival estimates for HLAi cohort for 1, 5, and 10 y is 95%, 90%, and 81% and 95%, 85%, and 70%, respectively.
-results were similar to the outcomes for first time, deceased donor transplants .
– significant difference in overall patient and graft survival between the HLAi study cohort and the standard live donor transplant cohort .
-Graft survival with a positive baseline CDC crossmatch is significantly lower than compared with the FC- and Bead-positive groups.
-graft survival of the CDC low titer group was similar to the CDC negative group.
-no statistical differences in death-censored graft survival when comparing cases with either HLA class I DSA, class II, or both.
**this report provides reassurance that HLAi transplantation can, overall, offer good long-term outcomes for highly sensitized patients with a low prospect of a compatible donor.
-female recipients with DSAs had poorer graft and patient survival compared with male recipients but no significant.
-AMR was the only rejection type that significantly reduced graft survival in comparison to TCMR or no rejection.
-No significant difference in graft survival between patients who had rejection within the 2 wk following transplantation and those who had no rejection at all.
-there was a signifiantly better outcomes in patients with the earlier, compared with those with later rejection episodes .
•STRENGTHS AND LIMITATIONS :
-first long-term study of a relatively large cohort of HLAi transplants that shows equivalent graft and patient survival to deceased donor transplantation.
– Exclusion of the highest immunologic risk cases, those with a CDC titer of >1 in 2, gives us an estimated 10-y graft survival of almost 75%. Similarly, those with AMR or TCMR diagnosed and treated within the 2 wk posttransplantation.
-retrospective study, the protocols were not standardized,
It is retrospective study level of evidence III.
The paired kidney exchange programs and the changes in the local allocation policies have led to a global decrease in HLAi kidney transplantation.
But with the use of extended criteria donors, retransplantation, reduced longevity of renal allografts, it is likely that more patients will be sensitized with potential increasing in the need for HLAi transplantation.
A retrospective study was conducted in UK at the University Hospitals Coventry and Warwickshire (UHCW) NHS Trust to evaluate the long terms outcomes of transplantation in HLA incompatible patients. Patients who underwent HLAi renal transplantation between 2003 and 2018 were included in the analysis.
The overall patient and graft survival data of the HLAi study cohort were compared to:
1- first-time deceased donor renal transplant, UK cohort,
2- first-time deceased donor transplant,
3- UHCW cohort
4- The standard live donor transplant of UHCW cohort.
Immunosuppression consisted of MMF, TAC, and prednisolone.
A total of 134 antibody incompatible transplants was analyzed in this study. The median follow-up for the HLAi study cohort was 6.93±3.33 y.
Results
Patient survival at 1,5 and 10 years was 95%, 90%, & 81%, whereas graft survival was 95%, 85% & 70%.
Graft survival in patients with positive CDC was lower than for positive FCXM and beads assay. This only occur when CDC titer >1in 2.
There was no impact on graft survival among different types of DSA (class I, II or both).
Recipient sex was shown to be of significance, because female patients had worse graft and patient survival.
AMR was strongly liked to graft outcome in terms of reduce survival, comparing to TCMR. Timing of rejection was important for short and long term graft survival.
Conclusion
Long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation. Whereas living donor kidney was associated with better graft and patient survival in the short and long term.
This article highlights the outcome of HLA incompatible (HLAi ) renal transplantation on long term outcomes. Kidney transplantation in patients who are HLA incompatible is risky and carries poor outcome . With the development of paired kidney donation and kidney allocation system it is possible to do renal transplants using living and deceased donors . For some patients who are HLA incompatible and cannot find a suitable donor through paired kidney donation or KAS, the only option is HLA incompatible kidney transplants which can have a poor outcome. The pain main problem here remains a positive cross match due to preformed antibodies. However with the development of newer methods to deals with DSA has made it possible to do kidney transplants in such HLAi patients. In spite the fact that there is high risk ABMR but early detection can improve prognosis. Different studies have shown different outcomes in HLAi transplants when compared to no transplant and dialysis. Some studies have shown improved outcomes while other have shown no benefit.
In this study 134 HLAi transplants were assessed between 2003-2008 for long term graft outcome. All patients had 5 sessions of PLEX, and transplanted with positive FXCM. Induction with Basiliximab and maintenance with Tacrolimus, MMF and steroids.
Outcome of study
Patient survival at 1, 5 and 10 years was 95%, 90% and 81%( similar to deceased donor) while graft survival at 1, 5 and 10 years was 95%,85% and 70 % respectively. Graft survival was poor in females s compared to males.
CDC negative and low titre DSA patients had better outcomes. Patients with compliment fixing DSA against class1 antigens had poor outcomes as compared to DSA against class 11 antigens.
In this study TCMR was mild responded well to treatment. ABMR was associated with graft loss. early rejection had better outcome as compared to late rejection.
Exclusion of those with CDC titre of >1 in 2 may give 10 year graft survival of 75%
ABMR and TCMR diagnosed and treated in first 2weeks post transplantation may have better outcome
Need for HLAi may increase in future even with the presence of PKE
Further studies looking at risk stratification, early diagnosis and management are required
What is this type of study
A retrospective Study
Level of evidence
Level 111
HLA incompatible (HLAi) transplants are associated with high immunological risk.
Although paired exchange programs provided an alternative to HLAi transplants, highly sensitized patients still have difficulties to find compatible donors.
Number of sensitized patients is increasing due to increase in extended criteria donors and lower levels of matching leading to the decreased longevity of these kidneys which increases the need for HLAi transplant.
Studies showed that HLAi transplant is associated with better patient survival than remaining on dialysis or remaining on the waiting list. However, a recent study failed to find any survival benefit in patients with HLAi transplant compared to those remaining on dialysis.
This study aimed to investigate the long-term outcome of HLAi transplant in highly sensitized patients.
Materials and methods:
A retrospective study included 134 patients with HLAi transplants.
Patient and graft survival of study cohort were compared with first deceased donor transplant in UK cohort and in UHCW cohort and with standard live donor transplant of UHCW cohort.
Sensitized patients with positive CDC, FCXM or microbead assay were selected, treated with plasmapheresis till achieve negative FCXM before transplant, however, some cases had positive FCXM before transplantation
ABO incompatible transplants were excluded.
Results:
Patient and graft survival estimates of HLAi cohort were similar to those seen in first time deceased donor transplant and were significantly worse when compared with standard live donor transplant.
Positive baseline CDC crossmatch (with high titer) was associated with significantly lower graft survival compared to flowcytometry and bead positive groups.
Death censored graft survival was the same when comparing cases with DSAs against either class I, II or both.
Female recipients with DSA had poorer graft and patient survival than male recipients.
Antibody mediated rejection (AMR) significantly reduced graft survival in comparison with TCMR or no rejection.
Early rejection episodes (after 2 weeks post transplant) significantly affect short and long-term graft survival.
>1 rejection episode significantly decreased graft survival.
Limitations:
Retrospective study, small number of cases, single center and used non-standardized protocols.
Strengths:
Long-term study
Determined points to improve graft outcome in highly sensitized patients as exclusion of cases with highest immunological risk whose CDC titer>1 in 2 and early diagnosis and treatment of AMR and TCMR.
Conclusion:
Long-term graft and patient survival in HLAi transplant are the same as deceased donor transplant and worse when compared with standard live donor transplant.
Subgroups associated with poor prognosis are those with positive CDC crossmatch>1 in 2, female patients with antibodies and unresolving or recurring AMR.
Type of study: Retrospective study
Level of evidence: 3
Summary:
This study was conducted at the University Hospitals Coventry, UK where 134 HLA incompatible renal transplantation patients from 2003 to 2018 with a median follow of 6.93 year were analysed retrospectively to estimate patient and graft survivals. Patients who had ABO incompatibility or had combined HLAi and ABOi transplants were excluded. Pre-transplant patients were typically treated with 5 alternate day sessions of double filtration plasmapheresis (DFPP) with the aim of achieving negative or low crossmatch at the time of surgery. Immunosuppression consisted of mycophenolate mofetil, tacrolimus, and prednisolone. Two doses of basiliximab 20mg were given, on days 0 and 4. Post-transplant serum samples for antibody analysis were taken daily for the first 2 wk and then 3 times a week for the next 2 wk.
Outcomes were compared with groups defined by baseline crossmatch status and the type and timings of rejection episodes. Patient survival and death-censored graft survival were analysed. Crossmatch Status Patients were divided into 3 groups: CDC, FC, and Bead-based on the crossmatch assay on the pretreatment/pretransplant serum samples. One-, 5-, and 10-y graft and patient survival were analyzed, and outcomes were compared between the groups. A further subgroup analysis based on gender was also performed in each of the groups. Patients were further categorized based on biopsy-proven definitive evidence of the type of rejection
Results:
· The overall patient survival of this HLAi cohort was 95%, 90%, and 81%; and graft survival was 95%, 85%, and 70% at 1, 5, and 10 y, respectively. This was similar to the first-time deceased donor transplant cohort in the United Kingdom. However, there was a significant difference in overall patient and graft survival between the HLAi study cohort and the standard live donor transplant cohort at the same center.
· The graft survival for pre-treatment cytotoxic-dependent crossmatch (CDC) positive crossmatch group was significantly low at 83%, 64%, and 40% at 1, 5, and 10 y, respectively, which is significantly lower than the other 2 groups (Bead versus CDC, P=0.007, CDC versus Flow, P=0.001, and Bead versus Flow, P=0.837).
· The graft survival for the 9 female CDC positive patients is 75%, 75%, and 30%, which is worse, although not significantly different than the 14 male CDC positive patients with survival of 87%, 59%, and 47% at 1, 5, and 10 y, respectively (P=0.572).
· CDC titer was also seen to influence graft survival. As a group, those with a cytotoxic titer >1 in 2 did significantly worse than those with a titer at 1 in 2 or below. The 1-, 5-, and 10-y graft survival for those with CDC+ titer of 1 in 2 or below was 100%, 92%, and 70%, which is similar to the CDC negative group and not statistically different. However, the group with a CDC+ titer of >1 in 2 have significantly worse outcomes with 1-, 5-, and 10-y survival of 60%, 30%, and 10%.
· The graft survival of the CDC low titer group was similar to the CDC negative group.
· No significant difference was observed in graft survival probability between patients who only had rejection within the first 2 wk following transplantation and those who had no rejection at all. However, there was a significant impact on graft survival if rejection occurred after the first 2 wk of transplantation.
· Experiencing >1 rejection episode caused a significant reduction in graft survival rates in our study.
In conclusion: HLA incompatible renal transplantation remains better therapeutic options for a subgroup of patients who are highly sensitized and difficult to match.
Please summarise this article:
HLA Antibody Incompatible Renal Transplantation: Long-term Outcomes Similar to Deceased Donor Transplantation:
INTRODUCTION:
Downward trend of HLA antibody incompatible (HLAi) renal transplantation worldwide.
There is an ongoing requirement for HLAi transplantation in patients wherein finding a
compatible donor through PKE is difficult.
For these highly sensitized patients, desensitization could be considered via a combined
approach wherein the recipients are offered a lower immunologic risk donor through the
PKE or directly from their potential donors after risk stratification.
Important to determine the benefit or detriment of HLA incompatible transplantation such
transplantations so that we can use this appropriately to optimize patient care.
MATERIALS AND METHODS:
A retrospective study was conducted at the University Hospitals Coventry and
Warwickshire (UHCW) NHS Trust.
Time of study:
Patients who underwent HLAi renal transplantation between 2003 and 2018 were
included.
Patients sensitized to HLA antigens were selected for antibody incompatible
transplantation if they had reactivity with donor HLA antigens measured by CDC, FC), or
microbead assay (Bead).
Patients who had ABO incompatibility or had combined HLAi and ABOi transplants were
excluded.
Pretransplant patients were typically treated with 5 alternate day sessions of double
filtration plasmapheresis (DFPP) with the aim of achieving negative #ow crossmatch at
the time of surgery.
Immunosuppression Protocols:
Mycophenolate mofetil, tacrolimus, and prednisolone.
Methylprednisolone 500mg was given as a single intravenous dose intraoperatively.
Two doses of basiliximab 20mg were given, at days 0 and 4.
Posttransplant serum samples for antibody analysis were taken daily for the first 2 wk
and then 3 times a week for the next 2 wk.
Treatment of Rejection:
antithymocyte globulin..
Data Analysis:
Patient Survival and Graft Survival:
Patient survival and death-censored graft survival were analyzed.
Crossmatch Status:
Patients were divided into 3 groups:
CDC, FC, and Bead based on the crossmatch assay on the pretreatment/Pretransplant
serum samples.
HLA Antibodies:
The study subjects were categorized based on their donor specific antibody (DSA) status
(class I, class II, class I+II antibody groups). One-, 5-, and 10-y.
Rejection:
Patients were classified as those who had rejection and those who did not based on
renal biopsy as described previously.
RESULTS:
Antibody Variables Relating to Outcome Graft Survival:
Immediately pretreatment DSA levels characterized by Bead positive only, FC positive
(Bead+, CDC–), and CDC positive (FC+, Bead+).
The graft survival for CDC positive group was 83%, 64%, and 40% at 1, 5, and 10 y,
respectively, which is significantly lower than the other 2 groups (Bead versus CDC,
P=0.007, CDC versus Flow, P=0.001, and Bead versus Flow, P=0.837.
The graft survival for FC-positive patient group was 100%, 93%, and 77%, and Bead
positive patient group was 95%, 86%, and 82% at 1, 5, and 10 y, respectively.
Patient Survival:
There was no difference in patient survival between the 3 groups based on DSA levels
characterize.
Rejection on Graft Survival Outcomes:
The 1-, 5-, and 10-y graft survival for patients who had rejection was 93%, 77%, and
54% when compared with those who did not have rejection which was 97%, 91%, and
82%. This was statistically significant.
DISCUSSION:
There has been a lack of published, long-term outcome data for HLAi renal
transplantation and we have addressed this.
The patient and graft survival estimates of this HLAi cohort for 1, 5, and 10 y is 95%,
90%, and 81% and 95%, 85%, and 70%, respectively.
This is similar to the outcomes seen for first time, deceased brain dead donor
transplants in the United Kingdom.
However, there was a significant difference in overall patient and graft survival between
the HLAi study cohort and the standard live donor transplant cohort at our center.
Given the higher risk nature of our cases, more than half of whom had repeat
transplants, this report provides reassurance that HLAi transplantation can, overall, offer
good long-term outcomes for highly sensitized patients with a low prospect of
a compatible donor.
Retrospective cohort study.
Level of evidence 111
CONCLUSIONS:
Long-term graft and patient survival for HLAi renal transplantation is similar to deceased
donor transplantation.
· Q1. Summary:
· HLA incompatible transplantation has decreased allover the world due to better matching and increased opportunity to find suitable donor either through: paired kidney donation or exchange in living donor or kidney allocation system in deceased ones.
· However, some of highly sensitized recipients who have been on waiting list for unaccepted long time are prone to HLA incompatible transplant (after certain desensitization protocols).
· The outcome of those cases compared to stay on dialysis may be doubtful, some suggest that it may better.
· This study was carried out to compare outcome with deceased transplant.
· Presence of preformed DSA were measured by either CDC, Flow cytometry or Luminex SAB.
· Recipients with concomitant ABO incompatibility were excluded.
· All cases received 5 sessions of PEX prior to transplant.
· All received tacrolimus based triple immunosuppressive therapy.
· As a conclusion:
o Positive cross match by CDC has worse prognosis( as it means that high titer of preformed DSA to be detectable by such insensitive method) .
o Most important complication was ABMR but advances in early diagnosis and treatment of ABMR the long term survival was acceptable
o Survival benefit was comparable to deceased donor transplantation
o Females had worse prognosis.
o Preformed DSA against HLA class I has worse graft outcome when compared to DSA against class II.
o ABMR especially if occur after the first 2 weeks of transplantation was was worse than early ABMR.
o TCMR was less frequent, less severe and respond well to treatment
Q2. type of this study? Retrospective cohort
Q3. level of evidence? Level III
☆HLA Antibody Incompatible Renal Transplantation: Long-term Outcomes
Similar to Deceased Donor Transplantation
¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤
☆INTRODUCTION
______________
▪︎ One of the significant barrier to successful kidney transplantation is anti HLA antibodies.
▪︎ Pretransplant antibody removal, or desensitization, was pioneered to
overcome this barrier.
▪︎There is a decrease of HLA antibody incompatible (HLAi) renal transplantation worldwide with concomitant increase in the paired kidney exchange (PKE) programs. Nevertheless, there is an ongoing requirement for HLAi transplantation in patients with difficult PKE.
▪︎Desensitization could be considered via a combined approach wherein the recipients are offered a lower immunologic risk donor through the PKE or directly from their potential donors after risk stratification.
☆MATERIALS AND METHODS:
______________________________
▪︎A retrospective study which was conducted at the University Hospitals Coventry and Warwickshire (UHCW) NHS Trust,
▪︎One hundred thirty-four HLA incompatible renal transplantation patients from 2003 to 2018 with a median follow of 6.93 y were analyzed retrospectively to estimate patient and graft survivals.
▪︎ These patients were referred from various centers in the United Kingdom and Ireland and all relevant clinical data, immunologic and histocompatibility related data were collated.
▪︎ Patients sensitized to HLA antigens were selected for antibody incompatible transplantation if they had reactivity with donor HLA antigens measured by cytotoxic-dependent crossmatch (CDC), Flow cytometry crossmatches (FC), or microbead assay (Bead).
▪︎Patients who had ABO incompatibility or had combined HLAi and ABOi transplants were excluded. Pretransplant patients were typically treated with 5 alternate day sessions of double filtration plasmapheresis (DFPP).
▪︎ Immunosuppression consisted of mycophenolate mofetil, tacrolimus, and prednisolone
▪︎ The study subjects were categorized based on their DSA status
▪︎Patients with suspicious rejection based on biopsy were included and further categorized into AMR, T-cell–mediated rejection (TCMR), or mixed rejection,
▪︎Further analyses were performed by grouping patients based on the number of rejection episodes
☆RESULTS:
_____________
▪︎ The median follow-up for the HLAi study cohort was 6.93±3.33 y.
▪︎ Outcomes were compared with groups defined by baseline crossmatch status and the type and timings of rejection episodes.
▪︎The patient and graft survival estimates of this HLAi study cohort were compared with:
(i) First-time deceased donor renal
transplant, UK cohort
(ii) First-time deceased donor transplant,
UHCW cohort,
(iii) The standard live donor transplant of
UHCW cohort
Fom the same time period of January 1, 2003 to December 31, 2018
▪︎The overall patient survival was similar to the first-time deceased donor transplant cohort.
▪︎ The graft survival for pretreatment cytotoxic-dependent crossmatch (CDC) positive crossmatch group was significantly low compared with other groups (microbead assay& flow cytometry crossmatch.
▪︎Female patients in general fared worse in both patient and graft survival outcomes in each of the 3 groups based on pretreatment crossmatch, although this did not reach statistical significance.
▪︎Antibody-mediated rejection was the most frequent type of rejection with significant decline in graft survival by 10 y when compared with no rejection.
▪︎ Rejection that occurred or continued to occur after the first 2 wk of
transplantation caused a significant reduction in graft survivals, whereas good outcomes were seen in those with a single early rejection episode.
☆STRENGTHS AND LIMITATIONS:
▪︎ This is a study from a tertiary international referral center for HLAi renal transplantation in the United Kingdom. So, it is not necessarily be extrapolated to other practices.
▪︎ The cases is limited given the constraints of a single center.
▪︎The protocols were not standardized, which could have resulted in a bias in the outcomes.
▪︎ It is the first long-term study of a relatively large cohort of HLAi transplants that shows equivalent graft and patient survival to deceased donor transplantation.
▪︎It identified 2 key areas that allow very good outcomes in what is considered high-risk transplantation. Exclusion of the highest immunologic risk cases, gives an estimated 10-y graft survival of almost 75%. Similarly, those with AMR or TCMR diagnosed and treated within the First 2 wk posttransplantation can be expected to
have a good chance of long-term transplant survival.
☆CONCLUSIONS:
__________________
▪︎Long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation and can be further improved by excluding high-CDC titer cases.
▪︎Antibody-positive female patients show worse long-term survival.
▪︎Resolution of early rejection is associated with good long-term graft survival
◇What is type of this study? Retrospective cohort study
◇What is the level of evidence? Level III
SUMMARY OF HLA ANTIDODY HLA INCOMPAITABLE TRANSPLAANTATION LONG TERNM OUTCOME SIMLAR DECEASESD TRANSPLA
Introduction
a) Paired kidney transplant exchange increasing in number
b) The change in the local allocation policies
MATERIAL AND METHOD
PATIENTS
Retrospective study was conducted at the (UHCW) NHS—for patients who under went HLAi renal transplant between2003 and 2018 were included:
group of patients selected patients sensitized to HLA Ags for antibodies incompaitabe transplant Alloreactive antibody to donor HLA antigens measured by:
Patients excluded from the study:
Pretransplant patients treated with 5 alternative day session of double filtration plasmapheresis(DFFPP) to achieve negative flow cross matching at the time of surgery although can be done with +ve flow cytometry
Immunosuppression Protocols:
Immunosuppression protocol consist of:
Posttransplant serum sample for antibodies analysis more taken daily for the first 2 wk and 3 time /wk for the next 2wk.
Treatment of rejection
Rejection diagnosis clinically or by renal biopsy
Increase dose of methylprednisolone for 3 days to treat rejection
ATG for steroid resistant
HLA antibodies testing
Data Analysis
Crossmatch Status:
HLA Antibody Testing
Rejection
Patients who had rejection compared 1-,5-,10- group survival were analysed .
Based on biopsy and type of rejection categorize:
Data analysed retaining only definitive diagnosis of rejection.
Another analysis performed by group patients based on the number of rejection:
The 1,5,10 y graft survival were compared between the 3 group based on the timing of rejection:
1-,5-,10-y group survival compared between 2 group.
Statistical Analysis
Statical analysis of comparison between groups was performed with nonparametric testing for interdependent groups using IBM SPSS Version 25.0 (SPSS Institute, Chicago, IL).
RESULTS
The median follow up for this study was 6.93+or_3.33y
Patients and graft survival estimate of HLAi study cohort were compared with
There was signifint difference with patents and graft survival between the UHCW live donor cohort and deceased donor (UK+UHCW) cohort.
Antibody Variables Relating to Outcome
Graft Survival
Graft survival was analysed based on immediate pretransplant DSA level detected by CDC,FC and Bead positive test.
Graft survival in CDC +ve group is significs lower than 2 group.
Graft survival for the 9 female CDC +ve patients which is worse although not signified different than 14 male CDC+ve influence the graft survival.
Graft survival analyse based on DSA specify for donor HLA class1,11 or both
Poor graft survival in group with both class1 and 2 DSA overall there was no different between 3 group.
Patient Survival
There was no difference in patients survival between 3 group based on DSA level.
Patients survival for CDC+ve and Bead positive group female lower survival but not statical signifince
No difference in patients survival based on CDC titter or Abs specificity to HLA class1,2,or 1+2.
Rejection on Graft Survival Outcomes
The 1-,5-,10-y graft survival for patients who had rejection was 93%,77% and 54% when compared with those who did not have rejection was 97%,91% and 82% , there was statically signifince.
P=0.002.
Type of Rejection
ABMR signifies lower graft survival than no rejection ,but graft survival of patents with TCMR was no signifying difference in graft survival compared with patients who had no rejection.
Number of Rejection Episodes
Graft survival decrease when the number of rejection episodes increase.
Timing of rejection
Graft survival was signific lower in those with occurring for the first time after 2wk in contrast to those have rejection with first 2wk,the graft survival did not signified decline.
DISCUSSION
HLAi renal transplant have been addressed as there is no publish long term outcome data for HLAi.
2factors affect outcome of HLAi renal transplant:
Graft survival for the group positive based CDC crossmatch is signify lower than FC and Bead positive groups.
No any statical difference in death censored graft survival when comparing cases with either HLAclass1,class2 or both1and 2.
The relationship between pregnancy and subsequent HLAi transplant need further study because
The consequence seem sever.
ABMR was the only rejection type that signify graft survival in compare to TCMR or no rejection in the study
TCMR in HLAi transplant decrease number in the study, seem to be more amenable to successful treatment and does not precipice graft loss.
This extended study show that lower 5 y graft survival in patients with ABMR.
Significant important on graft impact on survival if rejection occurred after the first 2wk of transplant or within and after 2wk of transplant.
STRENGTHS AND LIMITATIONS
Limitation of this study:
Strength of study:
. Exclusion of the highest immunologic risk cases, defined as those with a CDC titre of >1 in 2.
CONCLUSIONS
1- Cross match CDC titter >1 in 2
2-,antibody-positive female patients.
3-Unresolving or recurrence of AMR.
2-type of study
is retrospective cohort study.
3-level 3 evidence.
Aricle summary
Although HLA incompatible ( HLAi) renal transplantation still remains one of best therapeutic options for highly sensitized patients ; not much is known about its long-term ( i,e 10 years and above ) graft and patient survival .
This retrospective study was conducted to assess the the overall patient and graft survival data at 1 ,5 & 10 years taking into account the following characteristics :
#) Type ( AMR vs TCMR and MIxed)
#) timing ( first 2 w postTx vs after 2w postTx or continuing)
#) treatment
it was shown that :
It is important to note that in CDC+ cases , the higher cytotoxic reactivity ( i.e. CDC titre > 1 in 2 ) matters in determining reduced graft survival. The graft survival of the CDC low titer group was similar to the CDC negative group. This observation therefore should widen access to transplantation to almost half of cases referred with a positive CDC crossmatch who might otherwise be declined.
although no statistical differences in death-censored graft survival was found when comparing cases with either HLA class I, class II, or both class I and II DSAs. It has been shown that patients with complement !xing HLA class I DSAs had inferior graft survival compared with HLA class II DSAs .
CONCLUSIONS
1)Long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation.
2)There are certain subgroups, in particular those with a XM CDC titer of >1 in 2, antibody-positive female patients, and unresolving or recurrence of AMR, which are
associated with a poor prognosis.
Given that the need for HLAi transplantation exists and is likely to increase in the
future, despite PKE programs, further large studies looking at risk strati!cation, early diagnosis, and management of
rejection are needed.
Type of study : Retrospective cohort study
Level of evidence : Level III
SUMMARY:
HLA incompatible renal transplantation is still a reasonable option for highly sensitized renal transplant candidates in which PKE failed, due to improved long term survival to those who remained on dialysis.
This retrospective study conducted from 2003-2018 analyzed 134 patients from a single tertiary center with positive crossmatch( CDC, FCXM & microbes assay) and excluded combined HLAi and ABOi transplant patients or ABO incompatible patients.All patients were followed up for a median of 6.9 years , patient and graft survivals were estimated at the end .Patients were treated pre transplantation with 5 alternate day sessions of double filtration plasmapheresis. Immunosuppression protocol included mycophenolate mofetil, tacrolimus, and prednisolone.Induction with Basiliximab was prescribed on day 0 and 4 with single dose of methylprednisolone(500mg) intraoperatively. Rejection was diagnosed by renal biopsy or clinically and treated with high dose of methylprednisolone and with OKT3 and ATG in resistant cases.
RESULTS:
Graft survival at 1, 5 and 10 years was 95%, 85%, and 70% , and the patient survival was 95%, 90%, and 81% which is comparable to deceased donor transplantation.
Graft survival for patients with positive CDC was lower than for positive FCXM& microbes assay. This only occur when CDC titer >1in 2 (low titer CDC show similar survival for negative CDC patients).
Graft survival was worse in females with DSA when compared to male recipients
No difference in death-censored graft survival with either HLA class I, class II, or both class I and II DSAs
The graft survival of patients with AMR at 1-, 5-, and 10-y was significantly lower than those without rejection while graft survival for cases with TMR did not significantly different than cases without rejection.
Early ABMR was associated with better graft outcomes when compared to late rejection
CONCLUSION:
Long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation
What is type of this study? Retrospective cohort study
What is the level of evidence? Level III
–Summary
Studies demonstrated an increase in patient survival with HLA incompatible renal transplantation in comparison to those on the waiting list or on dialysis
The combination of desensitisation with Paired kidney programs provide to highly sensitised cases a less immunological risk transplantation.
Meanwhile the extended criteria donors render more patients sensitized because of the reduced graft survival and lower levels of HLA matching, therfore increasing the need for HLA incompatible transplantation.
Patients and methods
They compared the patient and graft survival data of the HLA incompatible study cohort with the first time deceased donor renal transplant, UK cohort, the first-time deceased donor transplant in their center cohort, and the standard live donor transplant of their center cohort.
Patients were treated pre transplantation with 5 alternate day sessions of double filtration plasmapheresis
Immunosuppression protocol included mycophenolate mofetil, tacrolimus, and prednisolone
Basiliximab was given on day 0 and 4 and methylprednisolone was given 500 mg intraoperatively.
Rejection was diagnosed by renal biopsy or clinically and treated with high dose of methylprednisolone and with OKT3 if it was steroid resistant then ATG replaced OKT3.
Results
There was a significant difference in patient survival and graft survival between their center live donor cohort versus their center HLAi cohort and the UK deceased donor cohort versus their center deceased donor cohort .
The graft survival for CDC positive group was lower than FC and Bead positive groups
CDC titre influences graft survival
There was no difference in patient survival between the CDC ,FC and Bead positive groups
The 1-, 5-, and 10-y graft survival for patients who had rejection was lower than those who did not have rejection.
higher relative median frequency on flow cytometry was associated with increased rates of rejection
The graft survival of patients with AMR at 1-, 5-, and 10-y was significantly lower than those without rejection while graft survival for cases with TMR did not significantly differ than cases without rejection.
As the number of rejection episodes increases, the graft survival decreases.
Rejection occurring in the first 2 weeks post transolanation did not significantly lower the graft survival on the other hand rejection occurring primarily after the first 2 weeks post trasnplanation was associated with significantly lower the graft survival.
Discussion
HLAi transplantation can provide good long-term outcomes for highly sensitized patients with a low possibility of having a compatible donor.
2 factors that significantly affect the outcome are measurements of sensitization and the nature of the rejection responses.
The graft survival of the CDC low titer group was similar to the CDC negative group increasing the availability of transplantation to some cases with a positive CDC crossmatch who are declined.
Recipients with complement fixing HLA class I DSAs had worse graft survival compared with HLA class II DSAs.
There was a clear bias towards combined class I and II DSAs in the patients with a positive CDC crossmatch this could be rendered to the reaction complexity of the sera facilitating complement activation on donor cells.
Female recipients with DSAs had worse graft and patient survival in comparison to male recipients.
It can be explained by the possibility of proinflammatory state in the postpartum period and increased sensitivity to pregnancy induced antigens resulting in decreased graft and patient survival.
AMR reduced graft survival significantly in comparison to TCMR , indicating that TCMR is more responsive to treatment.
Rejection episode recurrence lead to a significant reduction in graft survival rates
Rejection occurring after the first 2 wk of transplantation are associated with poorer graft survival than those cases suffering from rejection in the first 2 weeks of trasnplanation could be due to intensive monitoring during the first post transplantation period
There were some limitations as being a single centre retrospective study
Conclusion
Long-term graft and patient survival for HLAi renal transplantation is similar to deceased donor transplantation
–Type of the study is retrospective cohort study
– Level of evidence is level III
Most of transplant centers try to avoid HLA incompatible transplantation (constitutes 1.5% of transplantation in 2016) due to expected poor outcome and the development of good kidney allocation system (KAS) and national kidney paired donation (KPD) which facilitates deceased and living kidney transplantation and decrease the need for HLA incompatible transplantation.
But actually HLA i kidney transplantation may be the only solution for some transplant recipients who are highly sensitized and cannot find suitable donor through KAS or KPD.
An important barrier in HLA incompatible transplantation is the positive cross match due to preformed DSA, advances in antibody detection and in techniques of desensitization has decreased the risk associated with this type of transplantation
Most important concern in HLA incompatible transplantation is the occurrence of ABMR but again due to advances in early diagnosis and treatment of ABMR the long term survival was acceptable
Survival benefit of incompatible kidney transplantation in comparison with maintaning the patient on dialysis was addressed by several studies and was debatable, some found better and other found no survival benefit
The current study addresses the effect of transplanting HLA incompatible donor graft on long term outcome,
134 HLA incompatible renal transplantation patients with positive CDC or FCM cross match transplanted between 2003, 2018 were followed retrospectively, patients and graft survival were assessed
All patients received around 5 sessions of plasmapheresis to remove preformed DSA, and transplanted with positive FCM cross match, induction received in the form of basiliximab and maintenance tacrolimus based triple therapy
Conclusion
1. Graft survival at 1, 5 and 10 years was 95%, 85%, and 70% , and the patient survival was 95%, 90%, and 81% which is comparable to deseased donor transplantation
2. The worst graft survival was noticed in females with DSA when compared to male recipients
3. Patients with CDC negative or low titer positive cross match have better prognosis CDC titer of >1 in 2 is associated with the worst outcome
4. Patients with preformed complement fixing DSA against HLA class I has inferior graft survival when compared to patients with DSA against class II
5. ABMR especially if occur after the first 2 weeks of transplantation was strongly linked to graft loss, early ABMR were associated with better graft outcome when compared to late rejection
6. TCMR episodes in the current study was less frequent, less severe and respond well to treatment
7. Early successful treatment of ABMR was associated with better outcome
This is a Retrospective study, Level of evidence III
Please summarise this article :
1- the overall patient survival was 95%, 90% and 81% at 1,5 and 10 years post-transplantation.
2- the overall graft survival was 95%, 85% and 70% at 1,5 and 10 years post-transplantation.
3- these results were similar to the outcome of 1st time deceased-related kidney transplantation.
4- graft survival for patients with pre-treatment CDC+ve crossmatch was 83%, 64% and 40% at 1, 5 and 10 years post-transplantation. these rates of graft survivals were low as compared with other forms of crossmatch as microbead assay and flow cytometry. the outcome of patients with low CDC titre was comparable to that of CDC-ve crossmatch.
5- female patients generally have worse patient and graft survivals although this was statistically insignificant.
6- antibody mediated rejection (AMR) was the most frequent type of rejection with significant decline in graft survival by 10 years
1- the long-term graft and patient survival of highly sensitized recipients is comparable to deceased donor transplantation.
2-this outcome can be improved by excluding high CDC-titre cases.
3- antibody +ve female patients have worse long-term survival.
What is type of this study?
What is the level of evidence?
Retrospective study, level 3.
In 1969, DSA were identified & considered as a barrier to successful transplantation. But since introduction of recent desensitization protocoling mid 1980s, transplantation became feasible for sensitized patients, but still had high risk of complications with lower graft outcome. Transplantation of HLAi patients was reduced due to increasing use of PKE & changes in allocation polices. But the need for HLAi transplantation is increased due to failure of PKE to provide good chance for patients with high cPRA.
Several studies show that HLAi transplantation was associated with improvement in patient survival when compared to patients remain on dialysis. Improvement in DSA detection, HLA typing, and desensitization protocol associated with reduce the risk associated with HLAi transplantation.
This study is retrospective include all patients (134) receive HLAi transplantation in single tertiary center from 2003-2018. The study include only patient with positive crossmatch( CDC, FCXM & microbes assay) & exclude patient with ABO incompatible patients & positive crossmatch in ABO incompatible patients.
Enrolled patient receive 5 session of DFPP on alternating day to achieve negative FCXM at time of surgery.
Induction was with 2 doses of basiliximab. All patient maintained on triple ( MMF, Tac & steroids) immunosuppressants. DSA monitored daily in first 2 weeks & 3times/week for second 2 weeks.
Diagnosis of rejection based on finding of graft biopsy & DSA positivity. treatment of rejection was with OKT3 for those who had transplantation before 2007 & with ATG for those who receive transplantation after 2007.
Patient survival calculated from date of transplantation to patient death or last follow-up.
Graft survival calculated from date of transplantation to date of graft loss or last follow-up.
Graft failure mean returns or need to dialysis.
1,5 & 10 year graft survival were analyzed with measurement of class I &II DSA.
Results & discussion:
Strength of the study:
Limitation of the study:
Conclusion:
Similar to deceased donor transplant, what do think if compared with living transplant?
In this study there was a significant difference in patient & graft outcome between HLAi transplant & standard living donor transplantation
Please summarise this article
Paid kidney exchange programs have been decreasing the number of HLA-incompatible kidney transplants (HLAi) and changing local allocation policies. But studies show that HLAi patients have longer survival compared to those who remain on dialysis. Other precautions such as advances in detection and screening of antibody detection, HLA typing, and patient desensitization have improved the outcome of HLAi transplants.
It is a single-center retrospective cohort study from 2003 to 2018.
In pre-transplant protocols, patients with positive FCXM performed five sessions on alternate days of plasmapheresis in an attempt to turn negative antibodies for surgery. Some cases underwent extra sessions and others underwent transplantation in the presence of low titers and weakly positive FCXM.
Basiliximab 20mg on D0 and D4, methylprednisolone 500mg in surgery, and maintenance with tacrolimus, MMF, and prednisone were the most used protocol.
Antibody dosage in the first two weeks was collected daily and then three-time a week.
Patients were divided into three groups based on Crossmatch: CDC, FC, and bead
Rejection was diagnosed by biopsy or clinically (serum creatinine and DSA levels).
Patients with FCXM and beads had better results than those who were CDC-positive. Even titers greater than 1 had significant clinical worsening and graft loss.
There was no difference in mortality in the three groups based on DSA values. However, the higher number of rejections was an important predictor for graft loss. The later rejection time (greater than two weeks) decreased graft survival.
AMR was the only rejection type that significantly reduced graft survival in comparison to TCMR or no rejection in this study. Apparently, earlier rejections were treated more effectively probably by an earlier diagnosis or optimization of the patient’s early immune status.
What is the type of this study?
It is a single-center retrospective cohort study from 2003 to 2018.
What is the level of evidence?
Level 3
Excellent
Similar to deceased donor transplant, what do think if compared with living transplant?
Professor, there is no doubt that a transplant between the living is better for the recipient, although when the desensitization process is started, there is no statistical difference in graft survival in the first few years. However, the higher risk of ABMR, de novo lesions, transplant glomerulopathy should be considered in overall graft survival, closely monitoring renal function, biopsies, monitoring of immunosuppressants and DSA levels.
HLA Antibody Incompatible Renal Transplantation: Long-term Outcomes Similar to Deceased Donor Transplantation
HLAi transplant remain the problem of kidney disease but the best option rather than staying for long time on dialysis.
it’s retrospective study done from 2003 to 2018 where data collected from tertiary center and all patients with HLAi transplant included and patients with ABO incompatible or mixed ABO & HLAi excluded from study.
sensitised patients underwent plasma exchange alternative day before transplant in aim to remove DSA at time of surgery.
Induction therapy started with pulse therapy of steroid intraoperative and basiliximab at day 0 / day 4 post transplant and monitoring of DSA level daily for 2week and 3times /week for 3 weeks
Maintenance therapy by MFF tacrolimus and low dose steroid.
treatment of rejection:
if diagnostic clinical by oliguria and increase renal parameters and increase level of DSA or diagnostic by renal biopsy; it’s treated by steroid and Iv ATG.
Results:
There’s no significant difference between patients survival and graft outcome in HLAi in living donor than deceased transplant patients.
Graft survival worse in patients with CDC positive and in patients with DSA class I.
Graft survival decrease when numbers of rejection episodes increase.
Graft survival decrease when rejection occur after first 2week from transplant rather than patients with early rejection (before 2 weeks).
There’s 2 factors important for graft outcome
first: measuring of baseline sensitisation
second: natural of rejection response.
AMR may worse graft survival in comparison with TCMR.
This study give reassurance patients with HLAI can safely had good outcome of graft survival in sensitised patients same as deceased donor transplant.
This type of study are cohort retrospective study
Evidence 3
Thanks
The outcome of transplanting sensitised patients is similar to deceased donor transplant, what do think if compared with living transplant?
A compatible living donor transplant outcome is the best in terms of patient and allograft survival.
This study evaluated the outcome of HLAi transplant as a solution for recipients who are highly sensitized with no other transplantation options. The results showed that transplantation of HLAi allografts has a similar outcome to deceased donor allografts. Therefore, it may be a reasonable option for highly sensitised recipients to proceed for HLAi transplantation (after proper preparation) than to wait on the deceased donor waiting list.