Transplantation in highly sensitized patients: Challenges
· Growing accumulation of highly sensitized patients in the waiting list of transplantation, leading to more comorbidities and complications associated with remaining on dialysis.
· Highly sensitized patients have made antibodies to almost all frequent HLA antigens in the donor population, making negative crossmatch donor is extremely difficult.
Transplantation in highly sensitized patients: Recommendations
· To increase the donor population pool via allocation programs.
· To increase the chance on the exchange program(KPD), the following can be attempted:
a. To include compatible pairs in the program.
b. To cross the relatively lower ABO blood group barrier for highly sensitized patients.
c. Enlarging the donor pool via international cooperation by creating trans-borders KPD programs.
d. Combination of KPD with desensitization strategies.
· Using an advanced agents in the desensitization therapy as IdeS, Eculizumab and Bortezomib which can be used in conjunction with PP and RTX.
· HLA matching based on B cell epitopes, has shown to allow for transplanting HLA-mismatched organs that do not bear immunogenic epitopes for the specific patient, preventing DSA formation. This may not be feasible to majority of patients.
In the practice of rTX in my country we are restricted to matching and compatible living donor transplantation and we don’t proceed with an unacceptable mismatch.
Nandita Sugumar
2 years ago
Recommendations including practice
KPD
Desensitization
Acceptable mismatch program
Use of Bortezomib
Combine KPD and desensitization
Aggressive steroid regimen
Last edited 2 years ago by Nandita Sugumar
Nandita Sugumar
2 years ago
Challenges
Major challenges associated with transplanting highly sensitized patients include
presence of HLA antibodies. Patients with high anti HLA donor specific alloantibodies have a relative contraindication to transplantation, especially in the presence of a positive complement dependent cytotoxicity crossmatch. This leads to hyper acute rejection and graft loss.
presence and development of alloantibody can lead to antibody mediated rejection and graft loss post transplant. T cell mediators are important with respect to allograft rejection and B – cells and alloantibodies also play a critical role in allograft injury. DSA can lead to ABMR and chronic rejection form called transplant glomerulonephropathy.
ahmed saleeh
2 years ago
Challenges
*high percentage of sensitization due to sensitization events such as pregnancy, blood transfusion, previous tx.
*luminex single antigen bead increased the incidence of Abs detection making finding compatible donor more difficult.
*No clear standard guidelines for Tx especially in highly sensitized patients and every center has its own policy
*KAS not much successful in Tx patients as well as KPD system .. needs further improvement
*Desensetization outcomes are not very promising especially regarding long-term outcomes.
Recommendation:
*Avoid sensitization as much as possible
*Epitope matching if available.
*KPD and KAS may improve finding compatible tx donors.
*the use of Acceptable mismatch programs with good cost effectiveness.
Our practise : unfortunately KAS and KPD are not available in our country
And tx HLAi is mainly through desensitization techniques.
Transplantation in patients who are considered highly sensitized is challenging for doctors
These challenges are:
-sensitization against HLA may be due to blood transfusion, previous transplant and pregnancy .
-Making the waiting list for transplant more crowded.
-increase numbers of unacceptable antigens with decrease the chance of finding suitable donor .
-15%or less of the highly sensitized patients can find the compatible donor in the KPD match
-preformed DSA resulting in hyperacute rejection .
-increasing time of cold ischemia resulting in DGF
Recommendations :
* Avoid sensitization.
*Desensitization protocol
*Apply KPD system
*Using Bortezomeb which is proteasome inhibitor with plasmapharesis and rituximab
MICHAEL Farag
3 years ago
A. Challenges :
________________
▪︎ Accumulattion of highly sensitized patients in the transplant waiting list which this is associated with high mortality rates on dialysis.
▪︎ With the advent of new highly sensitive bead Luminex assay (SAB ) the definition of unacceptable antigens for highly sensitized pts has become more dependent on the interpretation and on expertise individuals.
▪︎SAB is a crude measure for Ab titre and/or binding strength and many factors affects It’s interpretation (prozone effect , antibody titre, antibody affinity, competition of shared epitopes on different beads, complement factors and immune complex interference, ..etc)
▪︎Due to HLA epitope sharing. This can lead to lower MFI on a single bead and thence a false negative result.
▪︎ In the new Kidney Allocation System (KAS) the patients with highest level of sensitization are still difficult to transplant and remain on the waiting list.
▪︎ The success of transplantation in New KAS is much dependent on the centers.
▪︎Also in KAS there is an increase in the number of organs that are shipped over long distances, thereby increasing cold ischemia times which result in increase delayed graft function rates .
▪︎The rates of zero HLA- A,-B,- DR mismatches is low in the new KAS, and there is an increase in HLA immunization in case of graft loss.
▪︎Regular allocation is based on avoidance of unacceptable HLA mismatches on donor organ and for highly sensitized pts, the breadth of unacceptable Ags therefore often precludes transplantation.
▪︎Highly sensitized pts ( cPRA >or = 97%) have significantly lower chance to find a suitable donor through Kidney paired donation programs (KPD).
▪︎ High level HLA Antibodies are often refractory to desensitization.
▪︎Despite desensitization with IVIG or Plasma pharesis with low dose IVIG some transplants are subject to increase risk of ABMR, both early and late.
B RECOMMENDATIONS :
________________________
▪︎Due to the above mentioned SAB assays limitations, a per- patient risk assessment with an individualized threshold for positivity, correlation to previous sensitizing events, HLA epitope analysis and taking into account the chance of receiving a transplant is advised.
▪︎Additional priority in regular allocation system for highly sensitized patients
▪︎ Special Kidney allocation system example (KAS) in which highly sensitized patients (in KAS defined as cPRA> or = 98%) relieve further priority.
▪︎ In Kidney paired donation programs (KPD):
1. Include compatible pairs on the program
2. Cross the relatively lower ABO blood group barrier for highly sensitized patients.
▪︎ Enlarging the potential donor pool through international cooperation by creating trans- border KPD programs.
▪︎ Desensitization protocols.
▪︎ Combination of KPD and desensitization
▪︎ Applying special program for highly sensitized pts such as Acceptable Mismatch (AM) which is based on positive identification of acceptable antigens.
▪︎ Introducing novel agents such as Proteasome Inhibitor ( brotezomb) in conjunction with plasmapheresis and Rituximab.
▪︎ Introducing a novel agent named IgG- degrading enzyme.
Shereen Yousef
3 years ago
Transplantation in highly sensitized patient is a major challenge for doctors
These Challenges include :
increased number highly sensitized ppatients on waiting list.
Increase the number of unacceptable antigens decreases the chance of finding matched donors.
SAB although very sensitive but crude measure of Ab level or strength.
SharedHLA epitope can lead to lower MFI on a single bead and hence a false negative result.
in KAS there is an increase in the number of organs that are shipped over long distances, thereby increasing cold ischemia times which result in increase DGF .
Regular allocation is based on avoidance of unacceptable HLA mismatches on donor organ and for highly sensitized patients, the breadth of unacceptable Ags therefore often precludes transplantation
Highly sensitized patients with high CPRA have significantly lower chance to find a suitable donor through Kidney paired donation programs .
Desensitization can be used with KPD
But still high level of DSA are refractory to desensitization
desensitization with different strategies include IVIG or Plasma pharesis with low dose IVIG plus B cells depletion with rituximab but still some transplants have increased risk of ABMR, both early and late.
Recommendations
-Offering higher priority for highly sensitized patients in kidney allocation programs.
-Enlarging the potential donor pool
-Kidney paired donation protocol offers a more suitable donor but not fully matched to decrease time on waiting list.
– Implementing a new program for highly sensitized patients such as AM programme.
– Desensitization protocol according to degree of mismatch With addition of novel agents such as Proteasome Inhibitor ( brotezomb) in conjunction with plasmapheresis and Rituximab.
In my paractice there is no deceased donor, and there is no organized paired kidney exchange programmes which if applied whould help to expand donor pool and avoid long waiting time on dialysis.
No ABOI-KT hope to be settled in near future.
Pretransplantation work up include CDC crossmatch, FCXM, SAB
desensitization for patients with high PRA.
Tahani Ashmaig
3 years ago
Transplantation in highly sensitized patients
A. Challenges :
________________
▪︎ Accumulattion of highly sensitized patients in the transplant waiting list which this is associated with high mortality rates on dialysis.
▪︎ With the advent of new highly sensitive bead Luminex assay (SAB ) the definition of unacceptable antigens for highly sensitized pts has become more dependent on the interpretation and on expertise individuals.
▪︎SAB is a crude measure for Ab titre and/or binding strength and many factors affects It’s interpretation (prozone effect , antibody titre, antibody affinity, competition of shared epitopes on different beads, complement factors and immune complex interference, ..etc)
▪︎Due to HLA epitope sharing. This can lead to lower MFI on a single bead and thence a false negative result.
▪︎ In the new Kidney Allocation System (KAS) the patients with highest level of sensitization are still difficult to transplant and remain on the waiting list.
▪︎ The success of transplantation in New KAS is much dependent on the centers.
▪︎Also in KAS there is an increase in the number of organs that are shipped over long distances, thereby increasing cold ischemia times which result in increase delayed graft function rates .
▪︎The rates of zero HLA- A,-B,- DR mismatches is low in the new KAS, and there is an increase in HLA immunization in case of graft loss.
▪︎Regular allocation is based on avoidance of unacceptable HLA mismatches on donor organ and for highly sensitized pts, the breadth of unacceptable Ags therefore often precludes transplantation.
▪︎Highly sensitized pts ( cPRA >or = 97%) have significantly lower chance to find a suitable donor through Kidney paired donation programs (KPD).
▪︎ High level HLA Antibodies are often refractory to desensitization.
▪︎Despite desensitization with IVIG or Plasma pharesis with low dose IVIG some transplants are subject to increase risk of ABMR, both early and late.
B RECOMMENDATIONS :
________________________
▪︎Due to the above mentioned SAB assays limitations, a per- patient risk assessment with an individualized threshold for positivity, correlation to previous sensitizing events, HLA epitope analysis and taking into account the chance of receiving a transplant is advised.
▪︎Additional priority in regular allocation system for highly sensitized patients
▪︎ Special Kidney allocation system example (KAS) in which highly sensitized patients (in KAS defined as cPRA> or = 98%) relieve further priority.
▪︎ In Kidney paired donation programs (KPD):
1. Include compatible pairs on the program
2. Cross the relatively lower ABO blood group barrier for highly sensitized patients.
▪︎ Enlarging the potential donor pool through international cooperation by creating trans- border KPD programs.
▪︎ Desensitization protocols.
▪︎ Combination of KPD and desensitization
▪︎ Applying special program for highly sensitized pts such as Acceptable Mismatch (AM) which is based on positive identification of acceptable antigens.
▪︎ Introducing novel agents such as Proteasome Inhibitor ( brotezomb) in conjunction with plasmapheresis and Rituximab.
▪︎ Introducing a novel agent named IgG- degrading enzyme.
Ahmed Omran
3 years ago
. Highly sensitized patients have c PRA from 85 to 100%. challenges:
* Sensitization against HLA can occur in case of pregnancy, previous transplants, & blood transfusions with prolonged waiting time.
* High HLA polymorphism, resulting in difficulty in finding fully matched unrelated donors.
*SAB testing, with high sensitivity, help to lower chances of finding an acceptable donor.
*KAS in US Increased cold ischemia times resulting in more delayed graft function.
* Less than 15% of the highly sensitized patients can find a compatible pair in the KPD match.
*Different protocols of desensitization. Recommendations :
* Prevention of sensitization.
* Use HLA matching using B cell epitopes.
* Use potential live donors.
*Increase the chance of regular allocation.
*Involving patient in special program..
*Desensitization.
Mohamed Essmat
3 years ago
Challenges of highly sensitized transplantation include: interpretation of cross-match techniques, priority of allocation system which depend on scoring, low chance of transplantation in high sensitized patients, the choice of proper desensitization protocol and to whom as well as Polymorphism of HLA antigens. Recommendations: More implementation of acceptable mismatch program which can reduce the waiting time for highly sensitized patients, increase organ exchange of allocation system as well as using of ABO incompatible transplantation, proper desensitization regimens if indicated. According to personal experience, most highly sensitized patients seen are for 2nd or 3rd transplant, positive CXM by CDC are excluded, while positive FCXM with +ve DSA’s, are desensitized accordingly till achieving –ve matching, if FCXM is –ve, and no DSA’s but the patient is highly sensitized, this is usually expert’s opinion and an individualized opinion regarding whether to desensitize or not. No cadaveric experience.
Nasrin Esfandiar
3 years ago
Highly sensitized patients have a wide range of antibodies against HLA against that exist in the donor pool population making their TX challenging.
Because of preformed DSA hyper-acute rejection results in graft loss in these patients. It needs exclusion of donors with unacceptable antigens and antigens and therefore these patients have prolonged waiting times.
In addition, by using Luminex SAB, which is a very sensitive method, detection of these antibodies is increased every day needing a good knowledge for proper interpretation, such as prozone effects, antibody titer based on MFI, competition for share epitopes and so on.
1- Allocation system:
A good solution is giving higher priority to these patients in allocation system.
For example in the USA there is a sliding scale for patients with cPRAfile:///C:/Users/user/AppData/Local/Temp/msohtmlclip1/01/clip_image002.png20%
Patients with CPRA 100% still have difficulties in finding donor.
In addition, transferring an organ in this condition may results in prolonged cold ischemic time and DGF.
2- Acceptable mismatch:
This program is used in euro-transplant and is based on the positive identification of acceptable antigens.
That patient has no antibody against them.
These antigens are recognized by luminex SAB combined with epitope analysis through HLA match maker of HLA I.
These antigens are added to patients HLA creating an extended HLA type and matching donors HLA based on it.
Using this program almost 1500 case received a transplant with acceptable 10-year graft survival. But for patients with uncommon HLA types or having antibodies against common HLA types, again finding compatible TX is difficult in this context and needs expansion of donor pools to national and international allocation program.
3- Kidney paired donation (KPD): this program is used in living donation.
Because of better outcome with living donors, finding on HLA compatible donor by exchanging the living donor is another option.
These couples are matched based on VXM and then with physical XM.
The result of KPD TX is excellent but finding a KPD match is less than 15%
A combination method with desensitization is used to increase their chance.
Desensitization:
To transplant HLAi kidneys desensitization is used to achieve a negative XM.
This method could be combined with KPD to find a living donor.
But high level HLA-abs are refractory to desensitization should be determined dose IVIG and plasmapheresis and sometimes with adding rituximab or proteasome inhibitor bortezomib and eculizumab.
Ides is a novel (agent endopeptidase) used for desensitization.
Prevention of sensitization by transfusions and TX based on HLA epitope matching.
In our center KPD program in combination with desensitization with IVIG plasmapheresis, rituximab +/- bortezomib to reach a negative XM in low level DSAs is used.
Ofonime Udoh
3 years ago
Renal transplantation remains the best option for treatment of End Stage Renal Disease. However, there are patients who are highly sensitized: have in their serum antibodies against almost all frequent HLA-antigens in their donor population. patients are regarged as being highly sensitized when they have an HLA-antibody profile that reacts to more than 85% to 100% of donors in the donor pool, and this sensitization is expressed as cPRA, cRF or vPRA. This sensitization makes the patients unable to get donors thus prolonging their waiting time for a transplant. It has been mnoted that within Eurotransplant about 20% have been sensitized, and about 5% are highly sensitized.The presence of these
As a result , alternative options have to be devised to ensure that these sensitized patients get donors and do not wait too long for their transplant.These options include
additional prioritisation in the regular allocation system. The challenge noted with this is the fact that organs have to be shipped long distances, and this increases the cold ischemia time, and increases delayed graft function.
special programs with the basis being the use of acceptable antigen allocation. A list of HLA antigens to which the patient does not have antibodies to is used to allocate a donor to them. This program is termed the Acceptable Match Program. The acceptable antigens are extensively mapped out, and added to the HLA type of the patients to create an ‘extended HLA type’, on which matching is performed for the patient. A study of this progrm has shown highly sensitized patients transplanted through this AM program have a significantly better 10 year graft survival compared to their counterparts transplanted through the regular allocation program: thus showing a benefit from transplanting based on acceptable antigens rather than focusing only on the unacceptable HLA antigens. Despite this, there are still some people who cannot get a donor using the AM program likely because they have HLA antigens uncommon in theEurotransplant population: thus they may have to search for donors outside their donor p[opulation
Paired kidney donation.: This involves kidney transplant from living donors, and it is known that trsansplant from living kidney donors have a superior long term graft survival compared to kidney donations from deceased donors. Different exchange combinations are possible, ranging from exchange btween couples to domino exchange by a non-directed anonymous donor. Though these programs help, still highly sensitized patients do have some difficulty in getting donors, and the donor pool may need to be widened to out of the region.
Desensitization protocols: these involve ways to reduce the load of antibodies to thus provide a window for transplantation. This can be done in conjuction with the KPD program. However it has been stated that high HLA antibodies levels are refractory to desensitization, and so there has to be a defined level above which desensitization is not indicated. Desensitization males use of Intravenous Immunoglobulin [IvIg], Rituximab [ a B-cell depleting agent], Bortezomib [a proteosome inhibitor], and IdeS [IgG degrading enzyme derived from Streptococcus pyogenes
a combination of Kidney paired donation and desenstization protocols
The above options require the combined effort of several renal transplant teams across states; but have proven to help highly sensitized patients shorten their wait time on the list.
Recommendations
Liasing with other transplant commitees in other regions, like Africa, to get a pool of donors with a different array of HLA antigens, to help these highly sensitized patients.
In my small practice here, there is no deceased donation, as all transplants are live donations. There is also no donor pool. But i believe that this can be started
Udoh
Wee Leng Gan
3 years ago
The challenges and recommendations for highly sensitised transplant recipients.
In Euro transplant, approximately 20% of kidney transplant recipients were sensitised and 5% were highly sensitised when c PRA , v PRA or c RF more than 85%. Highly sensitised transplant recipients eventually succumbed to the morbidity due to exhausted waiting time to receive kidney transplantation.
The challenges for highly sensitised transplant recipients are exponential increase in the cumulative number of sensitised transplant recipients which lead to technically very challenging to transplant this group of patients with a cross match negative donor organ. Meanwhile, highly polymorphism of HLA system lead to low probability to get fully match unrelated donor. However, sensitisation of HLA through pregnancy, blood transfusion and previous history of transplant may not have equal weightage. The luminax single antigen bead ( SAB ) assay is highly sensitive along with the great variation of unacceptable antigen listing policies between centres lower the threshold to classify kidney transplant recipient as highly sensitised which reduce the opportunity for kidney transplant. The causal relationship between cold ischaemia time and long term graft survival yet to define while attempt to search for compatible organ donor among other donor population. Ethical, legal, cultural issues while searching for compatible organ donor at other donor population. Although kidney transplant program (KDP) has good clinical outcome, but less than 15% of highly sensitised recipient able to find a compatible pair in kidney donation program match run.
The recommendations include prioritise highly sensitised recipients under the waiting list and running acceptable antigen ( AM ) program to reduce waiting time for transplant with good graft survival and cost effective. Patient specific approach to determine the truly relevant HLA antibody in KDP is essential when direct donation is impossible. Compatible pairs should be included in KDP. Alternatively, ABO blood group barrier need to revise for highly sensitised recipients. Combination fo KDP and effective sensitisation protocol allow transplantation of incompatible pairs. However, predefined criteria for DSA level amenable for desensitisation is essential. Desensitisation protocol involved high dose IVIG, or low dose IVIG couple with plasmaparesis, IV Rituximab, bortezomib, eculizumab and Ig G degraded enzyme derived from streptococcal pyogens under phase 2 trial for desensitisation.
In my opinion, managing highly sensitised transplant recipients should be individualised. Risks and benefits and expected outcome should be explained well to the potential recipients. We should making use of potential living donor, increase the chance of regular organ allocation. Improvement of local AM program with sensitisation protocol are essential for successful transplantation among highly sensitised recipients. Finally, local health authority policy, transplant experts, public awareness for organ donation and international cooperation are crucial for better outcome of highly sensitised kidney transplantation.
Zahid Nabi
3 years ago
The best possible option for patients on dialysis is transplant however the biggest hurdle is presence of antibodies in recipient against his potential donor.sensitization towards HLA can occur due to previous transplant, pregnancies and blood transfusions.patients are regarded highly sensitized when having an HLA antibody profile that reacts to more than 85-100% of donors in the donor population usually expressed as cPRA.
Highly sensitized patients have longer waiting time and subsequently higher mortality rates on dialysis. This review discusses various ways to overcome these hurdles and to facilitate these patients to find a suitable donor.
1. One way of addressing this issue is give priority points to highly sensitized patients in kidney allocation system(KAS).In USA by adopting this system the waiting time for highly sensitized patients decrease from 19 years to 3.2 yrs.
2. Acceptable mismatch (AM) program. identification of acceptable antigens that leads to extended HLA type ,thus increasing chances of finding a Crossmatch negative donor.This approach has reduced waiting time for highly sensitized patients in Eurotransplant region.
3.Kidney paired donation. This PKD was first initiated in South Korea 30 years ago.
Types of exchange combinations include:
a. Direct exchange.
b. Circular exchange between 3 or more couples .
c. Domino exchange made possibly by an non-direct anonymous donor with the final donor donating to a patient on the deceased donor waiting list.
The outcomes of this transplant program are excellent and comparable to outcomes of non-sensitized patients transplantation.
4.Desensitization. Finally desensitization is another way to render these highly sensitized patients fit for transplant .Different desensitization techniques are as follows
High dose IVIG.
Low dose IVIG with plasmapheresis
Rituximab
Bortezomib (proteasome inhibitor)
Eculizomab (complement C5 inhibitor)
Ides(IgG-degrading enzymes derived from streptococcal pyogens).
I think each highly sensitized patients should be offered a transplant depending upon center expertise.
In my country we don’t have a centralized program so for the time being we can’t adopt the recommendations of this review.
HLA is one of the most polymorphic protein,which decides our fate against infection but it also produce one of the greatest barrier in transplantation.
HLA sensitization occurs by blood transfusion,pregnancy, previous transplantation.
The main lab test to detect incompatibility in form of sensitization is CDC assay but not sensitive enough than flow cytometry mcs and luminex mfi.
So, due to sensitization many patient deprived of getting a graft kidney which increases the waiting list along with increases the financial burden.
These are some imp points to increase transplant in sensitized patients-
1.PRIORITY POINTS IN REGULAR ALLOCATION-
the kidney allocation system (KAS)in us giving
priority points in table to sensitized patients.
2.THE ACCEPTABLE MISMATCH APPROACH-
This approach is used by urotransplant ,which is solely based upon identification of acceptable antigens.laboratory test will identify the HLA antigen to which no antibodies are made, hence these accepted antigens are added to HLA type of patient creating an extended HLA type on matching will be performed.
3.KIDNEY PAIRED DONATION-
Highly sensitized patient can get compatible donor through kidney pairing, as compatible living donation have very high chance of survival.
4.DESENSITIZATION-
This is the last thing to be performed which plays god to cross the barrier of immunology.
A.high dose IVIg
B.low dose ivig with plasmapheresis
C.rituximab
D.bortezomib
E.eculizumab
F.ideS
Ahmed Abd El Razek
3 years ago
Challenges
1. Accumulation of highly sensitized patients on the waiting list.
2. Difficulty transplantation with a negative cross match donor.
3. Prolongation of waiting time is associated with increased mortality
4. High level of HLA polymorphism renders finding suitable fully matched donor an extreme difficult job especially in highly sensitized individuals.
5. Female patients are more highly sensitized due to pregnancies.
6. Positive cross match carries the risk of hyper acute rejection.
7. Increasing cold ischemia times resulted in delayed graft dysfunction.
Recommendations
1. Offering higher priority for highly sensitized patients in kidney allocation programs.
2. Implementing a new program for highly sensitized patients (acceptable mismatch AM program) and creating extended HLA type category.
3. Kidney paired donation protocol offers a more suitable donor but not fully matched with the advantage of minimizing time of dialysis and its comorbidities.
4. Desensitization protocol according to degree of mismatch, CDC, flow cytometry, DSA, cPRA and MFI.
5. Using novel agents in the future.
In our practice , we undergo essential investigations as CDC, flowcytometry, DSA, cPRA and MFI. we also try as much as possible to avoid blood transfusion with the concomitant use of erythropoietin stimulating agents. we use desensitization protocol for those highly sensitized patients including plasmapheresis and rituximab.
Reem Younis
3 years ago
. Highly sensitized patients have cPRA 85-100%. What are the challenges?
– Sensitization against HLA can occur due to pregnancy, previous transplants, and blood transfusions Highly sensitized patients experience prolonged waiting time.
– High HLA polymorphism, leading to difficulty in finding fully matched unrelated donors.
– SAB testing, with its high sensitivity, leads to lower chances of finding an acceptable donor.
– Kidney Allocation System (KAS) in US Increased cold ischemia times leading to increased delayed graft function.
-Only less than 15% of the highly sensitized patients can find a compatible pair in the KPD match.
– Different desensitization protocols. Summarise the recommendations and reflect on your practice :
– Prevention sensitization.
– Use HLA matching based on B cell epitopes.
– Use potential live donors.
-Increase the chance of regular allocation.
-Include patient in special program like AM program.
– Desensitization.
– In sudan , we have a living donor program ,and sometimes we used desentization and KPD.
saja Mohammed
3 years ago
Highly sensitized patient with CPRA of> 98% will be very difficult to find HLA Matched donor even if they have been allocated to DD program or KPD still their chances to get transplantation very low and continue on long waiting list of dialysis Recommendations to overcome such obstacles:
1-Priorities points in regular KAS for highly sensitized candidates with CPRA 98%.
2-Involve highly sensitized recipients in KAP with acceptable Miss-match program which depend on positive identification of acceptable antigens (21). BY using highly sensitive method for calculation of the acceptable match (AM) with single antigen bead (SAB) and using epitope antigen assay through matchmaker for HLA CLASS 1(25). This helped in shortening the wait list from > 19 years to < 3 years with acceptable 10 years graft survival and cost effective
3-Eurostam program for highly sensitized patients whom still have very low chance to get matched donor eve n through the AM program, by involve them in other Europe wide AM program from other population, such allocation program need address the ethical, logistic barriers for such allocation program between different national and international programs, have been in use since 2012 in Europe. 4- KPD program for allocation of better matched living donor preemptively for both HLA and ABOI patient – donor couple will enter the KPD for better allocation of matched donor. including direct couple paired exchange or circle exchange including 3 or more pairs or domino exchange, very successful program with excellent outcome, alone or in combination with desensitization program by using more noval agents to allow for rapid desensitization to allow for transplantation of HLA incompatible kidneys with negative crossmatch.
5- Further improvement in the crossmatch methods using epitope antigen assay, B-cell epitope assay to allow for HLA mismatched transplant that do not bear immunogenic epitopes not perform DSAs.
we still do not have KPD or DD program , but we do very infrequent DD transplantation and we are able to perform desensitization as part of LD program for highly sensitized patients
HLA matching also we have limitation as we don’t have FXCM or VXM , we still using CDCXM in addition to Luminex SAB assay
Sucharita Chakraborty
3 years ago
CHALLENGES-
1)HLA polymorphism- due to which finding a HLA match in an unrelated donor is extremely slim
2)Definition of unacceptable antigens dependant on interpretation and expertise of laboratories- after advent of bead based luninex assays.
3)Prioritizing such patients leads to long distance shipping of organs –> increases cold ischemia time–> poor long term Graft survival.
4)accumulation of such highly sensitized patients in the transplant waiting list , as well as in the kidney paired donation pool(when they are included in KPD programs)
5)No single treatment available that assures desensitization.
6)highly sensitized patients with no matched donors- whether to dare to cross that barrier by desensitization or advice them to continue hemodialysis .
7) setting the threshold or mark for DSA titre upto which desensitization may be attempted.
SUMMARY OF RECOMMENDATIONS
A stepwise approach to be followed.
1)Prioritizing patients on regular allocation system/ introducing more allocation systems
2)Acceptable mismatch program- identification of acceptable antigens that leads to extended HLA type ,thus increasing chances of finding a Crossmatch negative donor.
3)Including these patients in kidney paired donation program.- facilitates pre emptive transplants.
Crossing the ABO barrier (which has better outcone)
Including international cooperation for enlarging the pool of donors.
4)Finally consider desensitization protocols after ruling out all available options.
5)Most importantly- avoid sensitizing your ESRd patients. Decrease /avoid use of blood products and increase EPO and IV iron use.
REFLECTING ON CLINICAK PRACTICE
1) Increase use of EPO and IV iron and avoid use of blood products in all CkD patients.
2) use the stepwise approach for a highly sensitized patient
3)Transplant after desensitization should be our last option
4) Encourage ABO incompatible transplants over HLA incompatible transplants.
Drtalib Salman
3 years ago
What are the challenges?
1- the decision weather go ahead for transplant and expose patient to risk of rejection and over immunosuppression related morbidity and mortality ? or refuse donor and stay on HD for prolong waiting list ? for me really challenging .
2- HLA system is polymorphism gene with different peptide so it is so difficult to find compatible donor with zero mismatch .
3-those patient with highly sensitized more than 99.5 to 100 percent even with advanced allocation system and paired kidney donation ,it is difficult to find compatible donor so may be transplantable.
4- Allocation of organ to highly sensitized patient may shipped for long period of time so prolong cold ischemia that may cause delayed graft function .
5-Highly sensitize patient that refuse by standard alloaction system could be accept depend on acceptable mismatch system.
6-with kidney pair donation, very highly sensitizing patient still with no suitable donor ,so it solve some but not the whole problem.
7-There is no consensus about desensitization protocol ,there center to center regimen difference.
8-question about which DSA level amenable for desensitization regimen, and which is the safe lower level to go ahead for transplant .
9-Till now there is no effective therapy to Ab mediated rejection .
Summarise the recommendations and reflect on your practice
To give good chance for highly sinsitized patient to transplant we need :
1- Good allocation system.
2- Good acceptable mismatch system.
3-execlent kidney allocation system if possible international .
4-fixed evidence base protocol for desensitization ,for induction ,and for follow up
5-Trusted immunological lab.
Reflect on my practice ?
Highly sensitize patient that previously I think impossible to transplant could be possible and easy to transplant but this need good facility as mention above.
Ban Mezher
3 years ago
Challenges of highly sensitized transplantation:
extensive polymorphism of HLA system leading to difficulty in finding fully matched donor
increasing number of unacceptable Ags which necessitates careful Ab classification against these antigens.
interpretation of crossmatch techniques & expertise of lab personnel.
priority of allocation system which depend on scoring
increasing chance of HLA immunization( after graft loss), due to high mismatch in new KAS
low chance of transplantation in high sensitized patients through PKD
DSA level that need to desensitized ( high DSA may be resisted to desensitization & associated with poor outcome).
Recommendations:
Using point system to classify the patient according to the priority in KAS program
try to reduce cold ischemia time to improve long term outcome
increase acceptable mismatch program which can reduce the waiting time for highly sensitized patients
increase organ exchange between difference national & national allocation system
extend PKD to circular & domino exchange with adding international or multi center PKD program
using of ABO incompatible transplantation to increase chance of HLA compatible patients.
In my country there were no KAS or PKD, but desensitization program can be done for sensitized patients with PP+IVIG+ rituximab
CARLOS TADEU LEONIDIO
3 years ago
What are the challenges?
Some advances allowed better recognition of HLA antibodies and subsequent unacceptable antigen. The screening through CDC and PRA, using output of Luminex single antigen bead (SAB) assays is mean fluorescense intensity (MFI) and the individual beads increasing sensitivity were essential for this.
Changes in the regular allocation system of the programs for highly sensitized kidney transplant candidates was another advance, because the prioritization of sensitized patients. In the USA, was used a point system with sliding scale for patients with > 20% cPRA, in Eurotransplant the Acceptable Mismatch (AM) is based on positive identification of acceptable antigens. Kidney paired donation is other option.
However, desensitization appears to be a necessity for some recipients in all cases. And even then, there is a increase in the risk of ABMR.
Summarise the recommendations and reflect on your practice.
The main recommendations are:
– making use of a potential living donor
– increasing the chance in regular allocation
– Including patients in special programs such as the AM program;
– Protocols desensitization in the last;
In practice, there is a need for patients to adhere to regular monitoring of their awareness and follow-up by the team of this process for decision-making to follow up to the next step.
Mahmud Islam
3 years ago
Transplantation is a complicated process. Challenges start from selecting the eligible donors for specifies recipients and are endless. So we need to be careful when choosing our pairs and treatment protocols. The greatest challenge is HLA itself being post polymorphic making it difficult to find unrelated donors easily. Natural sensitization like multiple pregnancies and even infection or vaccination may contribute as well. Previous transplantation is also very important. Finding suitable donations through global programs and transfer of organs for long distances has an effect on cold ischemia time and delayed graft function. challenges in interpreting and standardization of SAB itself is an issue as it may not reflect the future in-vivo because multiple antibodies may have a dissipated effect on beads. contrary to that MFI itself is not my lead to unnecessary exclusions. Criteria and degree of mismatch is not standardized so the expectations are variable.
I do not work in a transplant center for the moment but I worked in a center that performs desensitization protocols using all available resources on patient-based protocols mostly with help of plasmapheresis and rituximab. I know centers with good pool for a paired kidney donation that perform circular pairing. I do not have experience or knowledge for the moment regarding cadaveric receipients
Naglaa Abdalla
3 years ago
Highly sensitized patients have antibodies against almost all frequent HLA types present in their donor population with cPRA ≥ 85-100%. So increasing the number of unacceptable antigens will decrease the chances of transplantation for those highly sensitized patients in the waiting list.
Main causes of sensitization :
1. Pregnancies
2. Blood transfusions
3. Prior transplant
The main laboratory tests to define sensitization (unacceptable antigens) are:
CDC assays.
luminex single antigen bead(SAB) assays and mean fluorescence intensity(MFI).
How to improve chances of transplantation for highly sensitized patients: 1. Priority points in regular allocation
The kidney allocation system(KAS) in united states improve this by using a point system with sliding scale for patients with cPRA≥20%.
Highly sensitized patients with cPRA≥98% receive further priority by regional allocation if cPRA
=99% and national allocation for cPRA
=100%.
Good enough the rate of transplantation of highly sensitized patients increased from 2.4% to 13.4% in the first year of implementation. 2. The Acceptable Mismatch Approach(AM):
AM program is used by Eurotransplant for almost 30 years and based on identification of acceptable antigens.
Extensive laboratory testing will define the HLA antigens to which no antibodies has been made by the patient. These accepted antigens are added to the HLA type of the patient creating an extended HLA type on which matching is performed.
So if an organ donor HLA is compatible to this extended HLA type, it is reported to Eurotransplant and the kidney is immediately offered to the AM patient Centre.
This approach significantly lower the waiting time for highly sensitized patients in Eurotransplant region. From 1989 onwards 1500 patients received transplant out of >2500 patients on AM program waiting list.
Studies showed that highly sensitized patients transplanted through AM program have a significant 10 year graft survival compared to others transplanted through regular allocation(72.8% versus 62.4%).
3. Kidney Paired Donation(PKD) :
living donor kidney transplant has a better long term graft survival and the procedure can be done preemptive .
Highly sensitized patients can go through PKD program to find an HLA compatible donor.
This PKD was first initiated in South Korea 30 years ago.
Types of exchange combinations include:
a. Direct exchange.
b. Circular exchange between 3 or more couples .
c. Domino exchange made possibly by an non-direct anonymous donor with the final donor donating to a patient on the deceased donor waiting list.
The outcomes of this transplant program are excellent and comparable to outcomes of non-sensitized patients transplantation.
4. Desensitization:
it can be used with KPD where the prospective donor has a lower HLA barrier than the original donor .
Desensitization protocols include :
High dose IVIG.
Low dose IVIG with plasmapheresis
Rituximab
Bortezomib (proteasome inhibitor)
Eculizomab (complement C5 inhibitor)
Ides(IgG-degrading enzymes derived from streptococcal pyogens).
Abdulrahman Ishag
3 years ago
What are the challenges?
1-HLA sensitization.
-HLA is highly polymorphic .The likelihood of finding a fully matched unrelated donor is extremely rare.
-Screening for HLA antibodies and subsequently unacceptable antigen definition with the advent bead-based luminex assays depends on the interpretation and expertise .
– The interpretation of these assays is affected by many factors like; antibody titre, antibody affinity, competition for shared epitopes on different beads, complement factors and immune complex interference, and irrelevant antibody reactivity against denaturated HLA molecules.
2- Priority points in regular allocation
The New- Kidney allocation system (KAS), which use a point system for patient with > 20% c PRA increases the chance to offer an organ transplantation . Although there is an increased rate of favorable transplantation ,the increased number of organ shipped over longer distances, thereby increasing cold ischemia time .
3- The acceptable mismatches approach
It is based on the positive identification of acceptable antigens, to which the patient has made no antibodies. It is relying on Luminex SAB analysis, combined with epitope analysis. Once acceptable antigens are defined, these are added to the HLA type of the patient, creating an extended HLA type on which matching is performed.
AM program;
If an organ donor with an HLA type compatible with this extended HLA type is reported to Eurotransplant, the kidney is immediately offered to the AM patient with mandatory shipment to the respective recipient centre. It associated with better 10-year survival rate than regular allocation program. Patients with a very low chance to get a suitable offer in their original population, may increase their chance through national and international organ exchanges. It is cost-effective way of transplanting highly sensitized patients.
4- kidney paired donation;
It depends on the definition of unacceptable antigen, too little versus too many
Increase the possibility to get compatible donors by including compatible couples in the program, and by creating trans-border KPD programs. Highly sensitized patients are not transplanted at a similar rate to other patients, they accumulate in the KPD pool, making it increasingly difficult to run successful match rounds.
5-Desensitization;
The results of desensitization remain controversial.
No standardized protocol.
Summarise the recommendations and reflect on your practice.
1-More allocation programs will introduce a sliding scale for increase priority based sensitization level .
2-Acceptable mismatch programs will expand to other donor population to facilitate transplantation of the more difficult to transplant patients .
3- kidney paired donation has the potential to be expanded , both in term of donor population ,as well as the type of patient-donor couples included.
4-Sensetization due to transplantation should become a relatively infrequent complication with the introduction of HLA epitope matching
5-Novel agent may allow for more rapid desensitization , although residual plasma cell and B memory cell activity needs to be addressed .
6- highly sensitized patients will always be part of the kidney transplant waiting list due to immunization by pregnancy and blood transfusion .
My own practice ;
Only small group of patients underwent desensitization in our country . Our experience in Paired kidney donor is through direct exchange ( in small number of patient ).
Mohamed Saad
3 years ago
What are the challenges? 1-HLA sensitization:
HLA system is highly polymorphic which keep getting full matched donor very difficult for example within Euro-transplant from period 2008 -2017 only 11% of patients received zero-mismatched kidney.
2-Exposure to foreign antigen through blood transfusion, pregnancy and previous organ transplant led to development of new DSA due to activation of memory cells.
3- Factors that interpret the SAB assay e.g. prozone effect, antibody titer ,antibody affinity, competition for shared epitopes on different beads, complement factors and immune-complex interference. Possibilities to increase rate of transplantation in highly sensitized patients:(Recommendation). A-Priority point in regular allocation:
To provide points for highly sensitized patients in kidney allocation system like regional allocation for them and national allocation for those with cPRA >100% although this lead to increase number of transplantation in highly sensitized patients but due to distance factor , cold ischemia also increased and DGF rate increased also.
Allocation of organ to highly sensitized patients based on absence of unacceptable antigens led o decreased long term graft survival. B-The acceptable mismatch approach:
Special euro-transplant program for highly sensitized patients that depends on identification of acceptable antigens which recipients not react against and no antibody produced which need to be proven by extensive laboratory testing.(Luminex and HLA matchmaker).
This led to decreasing waiting time on the list, with better 10-yrs graft survival than those on regular allocation system. C- Kidney Paired donation:
KPD has a great feedback on living kidney transplant , in this program initial match by virtual then physical match done, has many form couple, or more than circular exchange but still highly sensitized group need more facilities to increase their chance to find compatible donor which can be increased by including the compatible couples in the program for better matching or to cross relatively lower ABO blood group and increase donor pool by keep KPD international. D-Desensitization:
Role to keep negative cross-match before transplantation which when used with PKD to choose DSA load level lower than original donor.
There are many agents used for desensitization e.g. IVIG ,PEX with or without Rituximab ,Borteozomib also used in some trials.
Ides immunoglobulin degradation derived from streptococcus pyrogens.
Its promising but need more randomized control trials. Reflect on your practice:
-Decrease causes of sensitization for CKD patients specially blood transfusion.
-Highly selection for matched living transplantation which has better graft survival .
-Desensitization for low level HLA antibody (IVIG&PEX).
-Try to establish KPD between at least two incompatible donor-recipient pairs.
-Unfortunately KAS ,PKD program and acceptable mismatch approach costly programs and still not available in our practice here.
Mohamed Mohamed
3 years ago
III. Transplantation in highly sensitised patients: Challenges and Recommendations What are the challenges? – Definition of unacceptable antigens, using Luminex SAB, for highly sensitized recipients is subject to laboratory expertise & interpretation.
– SAB MFI is a sensitive but a crude method of defining antibody level or strength.
– Confounding factors in interpreting SAB results include: i.prozone effect ii.antibody titre & affinity iii.irrelevant antibody reactivity against denatured HLA molecules iv.complement factors & immune complex interference v.comptition for shared epitopes on different beads
– Prolonged waiting list time.
– Susceptible to removal from the list.
– Very low likelihood of finding a suitable donor.
– Increased mortality & morbidity while on dialysis.
– Transplanting truly high sensitized(cPRA )patients dependent on centre policy regarding acceptable antigens.
– Increased cold ischemia time due to shipment of organs for long distances.
– Long term graft survival data are not available.
– In the new KAS there is increased rate of zero HLA mm. This will likely increase the chance of HLA immunization in case of graft loss.
– Breadth of unacceptable antigens in allocation systems will preclude transplantation in many cases.
– Less than 15% of highly sensitized patients succeed to find acceptable organ in KPD program.
– highly sensitized patients accumulate in KPD pool making it difficult to run successful match runs.
– Increase risk of AMR in transplants carried after desensitization.
– Controversial results in studies looking into the benefits of desensitization compared to remaining on waitlist.
– A large single center study showed that there is no survival benefit of desensitization compared to remaining in waitlist. ================================================ Summarise the recommendations and reflect on your practice. Recommendations:
– Introduction of HLA epitope matching to decrease frequency of sensitization.
– Introduction of new strategies to address residual plasma cells & memory cells activity
– Expand KPD programs
– Expansion in acceptable mismatch programs
– Expansion in the use of sliding scale in allocation systems for prioritization of highly sensitized patients
Reflection on my practice:
In our transplant centre we are doing less than 80 transplants annually. All are live related donations.
We are not transplanting highly sensitized patients due to logistic issues. We are sending such patients for KPD to another centre in the country; this centre is doing around 200 transplants yearly. They are doing only small number of KPD transplants.
Batool Butt
3 years ago
Renal transplantation offers the highest survival benefit for ESRD patients when compared to other modalities of renal replacement therapies. Challenges in desensitization
Desensitization offers a good transplant opportunity and survival advantage for highly sensitized recipient who has a very low likehood for getting a transplant (living or deceased) due to positive cross-match.The goal of desensitization is to remove preformed DSA that cause positive cross-match with the donor.Three main treatment options for desensitization:Plasmapharesis, IVIG, and Rituximab, with the combination of low dose IVIG and plasmapheresis, is the most commonly used protocol
Although Desensitization was found to improve short-term graft and patient survival, long-term survival may be reduced due to rejection, increase risk of infection and malignancy from aggressive immunosuppression, moreover it is expensive. Thus desensitization should be limited to transplant recipients with no living donor who are highly sensitized that are in the top of the waiting list in KAS so cannot find deceased offer and are expected to be waitlisted for long time.
Also, Desensitization cannot be applicable in all patients it is indicated only in patients with positive FXM due to DSA provided that MCS< 250 and RIS <17 if MCS > 250 or RIS > 17 this donor should be excluded Challenges in Kidney Paired Donation (KPD)
KPD is the process of exchange of kidneys between living donor-recipient pairs due to ABO or HLA incompatibility, so allows recipients to receive a better-matched kidney.
The first challenge is that only 15% of highly sensitized transplant recipient with CPRA ≥ 98% has a chance to find a compatible donor, and recipients with blood group O are the most difficult to transplant
Highly sensitized patients will continue to be part of the transplant wait list due to pregnancy, blood transfusion & prior transplant
There has been an increase in cold ischemia times with a resultant increase in delayed graft function DGF rates as the organ is being shipped over long distances in new KAS.
Relatively poor 10-year graft survival rate in those who received kidney through KAS.
Although KPD programs are hugely successful, patients that are highly sensitized ( with => 97% cRF calculated Reaction Frequency ) have a significantly lower chance to get a suitable donor.
Less number of zero-mismatch HLA in KAS, which may increase sensitization in case of graft failure.
The highly sensitized patients are not transplanted at a similar rate to other patients, and they accumulate in the KPD pool, making it increasingly difficult to run successful match rounds.
Determining a DSA level that is amenable to desensitization is required.
< 15% of highly sensitized patients are able to get compatible donor in PKD program.
After desensitization, the transplanted kidney is at increased risk of early & late ABMR Summarize the recommendations and reflect on your practice.
The solution to these challenges lies in a step-wise approach:
1) Avoid sensitization: Prevention is always better than cure. So avoidable sensitization events like blood transfusion should be concentrated upon.
2) Use HLA matching based on B cell epitopes, to transplant patients with a kidney not having immunogenic epitopes for the specific recipient, helping in reduction in sensitization due to previous transplant, if the graft fails.
3) Use potential live donors with or without KPD program:
a. Patient specific approach is important in this.
b. ABO incompatible transplant can be performed for highly sensitized patients in KPD
c. Addition of compatible pairs in KPD can further increase chances of getting a kidney for highly sensitized patients.
d. Referring these highly sensitized patients to certain centers with high experiences in managing these difficult cases.
e. Use the acceptable mismatch program, especially by searching for donors outside their own donor pools, by national and international collaborations.
f. Desensitization, even for non-HLA antibodies, helps in increasing transplant rates in such patients. Our practice:
We have a living donor program at our center. We have performed a 2-3 transplants after desensitization. Although, at national level, many centers are doing transplants after desensitization and the chances of success of such highly sensitized patients, varies from center to center.
Weam Elnazer
3 years ago
The following are some of the difficulties associated with transplantation in highly sensitized patients:
-An increase in the number of patients who are sensitized or severely sensitive as a result of sensitizing events (like pregnancy, previous transplants and blood transfusions).
-A high level of HLA polymorphism, reduces the likelihood of obtaining a kidney with no mismatches.
Because of the high sensitivity of Luminex-single antigen bead testing, increased identification of antibodies in the recipient (depending on various aspects such as prozone effect, antibody levels, antibody affinity, epitope sharing, as well as antibody activity against denatured HLA) has resulted in a reduction in the likelihood of finding an acceptable donor.
The absence of clear rules has led to different transplant facilities having their own policies when it comes to treating patients with severe organ rejection.
The new Kidney Allocation System (KAS) in the United States gave higher priority to such patients, increasing their transplant rates from 2.5 per cent to 13.4 per cent and decreasing wait times from >19 years to 3.2 years. However, it still has many challenges, including a. increased cold ischemia times, resulting in delayed graft function, though with no effect on 6-month graft survival. b. increased cold ischemia times, leading to increased delayed graft function, though with no effect on 6-month
b. Graft survival is much lower during a 10-year period.
When there is a decrease in the rate of zero-mismatch, there is an increase in the likelihood of HLA immunization in the event of graft loss.
Although the kidney paired donor program (KPD) for a negative crossmatch kidney has demonstrated results comparable to non-sensitized patients, there are several obstacles with KPD, including the following: Inconsistent statistics about the outcomes of such individuals following transplantation from different facilities (US cohort pointing towards better outcomes than remaining on wait-list, while the UK cohort shows no survival benefits).
Recommendations:
-Eurostam is a project that aims to increase the chances of finding an acceptable graft for patients who have a very low chance of finding a suitable donor due to the presence of antibodies against common HLA antigens in the Eurotransplant donor population by expanding the donor pool to different national and international allocation programs and increasing the chances of finding an acceptable graft for patients who have a very low chance of finding a suitable donor due to the presence of antibodies against common HLA antigens in the Eurotrans.
-The use of a point system to prioritize highly sensitive patients in the allocation system, similar to what was done in the KAS system, allows for a reduction in waiting time.
If a donor’s HLA type is not compatible with an acceptable mismatch program, the program will be terminated. Acceptable mismatch programs have had positive outcomes in Eurotransplant, with improved 10-year donor graft survival and cost-effectiveness. They have also reduced the waiting time for transplants.
— The use of new desensitization agents such as Bortezomib, Ecluzimab, and IdeS was investigated, with preliminary results for IdeS being favourable.
The results of certain research indicated that a desensitization regimen was advantageous to graft survival, which was in contrast to the findings of other investigations.
reflect on your practice. 1-Expand KPD programs in addition to desensitisations to improve the chances of highly sensitised patients on dialysis. we have already a program but a limited number only those who agree to proceed for paired donation. 2- Improving the national system for kidney allocation will help to expand transplantation.
Asmaa Khudhur
3 years ago
Challenges to transplant in highly sensitized patients: 1-highly sensitized patients having cPRA or virtual (vPRA )or CRF is more than or equal 85–100%.
2-To increase transplanting of highly sensitized patients and decrease waiting time and mortality. 3-polymorphic HLA system which is a strong barrier against finding fully match unrelated donor . 4-previous events of sensitization like pregnancy, blood transfusion and prior transplantation. 5-depending on individual lab interpretations for the detection of an acceptable Ags. 6-new kidney allocation system as to increase rate of of transplanting highly sensitized patients and give them higher priority in the system so rate increase from 2.4 to 13.4% in first year of implementation 7-patient group with 99.9%-100% cPRA is transplant at the lowest level even with new system. 8- improve the outcome regarding graft survival in highly sensitized patients. 9-increasing the chance of receiving compatible organ offer for recipient in AM program is hard or difficult to be achieved. 11-in KPD highly sensitized population with CRF . or more than 97%,diffult to transplant. 12-transplantation with living donor for highly sensitized patients through KPD not be fully utilized. 13-most of studies for out come of transplant after desensitization are small studies,so existence of of large studies is crucial to add more result about desensitization. RECOMMENDATION : 1-avoid sensitization events such as blood transfusion . 2-transplant from living donor with or without paired kidney program. 3-acceptable mismatch added to HLA type of the patient forming extended HLA type is associated with better graft survival and more cost effective. 4-HLA matching based on B cell epitopes aiming to prevent DSA formation. 5-desensitization is for HLA and non HLA antibodies to increase success rate of transplantation,
In my country there is no KPD program or other programs we depend on living donor transplantation
And desensitization.
Hinda Hassan
3 years ago
What are the challenges?
The high number of highly sensitized patients on the waiting list
Antibodies against the common HLA antigens present in the donors pool
Prolonged waiting time on dialysis which is associated with high mortality
Techniqual issues: false positive mismatch due to use of high sensitive SAB which can detect even non function antibodies, prozone effect, low antibody titer, antibody with low affinity, competition for shared epitopes on different beads, immune complex interference and activity against denatured HLA.
Shipping of organ increases cold ischemia time resulting in more DGF
Allocation systems challenges : Despite the implementation of allocation systems like KAS, patients with the highest sensitization level remained in the waiting list. This could be due to centres unacceptable antigens listing policies which might list patients who are intermediately sensitized as highly sensitized. Poor 10 year graft survival of transplanted graft in highly sensitized patients when allocation is based on exclusion of unacceptable antigens. The rate of HLA mismatch in the new KAS is increased. So in case of graft loss, this will lead to more sensitization.
The approach of acceptable mismatch antigen also depends on luminex SAB. Those who are having less chance in this system are those who have the very uncommon HLA types besides having antibodies for the common HLA types. For those patients, search of donors should be from outside their population.
Summarise the recommendations
Adopt a step wise approach: 1. Use of available living donors whenever possible 2. Regular allocation systems like KAS. 3. Acceptable mismatch (AM) . Acceptable mismatch antigen approach (eurotransplant) identify the acceptable antigens to which the patient has no antibodies. This was done through CDC in the past but recently it has been done through single antigen lines SALs in flow cytometry. This prove to be cost effective ,3/5 the patients were transplanted, shorter waiting time on the waiting list with improved 10-year graft survival.Performing matching on Extended HLA type will combining the defined acceptable antigens to HLA type of the patient . Those who are having less chance in acceptable mismatch , search of donors should be from outside their population. EUROSTAM is a project funded by the European union to implement wide AM programme to get benefit from the variation in antigens prevalence in different populations. But this needs further workup in the ethical and legal prospective. 4. PKD: Kidney paired donation to overcome the incompatibilities in living donations.there are several modalities: direct exchange, circular exchange or domino exchange. The later provide a chance , each time, for one on the deceased donor waiting list. Kidney paired donation was faced with the small number of eligible donors esp for highly sensitized with PRA more than or equal to 97%. This can be overcome by indwelling of multicentre PKD. Acceptable antigens when too little can end with appositive final cross match which may disrupt the paired donation round.if unacceptable antigens are high , this will make finding a compatible donor.this xan be solved by using patient specific approach for relevant HLA.inclusion of compatible pairs increae the chance for finding a better match and give a chance for highly sensitized patients to find an acceptable donor. Use of ABO incompatible pairs also increase the donor pool. Utilization of trans-border KPD programms increases the donor pool.combineg PKD with desensitization .this need definition of DSA level that can be subjected to desensitization.high level are refractory to desensetzaion and are associated with poor outcome. 5. Desensitization: through the traditional protocols or through the use of new drugs such as bortezomib ,eculizumab,IdeS reflect on your practice In Sudan, we adopted the PKD through direct exchange mainly. Desensitization protocols which depend on plasma exchange, IVIg and rituximab are used but at a low rate due to the high costs.
Jamila Elamouri
3 years ago
Transplantation in highly sensitised patients: Challenges and Recommendations
Highly sensitized patients are those who have HLA antibodies that react to ≥ 85 –100% of the donors in their donor population (c PRA, v PRA, c RF)
They have prolonged waiting time and a high mortality rate on dialysis. Challenges: a- HLA related
1- Regarding HLA sensitization:
HLA is highly polymorphic so; the likelihood of finding a fully matched unrelated donor is extremely rare.
2- Screening for HLA antibodies and subsequently unacceptable antigen definition with the advent bead-based luminex assays depends on the interpretation and expertise of the individual laboratories as there is no universal standardization.
3- The interpretation of these assays is affected by many factors like; prozone effect, antibody titre, antibody affinity, competition for shared epitopes on different beads, complement factors and immune complex interference, and irrelevant antibody reactivity against denaturated HLA molecules.
4- By using these sensitive assays many patients may be classified as highly sensitized, and therefore decrease their chance to receive an organ offer through regular allocation. Recommendations: take into consideration the following in HLA ABs
1- Accurate classification of serum HLA antibodies for the definition of unacceptable antigens is essential.
2- Per-patient assessment with an individualized threshold for positivity.
3- correlation to previous sensitizing events.
4- HLA epitope analysis
5- the chance of the patient receiving a transplant.
Priority Points in regular allocation recommendation:
1- highly sensitised patients should give higher priority in the regular allocation system.
2- New- Kidney allocation system (KAS), which use a point system for patient with > 20% c PRA.
3- Further priority by regional allocation for c PRA of 98%, and national allocation to those with c PRA of 100% Transplantation of highly sensitized patients in the New KAS (challenges)disadvantages:
1- it is dependent on the centre’s policies for the definition of unacceptable antigen
2- cold ischemia time increased, with an ultimate increase in delayed graft function rates.
3- Long term effect needs to be determined.
4- Relatively poor 10-year graft survival rates, based on unacceptable antigens.
5- The rate of zero HLA mismatches significantly declined in the new KAS, increasing the chance of HLA immunization in case of graft loss.
The Acceptable Mismatch approach strategy:
It is based on the positive identification of acceptable antigens, to which the patient has made no antibodies. It is relying on Luminex SAB analysis, combined with epitope analysis. Once acceptable antigens are defined, these are added to the HLA type of the patient, creating an extended HLA type on which matching is performed. If an organ donor with an HLA type compatible with this extended HLA type is reported to Eurotransplant, the kidney is immediately offered to the AM patient with mandatory shipment to the respective recipient centre.
Advantages of AM program:
1- Better 10-year survival rate than regular allocation program.
2- Using allocation based on acceptable antigens is better than allocation based on avoidance of unacceptable antigens.
3- Very cost-effective way of transplanting highly sensitized patients.
4- Patients with a very low chance to get a suitable offer in their original population, may increase their chance through national and international organ exchanges. Kidney paired donation program
In this program; HLA and/ or ABO-incompatible patient-donor couples are entered into dedicated match rounds to find the highest number of compatible combinations.
Highly sensitized patients are not transplanted at a similar rate to other patients, they accumulate in the KPD pool, making it increasingly difficult to run successful match rounds.
It depends on the definition of unacceptable antigen, too little versus too many
Increase the possibility to get compatible donors by including compatible couples in the program, and by creating trans-border KPD programs.
Desensitization
With this strategy transplant of HLA incompatible kidneys with a negative crossmatch become possible.
The results of desensitization remain controversial. No standardized protocol. Expert commentary
1- Prevention of sensitization is important.
2- 2- HLA matching based on B cell epitopes has allowed for transplanting HLA mismatched organs that do not bear immunological epitopes for the specific patient, preventing DSA formation.
Wael Jebur
3 years ago
The challenges facing transplantation in highly sensitized patients (cPRA 85-100%) are:
1) the hypersensitized patients are those who have antibodies against HLA antigens in the donor population,in the community. These antibodies are acquired through pregnancy, blood transfusion and previous organ transplant. It’s usually reflected as cPRA, virtual PRA, calculated reaction frequency cRF
2) Those donors whom the recipients developed antibody against, they would be excluded due to their unacceptable HLA antigens.
3) The hypersensitized patients would be waiting for long time before getting an acceptable HLA antigens donors, exposing them to the high mortality risk associated with hemodialysis.
4) Identifying the HLA antibodies in the patients properly would make up the map for unaccptible antigens . Therefore the methods used to detect the antibodies intensity and affinity ,the current Single antigen bead SAB Luminex study is highly sensitive in detecting the HLA antibodies. Concerns related to HLA antibodies detected by SAB assay:
1) Prozon effect,Antibody titer and Antibody affinity.
2) competition on shared epitops in different beads.
3) Complement binding.
4) immune complexes interference.
5) irrelevant Antibody activity against denatured HLA molecules.
Therefore individualization of the results of HLA antibodies are essentially recommended.
Methodes to overcome the immunologic barrier in highly sensitized patients.
1) Priority point in regular allocation :
KAS resulted in improved rate of kidney transplant for highly sensitized patients.
Regional allocation for cPRA of 98% and national allocation for those with cPRA of 100%.
The draw backs related to this strategy are prolonged cold ischemia time with its consequent high risk of delayed graft function, in addition to poor 10 years graft survival
2) The acceptable mismatch approach:
The acceptable mismatch antigens are those HLA antigens against which the patient has no antibodies identified by CDC and SAB assays.
This method was adopted by Eurotransplant ,and it showed that allocation by acceptable mismatch is superior to the allocation based on the avoidance of unacceptable antigens.
3)kidney Paired donation KPD:
Depend on virtual cross matching of different life donors and physical cross match of the couple afterwards showed an excellent result.
4) Desensitization protocol:
Is to remove the preformed HLA antibodies from the patient s plasma and convert the positive flow cytometric assay to negative reaction. Performed by plasma pheresis ,and adminstration of IVIG and Rituximab to deplete the sensitized clone of B lymphocytes against HLA antigen.
It’s indicated for those patients who failed to get transplantation by other methodes discussed earlier.
The outcome of this method is still controversial with debatable long term prognosis..
In our practice ,we are looking for compatable HLA antigens with negative CDC.We don’t have PKD or desensitization protocol.
Manal Malik
3 years ago
Challenges to transplant in highly sensitized patients:
1) challenge to transplant in highly sensitized patients with cross match negative donor
highly sensitized patients having cPRA or virtual (vPRA )or CRF is more than or equal 85–100%.
2) successful transplant of highly sensitized patients and decrease waiting time and mortality.
3) finding fully match unrelated donor due to high level of HLA polymorphism.
4) unavoidable sensitization inform of allo antibodies, such as pregnancy and previous blood transfusion which are associated with strong immunization .
5) highly sensitized patients with in acceptable antigens their detection depend on expertise interpenetration of individual laboratory by lemunix Ag bead (SAB) and its affect by many factors.
6) new kidney allocation system as to increase rate of highly sensitized patients and give them higher priority in the system so transplant
rate increase from 2.4 to 13.4% in first year of implementation..
7)patient group with 99.9%-100% cPRA is transplant at the lowest level even with new system.
8)to improve relatives poor 10 years group survival rate for highly sensitized with a
obscene of unacceptable antigens.
9)avoidance of transplant highly sensitized with acceptable HLA mismatch and donor organ.
10)increasing the chance of receiving compatible organ offer for recipient in AM program is hard or difficult to be achieved.
11)in KPD highly sensitized population with CRF . or more than 97%,diffult to transplant.
12)transplantation with living donor for highly sensitized patients through KPD not be fully utilized.
13)most of studies for out come of transplant after desensitization are small studies,so existence of of large studies is crucial to add more result about desensitization.
SUMMARY OF RECOMMENDATION AND REFLECT YOUR PRACTICE
1-try to avoid sensitization such as blood transfusion .
2-transplant from living donor with or without paired kidney program.
3-acceptable mismatch added to HLA type of the patient forming extended HLA type is associated with better graft survival and more cost effective.
4-HLA matching based on B cell epitopes aiming to prevent DSA formation.
5-desensitization is for HLA and non HLA antibodies to increase success rate of transplantation,
in our center only available program living donor transplantation ,KPD and other program still not available.,
desensitization is done but unfortunately the out come is unfavorable.
0
Mohammed Sobair
3 years ago
Transplantation in highly sensitised patients: Challenges and Recommendations What are the challenges?
KAS:
Increase cold ischemia in KAS.
Poor 10 YEARS graft survival.
Risk of immunization in case of graft loss, less chance of HAL -A, HAL-B and HLA-DR
zero mismatch.
Acceptable mismatch approach:
25% have less chance due to uncommon HLA in Eurotransplant donor population
KPD:
Small number of donor participate in KPD.
Large number of high sanitized in KPD lead to accumulate of patient and less chance to
have match round.
͘ Desensitization:
Increase risk of ABMR, both early and late.
Summarize the recommendations and reflect on your practice:
Highly Sensitized patient should be always part of translation list.
Minimalize sensitization by organ transplant itself.
HLA matching based in B cell epitope, allow for transplanting HLA mismatch organ not
bear immunologic epitopes to the patient, preventing DSA antibodies formation.
Making use of LRD.
Increase chance of regular allocation.
Include patient in special program like AM program.
Finally desensitization.
KPD are expanding in term of type and population of donors.
Challenges in transplantation of highly sensitized patients include: 1) Increased number of sensitized and highly sensitized patients due to sensitizing events (like pregnancy, previous transplants and blood transfusions). 2) High HLA polymorphism, leading to decreased chance of finding a zero-mismatch kidney. 3) Advent of luminex- single antigen bead testing, with its high sensitivity, has led to increased identification of antibodies in the recipient (depending on various aspects like prozone effect, antibody levels, antibody affinity, epitope sharing as well antibody activity against denatured HLA) further leading to lower chances of finding an acceptable donor. 4) Due to lack of uniform guidelines, different transplant centers have individual policies for transplanting such patients. 5) Although the new Kidney Allocation System (KAS) in US gave higher priority to such patients, increasing their transplant rates from 2.5% to 13.4% and decreasing wait times from >19 years to 3.2 years, it still has many challenges like: a. Increased cold ischemia times leading to increased delayed graft function, though without any effect on 6-month graft survival. b. Relatively poorer 10-year graft survival c. Decreased rates of zero-mismatch, leading to increased chances of HLA immunization in case of graft loss. 6) The kidney paired donor program (KPD) for a negative crossmatch kidney have shown results similar to non-sensitized patients but there are challenges with KPD including: a. Only <15% of the highly sensitized patients are able to get a kidney in KPD b. Patients with cRF≥97% have a very low chance of getting a kidney through KPD. c. It is challenging to define unacceptable antigens for including the patient in KPD program. 7) Desensitization has been used as a modality for rendering sensitized patients transplantable, with (by lowering the HLA barrier with respect to the original donor) or without KPD, with good long-term outcomes. The challenges faced include: a. No guidelines for protocol of desensitization to be followed have been formulated, probably due to low number of cases and small number of centers performing such transplants. b. Conflicting data regarding transplant outcomes of such patients from different centers (US cohort pointing towards better outcomes than remaining on wait-list, while the UK cohort shows no survival benefits) 8) The acceptable mismatch program, despite showing excellent graft survival and cost-effectiveness, has certain challenges like: a) Presence of uncommon HLA type and antibodies against common HLA types in population is seen in 25% of the patients decreasing their chances to <0.015% to get a donor kidney. Hence the donor pool needs to be increased for such patients, by having national and international collaborations.
Summarise the recommendations and reflect on your practice.
The solution to these challenges lies in a step-wise approach: 1) Avoid sensitization: Prevention is always better than cure. So avoidable sensitization events like blood transfusion should be concentrated upon. 2) Use HLA matching based on B cell epitopes, to transplant patients with a kidney not having immunogenic epitopes for the specific recipient, helping in reduction in sensitization due to previous transplant, if the graft fails. 3) Use potential live donors with or without KPD program: a. Patient specific approach is important in this. b. ABO incompatible transplant can be performed for highly sensitized patients in KPD c. KPD with desensitization can be performed d. Addition of compatible pairs in KPD (bolstering their chances to get a better matched kidney) can further increase chances of getting a kidney for highly sensitized patients. e. International collaboration for KPD will further increase their chances. 4) Use the acceptable mismatch program, especially by searching for donors outside their own donor pools, by national and international collaborations. 5) Desensitization, even for non-HLA antibodies, helps in increasing transplant rates in such patients. 6) Enlarging donor pools with national and international collaboration.
Our practice:
We have a living donor program at our center. We enter such patients in KPD program, but it is very difficult to get a donor for them. We have performed a few transplants after desensitization. Although, at national level, certain transplant centers have collaborated to increase the donor pool and the chances of transplantation of such highly sensitized patients, we have not contributed to the program.
Abdul Rahim Khan
3 years ago
Renal transplantation offers better outcomes as compared to other modalities. Sensitization can develop due to blood transfusion, pregnancy and previous transplants. Those with cPRA>20 are labelled as sensitized and constitute 20% of transplant recipients in United kingdom. Patients with cPRA>85 % are called as highly sensitized and constitute 85% of the UK recipients and remain on waiting list for long times. Such patients who cannot find suitable donor have following options.
1– Stay on Haemodialysis
2- Try to find suitable living donor through KPD
3-Wait for suitable deceased donor and enrol in KAS. In UK waiting time has reduced from 19 years to 3 years.
4- To adopt desensitization protocols to make transplantation possible in highly sensitised patients.
Challenges in transplantation in highly sensitized recipients.
Repeated rejections leading to poor graft survival
Complication of immunosuppression like infections and malignancy
Applicable in only those with positive FXCM due to DSA if Mean channel shift <250 or RIS <17
Challenges in KPD
Those with negative Virtual cross match can have positive wet crossmatch
Those with blood group O and cPRA >98 have great difficulty in finding a donor
Challenges in KAS
Prolonged cold ischemia time
Antibodies to common HLA antigen may be present and such cases suitable donor may not be present locally and patient may have to find donor in another country.
Those with cPRA >98 have vary less chance of finding a suitable offer.
Recommendations
In highly sensitized patients , adopting the desensitization protocols and paired kidney donation may improve graft outcome and survival.
Effect on my current practice
In my current practice we are only doing live related renal transplantation and with current resources I think there is no room for PKD and KAS
Heba Wagdy
3 years ago
The challenges:
Highly sensitized patients have antibodies against almost all frequent HLA antigens in donor population and probability of having compatible living donor is low even with KPD.
Sensitization occur due to pregnancy, blood transfusion or prior transplant so they will always be part of waiting list.
Donors with unacceptable antigens are excluded to avoid hyper-acute rejection leading to difficulties in finding compatible donors and prolonged waiting time on dialysis which is associated with higher mortality rates.
Transplantation of highly sensitized patients based on absence of unacceptable antigens is associated with poor 10-year graft survival.
Increasing rate of transplantation in highly sensitized patients through giving them priority in allocation system increase clod ischemia time as organs are shipped over long distance resulting in increased rate of delayed graft function.
Patients with uncommon HLA type in donor population have low chance to find HLA match and mostly have antibodies against common HLA types in donor population.
Patients with high level HLA antibodies may be refractory to desensitization and is associated with inferior outcomes.
Transplants after desensitization are at increased risk of early and late AMR.
Results of studies comparing benefits of desensitization versus benefits of remaining on waiting list are controversial. Recommendations:
Immunological risk assessment should be individualized with consideration of previous sensitizing events, HLA epitope analysis, SAB assays results to determine truly relevant HLA antibody specificity and probability of receiving a transplant.
Highly sensitized patient should have higher priority in regular allocation system to decrease waiting time and to increase transplant rate.
Allocation according to acceptable antigens is more beneficial than that according to unacceptable antigens.
Acceptable mismatch (Antigens against which patient had made no antibodies) added to HLA type of the patient forming extended HLA type is associated with better graft survival and is more cost effective.
Searching for compatible donor outside donor population in patients with extremely low chance to receive organ in original donor population.
KPD program with inclusion of compatible pairs searching for better match to enlarge the potential donor pool.
combination of KPD and desensitization to facilitate transplantation.
Prevention of sensitization by organ transplant through HLA matching based on B cell epitopes aiming to prevent DSA formation.
A step wise approach is the optimal strategy starting with potential living donor, increase priority in regular allocation, special program as acceptable mismatch program and finally desensitization protocols.
In our practice,
We don’t have allocation program or PKD
Only living donor transplant
Desensitization with plasmapheresis and IVIG is used in sensitized patients who can afford the expenses and fails to find compatible donor.
We minimize blood transfusion in CKD patients to avoid sensitization
Recommendations to transplant highly sensitized patients ;
1.Priority points in regular allocation ; The new kidney allocation system(KAS) in USA ; a) cPRA >20% ; point system & sidling scale b)cPRA > =98% ; regional allocation c) cPRA >=100%; National allocation[13,5] Transplant rate increased from 2% to 13% in the first year after implementation[16] Median waiting time was reduced from 19 years to 3 years[17]
2.The Acceptable Mismatch approach in Europe ; Based on acceptable antigens[21] More than 1500 transplant since 1989 Excellent graft survival & very cost effective[28,29]
3.Kidney paired donation ; This approach is utilized in living kidney transplantation when direct donation is impossible due to ABO/ HLA incompatibility Started in South Korea 30 years back because they have shortages of living donation and they don’t have deceased donor transplant[30] Transplant outcomes in this program is comparable to outcomes of non-HLA sensitized patients[32,34]
4.Desensitization ; Removal of HLA antibodies and prevention of its production Achieved by combination of the following ;[52,53,75,58,61,62] a) Phasma pheresis
b) IVIG
C) Rituximab
D) Bortezomib
E) Ecluizumab
F) Ides = IgG- degrading enzyme derived from streptococcus pyogenes
5.Combined desensitization & KPD
New ideas which requires ethical,legal, and logistical barrier to be put be overcome between national and international program to help those patient who are still cannot make their way to transplantation ;
a) Europe-wide AM programs
b)Trans-border KPD programs
Challenges ;
Highly sensitized patients will continue to be part of transplant wait list due to pregnancy, blood transfusion & prior transplant
~20 % of patient on wait list are sensitized and 5% are highly sensitized[3]
Risk of delayed graft function due prolonged cold ischemia times as the organ being shipped over long distance in new KAS[16]
Relatively poor 10-year graft survival rate in those received kidney through KAS[20]
Less number of zero-mismatch HLA in KAS which may increase sensitization in case of graft failure[16]
25% of patients listed in Euro-transplant program have a possibility of< 0.015 to get a donor[27]
< 15% of highly sensitized patients are able to get compatible donor in PKD program[36]
After desensitization, the transplanted kidney is at increased risk of early & late ABMR[53,57]
My practice ;
At the moment we are doing only living donation program, and we able do de-sensitization (pp,IVIG,& Rituximab) as the only way to help this category of patients
PKD is potential option is future should the training,legal,logistical requirements are put in place.
Mohamad Habli
3 years ago
The HLA system is highly polymorphic, and every human being has its own HLA-fingerprint.
The immune system is not educated about non self HLA molecules, that’s why foreign molecules induces immune response. Sensitization of recipients occur through pregnancies, blood transfusion and previous transplantation.
The advances in HLA typing, crossmatching techniques and antibody screening techniques have increase the number of sensitized patients , recognizing unacceptable antigens. In the other hand, defining the specificity of antibodies (DSA vs non-DSA), and their strength and also binding capacity also facilitate some high risk sensitized patients.
The development of paired exchange kidney program, kidney allocation policies and also desensitization protocols also had a great impact in transplantation of sensitized recipients. The kidney allocation system resulted in increased transplant rated among sensitized patients with c-PRA > 20. In one year after implementation of KAS, the transplantation of highly sensitized pts c-PRA>99 increased by more than 11%.
The implementation of acceptable HLA antigens to which the patient has no antibodies against, using extensive laboratory testing, will increase the chance to get renal offer. The highly sensitized patients who received offer through the acceptable mismatch program have better overall survival rate comparing to counterparts transplanted via other allocation system. Despite this advance, around 25 % of patients have very low chance to get compatible offer and stay in the waiting list for a long period.
Transplantation from living donor is superior to DDK. Paired exchange program through direct, circular or domino kidney exchange improved the access to living donation with better and more compatible HLA and ABO match. The results of this program are excellent and comparable with transplantation among non-senstized patients. Despite this program, highly sensitized patients are still waiting for a long periods in the waiting list. Improving local and national Paired exchange program into international program could help many patients to find acceptable offer.
Desensitization is a preceding step, when proceeding with paired exchange program , as most of highly sensitized patient not only has HLA Mismatches but also preformed antibodies which will hazard any transplantation. The development of desensitization protocols using plasmapheresis/IVIG/B cell depleting agents/Bortezomib/Complement inhibitors , improve the chance to get more compatible and less risky transplantation. Patients with positive CDC or flowcytometry crossmatch before desensitization, are likely to get kidney offer after desensitization and negative crossmatch. Ides – a streptococcal derived IgG degrading enzyme, given as desensitization agent has been reported to be effective in managing sensitized patients with very promising results.
HLA matching transplantation should be considered to be done on the allele and epitope levels , to avoid sensitization from the transplantation itself. Highly sensitized patient should also be transplanted using different programs of paired exchange, allocation systems, acceptable matches and desensitization.
nawaf yehia
3 years ago
Challenges :
Having a relatively high percentage of sensitized patient on the waiting list ( about 20 – 30 % ) which is an obstacle for transplantation , which makes mortality rates higher of such patients with prolonged waiting times .
sensitization to HLA antigens can occur by differnt ways (mainly blood transfusion , pregnancy , previous transplantation ) .
The Luminex SAB assay is a very sensitive tool burt has various limitations in that it is a crude measure for Ab titre ( can detect Ab that is below the threshold associated with a +ve XM ) , it is aubjected to the prozon effect , due to HLA epitope sharing it can lead to lower MFI on a single bead and thence a false negative result , interference by immune complex and b drugs like IVIG ( which is used in desensitization protocols ) .
with the new Kidney Allocation System KAS higer priority for the sensitized patients , there has been an increasse in cold ischemia times with a resultant increase in delayed graft function DGF rates . Also with the declining rates of zero HLA mismatches , there is an increase in HLA immunization in case of graft loss .
although KPD programs are hugely successful , patients that are highly sensitized ( with => 97% cRF calculated Reaction Frequency ) have significantly lower chance to get a suitable donor.
Although desensitization is widely advoacted for sensitized patients , only few large studies on the benefit of desensitization compared to remaining on the waiting list have been performed , and their results remain controversial .
Multiple reports showed that high level HLA Abs are often refractory to desensitization .
RECOMMENDATIONS ;
for the aforementioned limitatoins of Luminex assay , a per- patient risk assessment with an individualized threshold for positivity , correlation to previous sensitizing events , HLA epitope analysis is advised
applying the new KAS to increase the rate of Tx for the sensitized patients .
applying the Acceptable mismatch approach with the extended HLA type instead of relying on the avoidance strategy of the unacceptable HLA mismatches
More application of KPD programs with the intend to extend it to the regional or even international setting .
Using novel agents namely Ides ( IgG degrading enzyme derived from Streptococcus pyogens ) allow for radid desensitization , however , residual Plasma cells and memory B cells need to be addressed.
sensitization due to Tx can be minimized by introducing HLA epitope matching .
Reflection on my practice :
currently while still not having allocation or KPD programs , nothing can be reflected from this point of view .
Huda Al-Taee
3 years ago
What are the challenges?
Due to the high polymorphic nature of the HLA system, the likelihood of finding a fully matched unrelated donor is difficult.
Multiple sources of sensitization; some occur naturally, such as pregnancy.
The definition of unacceptable antigens needs to be clarified.
Despite changes in the allocation system, patients with the highest level of sensitization are still difficult to transplant and remain on the waitlist.
increased number of organs that are shipped over long distances with a resultant increase in the cold ischemia time and delayed graft function.
The long term graft survival of transplanted highly sensitized patients is poor, indicating that merely providing priority to highly sensitized patients in regular allocation may not be sufficient.
Very uncommon HLA types and HLA profiles that contain antibodies directed against common HLA types.
The highly sensitized patients are not transplanted at a similar rate to other patients, and they accumulate in the KPD pool, making it increasingly difficult to run successful match rounds.
Determining a DSA level that is amenable to desensitization is required.
The studies that address the potential benefit of desensitization are small, single-centre studies without a proper control arm.
Summarise the recommendations
More allocation programs will introduce a sliding scale for increased priority based on sensitization level.
Acceptable mismatch programs will expand to other donor populations to facilitate transplantation of the most difficult to transplant patients.
KPD has the potential to be expanded both in terms of donor populations as well as the type of patient-donor couples included.
Novel agents may allow for more rapid desensitization, although residual plasma cells and memory B cells activity needs to be addressed.
Sensitization due to transplantation should become a relatively infrequent complication with the introduction of epitope matching.
reflect on your practice
In my practice, our program is a live donor program, we don’t have a PKD program, and for sensitized patients who are amenable to desensitization, we use PP+IVIG+-Rituximab.
Ibrahim Omar
3 years ago
What are the challenges?
there is a growing problem of accumulation of highly sensitized patients on the transplant waiting list. patients are regarded highly sensitized when they have HLA antibody profile that reacts to 85-100% of donors in the donor pool. it is usually expressed as cPRA.
sensitization to HLA antigens usually occurs due to blood transfusion or previous transplantations. however, it can also occur in female patients during unavoidable life events as pregnancy.
the 2 main therapeutic options for these patients are kidney paired donation (KPD) and desensitization. however, both options have several limitations.
regarding PKD, it is done through a complex system and it is successful in only 15 % of cases. it is done as following :
1- incompatible pairs are entered into dedicated match rounds to find the highest number of compatible combinations.
2- initial match rounds are generally based on virtual cross matching with a physical cross match performed for every pair thereafter.
3- logistically, there are several types of exchange combinations as :
a- direct exchange between 2 pairs.
b- circular exchange between 3 or more pairs.
c- domino exchange by an non-directed anonymous donor with the final donor donating to a patient on the deceased donor waiting list.
regarding desensitization, its protocols are expensive and need specialized centers with higher experiences and skills. furthermore, these protocols include intensive immunosuppression with serious side effects and also poorer graft and patient survivals.
Summarise the recommendations and reflect on your practice :
proper use of the kidney allocation system (KAS). more allocation programs will introduce a sliding scale for increased priority based on sensitization level.
novel agents for desensitizations can be applied for increasing the rate of successful cases.
combination of these 2 options are highly recommended as this has been proved to be highly successful.
referring these highly sensitized patients to certain centers with high experiences in managing these difficult cases.
for my practice, I will adhere to the local policies in my center then negotiate new options with senior colleagues and the whole team.
Doaa Elwasly
3 years ago
Challenges
-The increasing number of HLA sensitised cases on the transplantation waiting list
– HLA is polymorphic rendering it difficult to attain a fully matched donor
-HLA sensitisation is acquired through pregnancy , blood transfusion and previous transplantation,in fact each one has different immunisation intensity .
-Highly sensitised cases are those having c PRA >85-100%
– The luminex single antigen bead assay output MFI is very sensitive and is influenced by different factors which can overestimate hypersensitivity in some cases.
-The increase of transplanting of highly sensitised patients is associated with increased cold ischemia time of organs shipped for long distances , increasing the possibility of delayed graft function
– The more the zero HLA A B C mismatch the more the HLA immunisation leading to graft loss
Recommendations
-To prioritize highly sensitised patients in the allocation system as done in KAS using a point system which enabled reducing waiting time
-In Eurotransplant , Acceptable mismatch programs define acceptable antigens based on Luminex and epitope analysis forming an extended HLA type to which a donor will be offered if compatible to it ,it had favourable outcomes with better 10 y graft survival, cost effective and reduced the waiting time too.
-EUROSTAM project aimed at widening the donor pool to different national and international allocation program increasing the chance of finding an acceptable graft for the group of patients with very low chance to find a suitable donor due to having antibodies against common HLA antigens in the Eurotransplant donor population
-Kidney paired donation (KPD) program is beneficial to highly sensitised patients with access to an incompatible living donor it can be processed either by direct ,circular or domino exchange method, inspite of it’s successful outcomes the chance is low for highly sensitised cases to find an acceptable donor through KPD, this can be solved by widening the donor pool by creating transborder KPD program as well as combining it with desensitisation protocol.
– DSA level amenable for desensitisation need to be addressed .
-Desensitisation protocol usually includes either high or low dose of IVIG with plasmapheresis with or without Rituximab meanwhile still transplanted grafts are susceptible to early and late AMR.
– New desensitisation agents as Bortezomib , Ecluzimab , and IdeS were used ,while the IdeS preliminary results were favourable.
-Some studies showed that desensitisation regimen had beneficial effects on graft survival which was contradictory to other studies.
-A stepwise approach can be the best policy for highly sensitised patients starting by making use of the potential living donor , increasing their chance in allocation programs, involving them in programs as AM program , KPD program as well as combining it with desensitisation protocols.
mai shawky
3 years ago
Etiology and impact of high sensitization:
· Many sensitizing events as pregnancy, blood transfusion and previous transplant leads to development of anti HLA antibodies.
· Sometimes spontaneous sensitization by viral infections, vaccinations can play a role.
· Those with cRA≥ 20% are considered sensitized and cPRA ≥85 % is considered highly sensitized.
· Determination of unacceptable antigens which are contraindication to transplantation.
· In KAS, usually highly sensitized ones take priority points.
· After failed PKD in living donor and KSA in deceased ones to find suitable donor especially in those with cPRA ≥ 98% and in case of very long waiting list, we are obligated to use desensitization protocols as (PEX, rituximab or IVIG) to remove preformed DSA and convert cross match from positive to negative.
Challenges in transplanting highly sensitized recipients:
Challenges in desensitization
Long term survival may be reduced due to repeated rejection episodes.
Higher risk of infection and malignancy from aggressive immunosuppression, moreover it is expensive.
It can not be applicable in all patients it is indicated only in patients with positive FXM due to DSA provided that MCS< 250 and RIS <17 if MCS > 250 or RIS > 17 this donor should be excluded
Challenge in KPD and KSA
Still those have cPRA ≥ 98% has very difficulty to find compatible donor, and especially with blood group O.
Highly sensitized recipients with negative virtual cross match can have positive wet cross match
Recommendations:
Sometimes, best option is hybrid approach with desensitization and implementation of PKD or prioritization in KSA.
In our local practice
We are exclusively living-donor transplant, due to religious issues.
PKD and KSA is not utilized or available in Egypt.
In addition, we can not afford desensitization protocols, due to financial issues.
· Unfortunately, such highly sensitized patients are let to die on dialysis.
· I don’t know how to apply these protocols in my practice.
Sahar elkharraz
3 years ago
Still there is waited list for long time of sensitised patients which are accounted 20% of total transplant and 5% of highly sensitised patients.
Those patients have antibodies against allograft.
These antibodies develops due to exposure to pregnancy and transfusion immunization.
HLA antibody detected by CDC and cPRA > 20% considered unacceptable antigen.
Recommendation:
Highly sensitised patients who are waited for long time better put them in priority of allocation system; by this ways recently there’s increase number of transplanted patients from deceased donor and decrease waiting list from 19 years to 3.2 years but there’s challenges for patients with cPRA > 99% better avoid to transplant.
Despite decrease rate of waiting list but kidney allocation system based on avoidance of unacceptable mismatch.
Acceptable mismatch approach:
first identify of acceptable antigen .
it’s HLA antigen which are no match antibody .
this is detected by CDC / single antigen assay and MIF.
this is a chance about 25% to get transplant of sensitised patients who are waited list .
They recommended to Kidney paired donation.
Transplant with living donor is associated with superior long term graft survival.
Types of exchanges:
1. Direct exchange between 2 couples
2. Circular exchange between 3 or more couples
3. Donor donation to patients on deceased donor waiting.
Transplant outcome with cross match negative donor by kidney paired donation are excellent and give same results of transplant outcome of non sensitised patients.
Several ways to increase chance of successfully transplant in highly sensitised patients in kidney paired donation.
1. Compatible pairs in the program
2. Cross the relatively lower ABO groups and increase possibilities of HLA compatible match
3. Combination of Kidney paired donation with desensitisation strategies are used to allow for transplant of seemingly incompatible pairs.
Desensitisation:
Many reports show high level of HLA antibodies are refractory to desensitisation.
Most desensitisation protocol are high dose of IV Ig or low dose Iv Ig associated with plasma exchange plus rituximab.
Despite this protocol still there risk of early and late ABMR occur.
Recent years novel agents have been introduced such as proteosome inhibitors ( bortezomib ) C5 inhibitors eculizumab
This agents not show significant benefits in patients with DSA level high.
Another agents still under study Ig G degradation enzymes derived of streptococcus pyrogens.
Recommendation:
Desensitisation protocol in combination kidney paired donation help to minimize list of patients waited for transplant and help to improve outcome of graft survival in sensitised patients.
Filipe Prohaska Batista
3 years ago
This study describes the introduction of Eurotransplant and its impact on the promotion of transplants in Europe, comparing it with other modalities in the world.
As in other parts of the world, the classification of highly sensitized patients originates from blood transfusions, immunization, and activation of humoral humanity, whether due to underlying disease or infections. Screening with crossmatch positivity is similar.
Unlike the Americans, who use a cPRA above 80% to consider the patient sensitized, Europe uses a cut-off of 85%. Regardless, patients above 99.95% cPRA still have a lot of difficulty having an organ available. The more sensitized the patient, the greater the area of expansion to search for the organ, which directly impacts the time of cold ischemia. These protocols for highly sensitized patients increased transplantation from 2.4 to 13.4% and decreased waiting time from 19 to 3.2 years. There is still the challenge of quality and standardization of exams for correct classification of cases.
Kidney paired donation (KPD) has become an alternative option to find an HLA-compatible donor. Associated with the Acceptable Mismatch (AM) program, if an organ is offered to Eurotransplant, the kidney is immediately offered and prioritized at the transplant center where the recipient waits. This combination of programs (Eurotransplant and AM) improved graft survival in highly sensitized patients at ten years when compared to the traditional model (72.8 vs 62.4%). In addition to good results, it is a very cost-effective program.
Kidney Paired Donation transplants have grown significantly to include subpopulations and more advanced laboratory techniques have included patients with positive Crossmatch who initially were virtually negative. The expansion to include ABO mismatch has increased HLA match compatibility.
The possibility of desensitization is practically mandatory in this profile of patients with high cPRA, in an attempt to reduce the ability of humoral immunity to promote rejection.
The lack of standardization of techniques such as plasma exchange associated with immunoglobulins in the most varied doses, rituximab (anti-CD20 blocking the maturation of B lymphocytes but unable to restrict antibody-producing plasma cells), bortezomib (high cost but blocking the action of plasma cells), eculizumab (blocking complement complex formation). Recently changes in Streptococcus pyogenes lead to IgG degrading proteins, preventing the antibody from promoting a local humoral response.
HLA matching based on humoral response (B cell epitopes) has been shown to allow for transplanting HLA mismatched organs that do not bear immunogenic epitopes for the specific patient, preventing DSA formation.
Sherif Yusuf
3 years ago
Renal transplantation offers the highest survival benefit for ESRD patients when compared to other modalities of renal replacement therapies.
Exposure to sensitizing events like pregnancy, blood transfusion and previous HLA mismatched transplant leads to the development of HLA antibodies.
Patients with c PRA≥ 20% are considered sensitized (constitute 20% of UK transplant recipients), and patients with cPRA ≥85 % are considered highly sensitized (constitute 5% of UK transplant recipients)
Highly sensitized transplant recipients are extremely difficult to find a suitable living donor and usually are maintained for a long time in the waiting list for deceased donor.
Highly sensitized transplant candidate who cannot find a suitable donor has one of the following possibilities:
1- Keeping the patient on hemodialysis which is associated with higher mortality
2-Try to find compatible living kidney donor, it may be difficult but because of KPD (local or preferred national) any recipient who have a living donor even if ABO or HLA incompatible can exchange the donor with another pairs
3- Wait for a compatible deceased donor and this will take a very long time, but because of improvement in the kidney allocation system (in UK it is called acceptable mismatch program -AM) waiting time is reduced from > 19 years to around 3 years
4- Desensitization to render incompatible donor possible for transplantation
Challenges in Finding deceased donor offer through KAS
KAS is either regional or national which permits expansion of donor pool
Sensitized transplant recipient take waitlist priority points according to his/her cPRA which starts from cPRA of 20% and increase gradually till reaching to patients with cPRA ≥ 98%
This is done through what is known as extended HLA typing which in addition to HLA matching of the donor and recipient takes into consideration (using virtual crossmatch) the acceptable antigens to which there is no DSA (was done using CDC and now using Luminex) and avoid unacceptable antigens.
But highly sensitized transplant recipients with cPRA ≥ 98% remain a problem with 25% of waitlisted patients having < 0,015 probability of getting an acceptable offer
Some patients have antibodies to a common HLA antigen and the only way is to find a donor in another country where this common antigen is not frequent
Another problem is prolonged cold ischemia time due to shipping which is associated with DGF but fortunately, the graft outcome is not affected in most of the cases
Challenges in desensitization
Desensitization offer a good transplant opportunity and survival advantage for highly sensitized recipient who has very low like hood for getting a transplant (living or deceased) due to positive cross match.
The goal of desensitization is to remove preformed DSA that cause positive cross match with the donor
3 main lines are available for desensitization Plasmapharesis, IVIG, and Rituximab, with the combination of low dose IVIG and plasmapheresis is the most commonly used protocol
Although Desensitization was found to improve short term graft and patient survival, long term survival may be reduced due to rejection, increase risk of infection and malignancy from aggressive immunosupression, moreover it is expensive. thus desensitization should be limited to transplant recipients with no living donor and are highly sensitized that are in the top of waiting list in KAS so cannot find deceased offer and expected to be waitlisted for long time.
Also Desensitization can not be applicable in all patients it is indicated only in patients with positive FXM due to DSA provided that MCS< 250 and RIS <17 if MCS > 250 or RIS > 17 this donor should be excluded
Challenge in Kidney Paired Donation (KPD)
KPD is the process of exchange of kidneys between living donor- recipient pairs due to ABO or HLA incompatibility, so allow recipients to receive a better-matched kidney.
First challenge is that only 15% of highly sensitized transplant recipient with cPRA ≥ 98% has a chance to find compatible donor, and recipients with blood group O are the most difficult to transplant
Another challenge that many highly sensitized recipients with negative virtual cross match have positive wet cross match
Recommendations
3 options are available for transplanting highly sensitized patients, either wait for a deceased donor offer through the allocations system or if has incompatible living donor can be exchanged with another pair or lastly desensitization
The development of good kidney allocation system (KAS) and national kidney paired donation (KPD) facilitates deceased and living kidney transplantation and decrease the need for desensitization.
Extension of the donor list to outside the recipient country may provide a good opportunity for those having antibodies to a common antigen
Desensitization provide a good opportunity to transplant recipients with no living donor who are highly sensitized so cannot find deceased donor offer and are expected to be waitlisted for a long time.
A combination of both desensitization and KPD may offer the best chance for highly sensitized transplant recipient
In my practice
We are dealing with living-related transplant recipients
We have no kidney allocation system nor system for KPD, also we do not do desensitization
Thus if the transplant recipient is not compatible with the donor due to a positive crossmatch we do not proceed with transplantation
There is accumulation of highly sensitised patients on the transplant waiting list.
These patients have antibodies against most commonly found HLA types present in the donor pool.
Patients are considered sensitised when having an HLA antibody profile that reacts to > 85%-100% of donors in the donor population.
Within eurotransplant among patients awaiting transplant around 20% are sensitised and 5% are highly sensitised.
Within eurotransplant between 2008- 2017 only 11% of patients received a zero mismatched kidney when only considering HLA-A and HLA-B on the broad and HLA-DR on the split antigen level.
Luminex SAB is very sensitive but crude and its interpretation is affected by-
prozone effect
antibody titre
antibody affinity
competition for shared epitopes on different beads, complement factors
Immune complex interference
Irrelevant antibody reactivity against denatured HLA molecules.
Centres unacceptable antigen listing policies may lead to listing intermediately sensitised patients as highly sensitised.
Increased no of organs shipped over long distances increasing cold schema time and DGF rates.
With the new KAS the rate of zero HLA A,B, DR and zero DR mismatches significantly declined increasing the chance of HLA immunisation in case of graft loss.
Definition of DSA levels amenable to desensitisation is needed.
Conflicting outcomes of benefit vs no benefit from studies comparing desensitization vs remaining on dialysis ,getting deceased donor or KPD.
Residual plasma cells and memory B cell activity needs to be addressed.
Summarise the recommendations and reflect on your practice.
A)Priority points in regular allocation
Point system with a sliding scale is used for patients with >20% cPRA.
Regional allocation for patients with cPRA of 99% and national allocation to those with a cPRA of 100%.
B) Acceptable mismatch approach
Based on positive identification of acceptable antigens, which are defined as HLA antigens to which the patient has made no antibodies.
Once acceptable antigens defined they are added to the HLA type of the patient creating an extended HLA type on which matching is performed.
C) EUROSTAM project- Europe wide AM program
D) Kidney paired donation –
Direct exchange, circular exchange or dominos exchange can be done.Less than 15% of highly sensitised patients can find a compatible pair in a KPD match run, especially patients with cRF >97%.Hence for such patients international or multi centre KPD programs are needed.one can include compatible pairs to increase chance of successful transplantation in KPD.Also crossing the ABOi barrier can increase the possibility of a HLA compatible match.combining KPD with desensitisation is a third option to increase transplantation rates in highly sensitised.
E) Desensitisation –
Desensitisation with KPD is needed to be considered.
Some protocols for desensitisation
High dose ivig
Low dose ivig with plasmapheresis
Both with/ without rituximab
kidney paired donation was not done in our unit . desensitisation was not carried out,CDC used to be done and if negative transplanted and if positive rejected. it was mainly a live related transplant program
highly sensitized transplant recipients should be managed in countries experienced in transplantation of these types of patients since PKD, deceased donor allocation system, and desensitization are complex techniques that requires coordination between centers; computer-based matching system and shipping of organs which is not available in all countries
Transplantation in highly sensitized patients: Challenges
· Growing accumulation of highly sensitized patients in the waiting list of transplantation, leading to more comorbidities and complications associated with remaining on dialysis.
· Highly sensitized patients have made antibodies to almost all frequent HLA antigens in the donor population, making negative crossmatch donor is extremely difficult.
Transplantation in highly sensitized patients: Recommendations
· To increase the donor population pool via allocation programs.
· To increase the chance on the exchange program(KPD), the following can be attempted:
a. To include compatible pairs in the program.
b. To cross the relatively lower ABO blood group barrier for highly sensitized patients.
c. Enlarging the donor pool via international cooperation by creating trans-borders KPD programs.
d. Combination of KPD with desensitization strategies.
· Using an advanced agents in the desensitization therapy as IdeS, Eculizumab and Bortezomib which can be used in conjunction with PP and RTX.
· HLA matching based on B cell epitopes, has shown to allow for transplanting HLA-mismatched organs that do not bear immunogenic epitopes for the specific patient, preventing DSA formation. This may not be feasible to majority of patients.
In the practice of rTX in my country we are restricted to matching and compatible living donor transplantation and we don’t proceed with an unacceptable mismatch.
Recommendations including practice
Challenges
Major challenges associated with transplanting highly sensitized patients include
Challenges
*high percentage of sensitization due to sensitization events such as pregnancy, blood transfusion, previous tx.
*luminex single antigen bead increased the incidence of Abs detection making finding compatible donor more difficult.
*No clear standard guidelines for Tx especially in highly sensitized patients and every center has its own policy
*KAS not much successful in Tx patients as well as KPD system .. needs further improvement
*Desensetization outcomes are not very promising especially regarding long-term outcomes.
Recommendation:
*Avoid sensitization as much as possible
*Epitope matching if available.
*KPD and KAS may improve finding compatible tx donors.
*the use of Acceptable mismatch programs with good cost effectiveness.
Our practise : unfortunately KAS and KPD are not available in our country
And tx HLAi is mainly through desensitization techniques.
Transplantation in patients who are considered highly sensitized is challenging for doctors
These challenges are:
-sensitization against HLA may be due to blood transfusion, previous transplant and pregnancy .
-Making the waiting list for transplant more crowded.
-increase numbers of unacceptable antigens with decrease the chance of finding suitable donor .
-15%or less of the highly sensitized patients can find the compatible donor in the KPD match
-preformed DSA resulting in hyperacute rejection .
-increasing time of cold ischemia resulting in DGF
Recommendations :
* Avoid sensitization.
*Desensitization protocol
*Apply KPD system
*Using Bortezomeb which is proteasome inhibitor with plasmapharesis and rituximab
A. Challenges :
________________
▪︎ Accumulattion of highly sensitized patients in the transplant waiting list which this is associated with high mortality rates on dialysis.
▪︎ With the advent of new highly sensitive bead Luminex assay (SAB ) the definition of unacceptable antigens for highly sensitized pts has become more dependent on the interpretation and on expertise individuals.
▪︎SAB is a crude measure for Ab titre and/or binding strength and many factors affects It’s interpretation (prozone effect , antibody titre, antibody affinity, competition of shared epitopes on different beads, complement factors and immune complex interference, ..etc)
▪︎Due to HLA epitope sharing. This can lead to lower MFI on a single bead and thence a false negative result.
▪︎ In the new Kidney Allocation System (KAS) the patients with highest level of sensitization are still difficult to transplant and remain on the waiting list.
▪︎ The success of transplantation in New KAS is much dependent on the centers.
▪︎Also in KAS there is an increase in the number of organs that are shipped over long distances, thereby increasing cold ischemia times which result in increase delayed graft function rates .
▪︎The rates of zero HLA- A,-B,- DR mismatches is low in the new KAS, and there is an increase in HLA immunization in case of graft loss.
▪︎Regular allocation is based on avoidance of unacceptable HLA mismatches on donor organ and for highly sensitized pts, the breadth of unacceptable Ags therefore often precludes transplantation.
▪︎Highly sensitized pts ( cPRA >or = 97%) have significantly lower chance to find a suitable donor through Kidney paired donation programs (KPD).
▪︎ High level HLA Antibodies are often refractory to desensitization.
▪︎Despite desensitization with IVIG or Plasma pharesis with low dose IVIG some transplants are subject to increase risk of ABMR, both early and late.
B RECOMMENDATIONS :
________________________
▪︎Due to the above mentioned SAB assays limitations, a per- patient risk assessment with an individualized threshold for positivity, correlation to previous sensitizing events, HLA epitope analysis and taking into account the chance of receiving a transplant is advised.
▪︎Additional priority in regular allocation system for highly sensitized patients
▪︎ Special Kidney allocation system example (KAS) in which highly sensitized patients (in KAS defined as cPRA> or = 98%) relieve further priority.
▪︎ In Kidney paired donation programs (KPD):
1. Include compatible pairs on the program
2. Cross the relatively lower ABO blood group barrier for highly sensitized patients.
▪︎ Enlarging the potential donor pool through international cooperation by creating trans- border KPD programs.
▪︎ Desensitization protocols.
▪︎ Combination of KPD and desensitization
▪︎ Applying special program for highly sensitized pts such as Acceptable Mismatch (AM) which is based on positive identification of acceptable antigens.
▪︎ Introducing novel agents such as Proteasome Inhibitor ( brotezomb) in conjunction with plasmapheresis and Rituximab.
▪︎ Introducing a novel agent named IgG- degrading enzyme.
Transplantation in highly sensitized patient is a major challenge for doctors
These Challenges include :
increased number highly sensitized ppatients on waiting list.
Increase the number of unacceptable antigens decreases the chance of finding matched donors.
SAB although very sensitive but crude measure of Ab level or strength.
SharedHLA epitope can lead to lower MFI on a single bead and hence a false negative result.
in KAS there is an increase in the number of organs that are shipped over long distances, thereby increasing cold ischemia times which result in increase DGF .
Regular allocation is based on avoidance of unacceptable HLA mismatches on donor organ and for highly sensitized patients, the breadth of unacceptable Ags therefore often precludes transplantation
Highly sensitized patients with high CPRA have significantly lower chance to find a suitable donor through Kidney paired donation programs .
Desensitization can be used with KPD
But still high level of DSA are refractory to desensitization
desensitization with different strategies include IVIG or Plasma pharesis with low dose IVIG plus B cells depletion with rituximab but still some transplants have increased risk of ABMR, both early and late.
Recommendations
-Offering higher priority for highly sensitized patients in kidney allocation programs.
-Enlarging the potential donor pool
-Kidney paired donation protocol offers a more suitable donor but not fully matched to decrease time on waiting list.
– Implementing a new program for highly sensitized patients such as AM programme.
– Desensitization protocol according to degree of mismatch With addition of novel agents such as Proteasome Inhibitor ( brotezomb) in conjunction with plasmapheresis and Rituximab.
In my paractice there is no deceased donor, and there is no organized paired kidney exchange programmes which if applied whould help to expand donor pool and avoid long waiting time on dialysis.
No ABOI-KT hope to be settled in near future.
Pretransplantation work up include CDC crossmatch, FCXM, SAB
desensitization for patients with high PRA.
Transplantation in highly sensitized patients
A. Challenges :
________________
▪︎ Accumulattion of highly sensitized patients in the transplant waiting list which this is associated with high mortality rates on dialysis.
▪︎ With the advent of new highly sensitive bead Luminex assay (SAB ) the definition of unacceptable antigens for highly sensitized pts has become more dependent on the interpretation and on expertise individuals.
▪︎SAB is a crude measure for Ab titre and/or binding strength and many factors affects It’s interpretation (prozone effect , antibody titre, antibody affinity, competition of shared epitopes on different beads, complement factors and immune complex interference, ..etc)
▪︎Due to HLA epitope sharing. This can lead to lower MFI on a single bead and thence a false negative result.
▪︎ In the new Kidney Allocation System (KAS) the patients with highest level of sensitization are still difficult to transplant and remain on the waiting list.
▪︎ The success of transplantation in New KAS is much dependent on the centers.
▪︎Also in KAS there is an increase in the number of organs that are shipped over long distances, thereby increasing cold ischemia times which result in increase delayed graft function rates .
▪︎The rates of zero HLA- A,-B,- DR mismatches is low in the new KAS, and there is an increase in HLA immunization in case of graft loss.
▪︎Regular allocation is based on avoidance of unacceptable HLA mismatches on donor organ and for highly sensitized pts, the breadth of unacceptable Ags therefore often precludes transplantation.
▪︎Highly sensitized pts ( cPRA >or = 97%) have significantly lower chance to find a suitable donor through Kidney paired donation programs (KPD).
▪︎ High level HLA Antibodies are often refractory to desensitization.
▪︎Despite desensitization with IVIG or Plasma pharesis with low dose IVIG some transplants are subject to increase risk of ABMR, both early and late.
B RECOMMENDATIONS :
________________________
▪︎Due to the above mentioned SAB assays limitations, a per- patient risk assessment with an individualized threshold for positivity, correlation to previous sensitizing events, HLA epitope analysis and taking into account the chance of receiving a transplant is advised.
▪︎Additional priority in regular allocation system for highly sensitized patients
▪︎ Special Kidney allocation system example (KAS) in which highly sensitized patients (in KAS defined as cPRA> or = 98%) relieve further priority.
▪︎ In Kidney paired donation programs (KPD):
1. Include compatible pairs on the program
2. Cross the relatively lower ABO blood group barrier for highly sensitized patients.
▪︎ Enlarging the potential donor pool through international cooperation by creating trans- border KPD programs.
▪︎ Desensitization protocols.
▪︎ Combination of KPD and desensitization
▪︎ Applying special program for highly sensitized pts such as Acceptable Mismatch (AM) which is based on positive identification of acceptable antigens.
▪︎ Introducing novel agents such as Proteasome Inhibitor ( brotezomb) in conjunction with plasmapheresis and Rituximab.
▪︎ Introducing a novel agent named IgG- degrading enzyme.
. Highly sensitized patients have c PRA from 85 to 100%.
challenges:
* Sensitization against HLA can occur in case of pregnancy, previous transplants, & blood transfusions with prolonged waiting time.
* High HLA polymorphism, resulting in difficulty in finding fully matched unrelated donors.
*SAB testing, with high sensitivity, help to lower chances of finding an acceptable donor.
*KAS in US Increased cold ischemia times resulting in more delayed graft function.
* Less than 15% of the highly sensitized patients can find a compatible pair in the KPD match.
*Different protocols of desensitization.
Recommendations :
* Prevention of sensitization.
* Use HLA matching using B cell epitopes.
* Use potential live donors.
*Increase the chance of regular allocation.
*Involving patient in special program..
*Desensitization.
Challenges of highly sensitized transplantation include: interpretation of cross-match techniques, priority of allocation system which depend on scoring, low chance of transplantation in high sensitized patients, the choice of proper desensitization protocol and to whom as well as Polymorphism of HLA antigens.
Recommendations: More implementation of acceptable mismatch program which can reduce the waiting time for highly sensitized patients, increase organ exchange of allocation system as well as using of ABO incompatible transplantation, proper desensitization regimens if indicated.
According to personal experience, most highly sensitized patients seen are for 2nd or 3rd transplant, positive CXM by CDC are excluded, while positive FCXM with +ve DSA’s, are desensitized accordingly till achieving –ve matching, if FCXM is –ve, and no DSA’s but the patient is highly sensitized, this is usually expert’s opinion and an individualized opinion regarding whether to desensitize or not. No cadaveric experience.
Highly sensitized patients have a wide range of antibodies against HLA against that exist in the donor pool population making their TX challenging.
Because of preformed DSA hyper-acute rejection results in graft loss in these patients. It needs exclusion of donors with unacceptable antigens and antigens and therefore these patients have prolonged waiting times.
In addition, by using Luminex SAB, which is a very sensitive method, detection of these antibodies is increased every day needing a good knowledge for proper interpretation, such as prozone effects, antibody titer based on MFI, competition for share epitopes and so on.
1- Allocation system:
A good solution is giving higher priority to these patients in allocation system.
For example in the USA there is a sliding scale for patients with cPRAfile:///C:/Users/user/AppData/Local/Temp/msohtmlclip1/01/clip_image002.png20%
Patients with CPRA 100% still have difficulties in finding donor.
In addition, transferring an organ in this condition may results in prolonged cold ischemic time and DGF.
2- Acceptable mismatch:
This program is used in euro-transplant and is based on the positive identification of acceptable antigens.
That patient has no antibody against them.
These antigens are recognized by luminex SAB combined with epitope analysis through HLA match maker of HLA I.
These antigens are added to patients HLA creating an extended HLA type and matching donors HLA based on it.
Using this program almost 1500 case received a transplant with acceptable 10-year graft survival. But for patients with uncommon HLA types or having antibodies against common HLA types, again finding compatible TX is difficult in this context and needs expansion of donor pools to national and international allocation program.
3- Kidney paired donation (KPD): this program is used in living donation.
Because of better outcome with living donors, finding on HLA compatible donor by exchanging the living donor is another option.
These couples are matched based on VXM and then with physical XM.
The result of KPD TX is excellent but finding a KPD match is less than 15%
A combination method with desensitization is used to increase their chance.
Desensitization:
To transplant HLAi kidneys desensitization is used to achieve a negative XM.
This method could be combined with KPD to find a living donor.
But high level HLA-abs are refractory to desensitization should be determined dose IVIG and plasmapheresis and sometimes with adding rituximab or proteasome inhibitor bortezomib and eculizumab.
Ides is a novel (agent endopeptidase) used for desensitization.
Prevention of sensitization by transfusions and TX based on HLA epitope matching.
In our center KPD program in combination with desensitization with IVIG plasmapheresis, rituximab +/- bortezomib to reach a negative XM in low level DSAs is used.
Renal transplantation remains the best option for treatment of End Stage Renal Disease. However, there are patients who are highly sensitized: have in their serum antibodies against almost all frequent HLA-antigens in their donor population. patients are regarged as being highly sensitized when they have an HLA-antibody profile that reacts to more than 85% to 100% of donors in the donor pool, and this sensitization is expressed as cPRA, cRF or vPRA. This sensitization makes the patients unable to get donors thus prolonging their waiting time for a transplant. It has been mnoted that within Eurotransplant about 20% have been sensitized, and about 5% are highly sensitized.The presence of these
As a result , alternative options have to be devised to ensure that these sensitized patients get donors and do not wait too long for their transplant.These options include
The above options require the combined effort of several renal transplant teams across states; but have proven to help highly sensitized patients shorten their wait time on the list.
Recommendations
In my small practice here, there is no deceased donation, as all transplants are live donations. There is also no donor pool. But i believe that this can be started
Udoh
The challenges and recommendations for highly sensitised transplant recipients.
In Euro transplant, approximately 20% of kidney transplant recipients were sensitised and 5% were highly sensitised when c PRA , v PRA or c RF more than 85%. Highly sensitised transplant recipients eventually succumbed to the morbidity due to exhausted waiting time to receive kidney transplantation.
The challenges for highly sensitised transplant recipients are exponential increase in the cumulative number of sensitised transplant recipients which lead to technically very challenging to transplant this group of patients with a cross match negative donor organ. Meanwhile, highly polymorphism of HLA system lead to low probability to get fully match unrelated donor. However, sensitisation of HLA through pregnancy, blood transfusion and previous history of transplant may not have equal weightage. The luminax single antigen bead ( SAB ) assay is highly sensitive along with the great variation of unacceptable antigen listing policies between centres lower the threshold to classify kidney transplant recipient as highly sensitised which reduce the opportunity for kidney transplant. The causal relationship between cold ischaemia time and long term graft survival yet to define while attempt to search for compatible organ donor among other donor population. Ethical, legal, cultural issues while searching for compatible organ donor at other donor population. Although kidney transplant program (KDP) has good clinical outcome, but less than 15% of highly sensitised recipient able to find a compatible pair in kidney donation program match run.
The recommendations include prioritise highly sensitised recipients under the waiting list and running acceptable antigen ( AM ) program to reduce waiting time for transplant with good graft survival and cost effective. Patient specific approach to determine the truly relevant HLA antibody in KDP is essential when direct donation is impossible. Compatible pairs should be included in KDP. Alternatively, ABO blood group barrier need to revise for highly sensitised recipients. Combination fo KDP and effective sensitisation protocol allow transplantation of incompatible pairs. However, predefined criteria for DSA level amenable for desensitisation is essential. Desensitisation protocol involved high dose IVIG, or low dose IVIG couple with plasmaparesis, IV Rituximab, bortezomib, eculizumab and Ig G degraded enzyme derived from streptococcal pyogens under phase 2 trial for desensitisation.
In my opinion, managing highly sensitised transplant recipients should be individualised. Risks and benefits and expected outcome should be explained well to the potential recipients. We should making use of potential living donor, increase the chance of regular organ allocation. Improvement of local AM program with sensitisation protocol are essential for successful transplantation among highly sensitised recipients. Finally, local health authority policy, transplant experts, public awareness for organ donation and international cooperation are crucial for better outcome of highly sensitised kidney transplantation.
The best possible option for patients on dialysis is transplant however the biggest hurdle is presence of antibodies in recipient against his potential donor.sensitization towards HLA can occur due to previous transplant, pregnancies and blood transfusions.patients are regarded highly sensitized when having an HLA antibody profile that reacts to more than 85-100% of donors in the donor population usually expressed as cPRA.
Highly sensitized patients have longer waiting time and subsequently higher mortality rates on dialysis. This review discusses various ways to overcome these hurdles and to facilitate these patients to find a suitable donor.
1. One way of addressing this issue is give priority points to highly sensitized patients in kidney allocation system(KAS).In USA by adopting this system the waiting time for highly sensitized patients decrease from 19 years to 3.2 yrs.
2. Acceptable mismatch (AM) program. identification of acceptable antigens that leads to extended HLA type ,thus increasing chances of finding a Crossmatch negative donor.This approach has reduced waiting time for highly sensitized patients in Eurotransplant region.
3.Kidney paired donation. This PKD was first initiated in South Korea 30 years ago.
Types of exchange combinations include:
a. Direct exchange.
b. Circular exchange between 3 or more couples .
c. Domino exchange made possibly by an non-direct anonymous donor with the final donor donating to a patient on the deceased donor waiting list.
The outcomes of this transplant program are excellent and comparable to outcomes of non-sensitized patients transplantation.
4.Desensitization. Finally desensitization is another way to render these highly sensitized patients fit for transplant .Different desensitization techniques are as follows
High dose IVIG.
Low dose IVIG with plasmapheresis
Rituximab
Bortezomib (proteasome inhibitor)
Eculizomab (complement C5 inhibitor)
Ides(IgG-degrading enzymes derived from streptococcal pyogens).
I think each highly sensitized patients should be offered a transplant depending upon center expertise.
In my country we don’t have a centralized program so for the time being we can’t adopt the recommendations of this review.
HLA is one of the most polymorphic protein,which decides our fate against infection but it also produce one of the greatest barrier in transplantation.
HLA sensitization occurs by blood transfusion,pregnancy, previous transplantation.
The main lab test to detect incompatibility in form of sensitization is CDC assay but not sensitive enough than flow cytometry mcs and luminex mfi.
So, due to sensitization many patient deprived of getting a graft kidney which increases the waiting list along with increases the financial burden.
These are some imp points to increase transplant in sensitized patients-
1.PRIORITY POINTS IN REGULAR ALLOCATION-
the kidney allocation system (KAS)in us giving
priority points in table to sensitized patients.
2.THE ACCEPTABLE MISMATCH APPROACH-
This approach is used by urotransplant ,which is solely based upon identification of acceptable antigens.laboratory test will identify the HLA antigen to which no antibodies are made, hence these accepted antigens are added to HLA type of patient creating an extended HLA type on matching will be performed.
3.KIDNEY PAIRED DONATION-
Highly sensitized patient can get compatible donor through kidney pairing, as compatible living donation have very high chance of survival.
4.DESENSITIZATION-
This is the last thing to be performed which plays god to cross the barrier of immunology.
A.high dose IVIg
B.low dose ivig with plasmapheresis
C.rituximab
D.bortezomib
E.eculizumab
F.ideS
Challenges
1. Accumulation of highly sensitized patients on the waiting list.
2. Difficulty transplantation with a negative cross match donor.
3. Prolongation of waiting time is associated with increased mortality
4. High level of HLA polymorphism renders finding suitable fully matched donor an extreme difficult job especially in highly sensitized individuals.
5. Female patients are more highly sensitized due to pregnancies.
6. Positive cross match carries the risk of hyper acute rejection.
7. Increasing cold ischemia times resulted in delayed graft dysfunction.
Recommendations
1. Offering higher priority for highly sensitized patients in kidney allocation programs.
2. Implementing a new program for highly sensitized patients (acceptable mismatch AM program) and creating extended HLA type category.
3. Kidney paired donation protocol offers a more suitable donor but not fully matched with the advantage of minimizing time of dialysis and its comorbidities.
4. Desensitization protocol according to degree of mismatch, CDC, flow cytometry, DSA, cPRA and MFI.
5. Using novel agents in the future.
In our practice , we undergo essential investigations as CDC, flowcytometry, DSA, cPRA and MFI. we also try as much as possible to avoid blood transfusion with the concomitant use of erythropoietin stimulating agents. we use desensitization protocol for those highly sensitized patients including plasmapheresis and rituximab.
. Highly sensitized patients have cPRA 85-100%.
What are the challenges?
– Sensitization against HLA can occur due to pregnancy, previous transplants, and blood transfusions Highly sensitized patients experience prolonged waiting time.
– High HLA polymorphism, leading to difficulty in finding fully matched unrelated donors.
– SAB testing, with its high sensitivity, leads to lower chances of finding an acceptable donor.
– Kidney Allocation System (KAS) in US Increased cold ischemia times leading to increased delayed graft function.
-Only less than 15% of the highly sensitized patients can find a compatible pair in the KPD match.
– Different desensitization protocols.
Summarise the recommendations and reflect on your practice :
– Prevention sensitization.
– Use HLA matching based on B cell epitopes.
– Use potential live donors.
-Increase the chance of regular allocation.
-Include patient in special program like AM program.
– Desensitization.
– In sudan , we have a living donor program ,and sometimes we used desentization and KPD.
Highly sensitized patient with CPRA of> 98% will be very difficult to find HLA Matched donor even if they have been allocated to DD program or KPD still their chances to get transplantation very low and continue on long waiting list of dialysis
Recommendations to overcome such obstacles:
1-Priorities points in regular KAS for highly sensitized candidates with CPRA 98%.
2-Involve highly sensitized recipients in KAP with acceptable Miss-match program which depend on positive identification of acceptable antigens (21). BY using highly sensitive method for calculation of the acceptable match (AM) with single antigen bead (SAB) and using epitope antigen assay through matchmaker for HLA CLASS 1(25). This helped in shortening the wait list from > 19 years to < 3 years with acceptable 10 years graft survival and cost effective
3-Eurostam program for highly sensitized patients whom still have very low chance to get matched donor eve n through the AM program, by involve them in other Europe wide AM program from other population, such allocation program need address the ethical, logistic barriers for such allocation program between different national and international programs, have been in use since 2012 in Europe.
4- KPD program for allocation of better matched living donor preemptively for both HLA and ABOI patient – donor couple will enter the KPD for better allocation of matched donor. including direct couple paired exchange or circle exchange including 3 or more pairs or domino exchange, very successful program with excellent outcome, alone or in combination with desensitization program by using more noval agents to allow for rapid desensitization to allow for transplantation of HLA incompatible kidneys with negative crossmatch.
5- Further improvement in the crossmatch methods using epitope antigen assay, B-cell epitope assay to allow for HLA mismatched transplant that do not bear immunogenic epitopes not perform DSAs.
we still do not have KPD or DD program , but we do very infrequent DD transplantation and we are able to perform desensitization as part of LD program for highly sensitized patients
HLA matching also we have limitation as we don’t have FXCM or VXM , we still using CDCXM in addition to Luminex SAB assay
CHALLENGES-
1)HLA polymorphism- due to which finding a HLA match in an unrelated donor is extremely slim
2)Definition of unacceptable antigens dependant on interpretation and expertise of laboratories- after advent of bead based luninex assays.
3)Prioritizing such patients leads to long distance shipping of organs –> increases cold ischemia time–> poor long term Graft survival.
4)accumulation of such highly sensitized patients in the transplant waiting list , as well as in the kidney paired donation pool(when they are included in KPD programs)
5)No single treatment available that assures desensitization.
6)highly sensitized patients with no matched donors- whether to dare to cross that barrier by desensitization or advice them to continue hemodialysis .
7) setting the threshold or mark for DSA titre upto which desensitization may be attempted.
SUMMARY OF RECOMMENDATIONS
A stepwise approach to be followed.
1)Prioritizing patients on regular allocation system/ introducing more allocation systems
2)Acceptable mismatch program- identification of acceptable antigens that leads to extended HLA type ,thus increasing chances of finding a Crossmatch negative donor.
3)Including these patients in kidney paired donation program.- facilitates pre emptive transplants.
Crossing the ABO barrier (which has better outcone)
Including international cooperation for enlarging the pool of donors.
4)Finally consider desensitization protocols after ruling out all available options.
5)Most importantly- avoid sensitizing your ESRd patients. Decrease /avoid use of blood products and increase EPO and IV iron use.
REFLECTING ON CLINICAK PRACTICE
1) Increase use of EPO and IV iron and avoid use of blood products in all CkD patients.
2) use the stepwise approach for a highly sensitized patient
3)Transplant after desensitization should be our last option
4) Encourage ABO incompatible transplants over HLA incompatible transplants.
What are the challenges?
1- the decision weather go ahead for transplant and expose patient to risk of rejection and over immunosuppression related morbidity and mortality ? or refuse donor and stay on HD for prolong waiting list ? for me really challenging .
2- HLA system is polymorphism gene with different peptide so it is so difficult to find compatible donor with zero mismatch .
3-those patient with highly sensitized more than 99.5 to 100 percent even with advanced allocation system and paired kidney donation ,it is difficult to find compatible donor so may be transplantable.
4- Allocation of organ to highly sensitized patient may shipped for long period of time so prolong cold ischemia that may cause delayed graft function .
5-Highly sensitize patient that refuse by standard alloaction system could be accept depend on acceptable mismatch system.
6-with kidney pair donation, very highly sensitizing patient still with no suitable donor ,so it solve some but not the whole problem.
7-There is no consensus about desensitization protocol ,there center to center regimen difference.
8-question about which DSA level amenable for desensitization regimen, and which is the safe lower level to go ahead for transplant .
9-Till now there is no effective therapy to Ab mediated rejection .
Summarise the recommendations and reflect on your practice
To give good chance for highly sinsitized patient to transplant we need :
1- Good allocation system.
2- Good acceptable mismatch system.
3-execlent kidney allocation system if possible international .
4-fixed evidence base protocol for desensitization ,for induction ,and for follow up
5-Trusted immunological lab.
Reflect on my practice ?
Highly sensitize patient that previously I think impossible to transplant could be possible and easy to transplant but this need good facility as mention above.
Challenges of highly sensitized transplantation:
Recommendations:
In my country there were no KAS or PKD, but desensitization program can be done for sensitized patients with PP+IVIG+ rituximab
Some advances allowed better recognition of HLA antibodies and subsequent unacceptable antigen. The screening through CDC and PRA, using output of Luminex single antigen bead (SAB) assays is mean fluorescense intensity (MFI) and the individual beads increasing sensitivity were essential for this.
Changes in the regular allocation system of the programs for highly sensitized kidney transplant candidates was another advance, because the prioritization of sensitized patients. In the USA, was used a point system with sliding scale for patients with > 20% cPRA, in Eurotransplant the Acceptable Mismatch (AM) is based on positive identification of acceptable antigens. Kidney paired donation is other option.
However, desensitization appears to be a necessity for some recipients in all cases. And even then, there is a increase in the risk of ABMR.
The main recommendations are:
– making use of a potential living donor
– increasing the chance in regular allocation
– Including patients in special programs such as the AM program;
– Protocols desensitization in the last;
In practice, there is a need for patients to adhere to regular monitoring of their awareness and follow-up by the team of this process for decision-making to follow up to the next step.
Transplantation is a complicated process. Challenges start from selecting the eligible donors for specifies recipients and are endless. So we need to be careful when choosing our pairs and treatment protocols. The greatest challenge is HLA itself being post polymorphic making it difficult to find unrelated donors easily. Natural sensitization like multiple pregnancies and even infection or vaccination may contribute as well. Previous transplantation is also very important. Finding suitable donations through global programs and transfer of organs for long distances has an effect on cold ischemia time and delayed graft function. challenges in interpreting and standardization of SAB itself is an issue as it may not reflect the future in-vivo because multiple antibodies may have a dissipated effect on beads. contrary to that MFI itself is not my lead to unnecessary exclusions. Criteria and degree of mismatch is not standardized so the expectations are variable.
I do not work in a transplant center for the moment but I worked in a center that performs desensitization protocols using all available resources on patient-based protocols mostly with help of plasmapheresis and rituximab. I know centers with good pool for a paired kidney donation that perform circular pairing. I do not have experience or knowledge for the moment regarding cadaveric receipients
Highly sensitized patients have antibodies against almost all frequent HLA types present in their donor population with cPRA ≥ 85-100%. So increasing the number of unacceptable antigens will decrease the chances of transplantation for those highly sensitized patients in the waiting list.
Main causes of sensitization :
1. Pregnancies
2. Blood transfusions
3. Prior transplant
The main laboratory tests to define sensitization (unacceptable antigens) are:
CDC assays.
luminex single antigen bead(SAB) assays and mean fluorescence intensity(MFI).
How to improve chances of transplantation for highly sensitized patients:
1. Priority points in regular allocation
The kidney allocation system(KAS) in united states improve this by using a point system with sliding scale for patients with cPRA≥20%.
Highly sensitized patients with cPRA≥98% receive further priority by regional allocation if cPRA
=99% and national allocation for cPRA
=100%.
Good enough the rate of transplantation of highly sensitized patients increased from 2.4% to 13.4% in the first year of implementation.
2. The Acceptable Mismatch Approach(AM):
AM program is used by Eurotransplant for almost 30 years and based on identification of acceptable antigens.
Extensive laboratory testing will define the HLA antigens to which no antibodies has been made by the patient. These accepted antigens are added to the HLA type of the patient creating an extended HLA type on which matching is performed.
So if an organ donor HLA is compatible to this extended HLA type, it is reported to Eurotransplant and the kidney is immediately offered to the AM patient Centre.
This approach significantly lower the waiting time for highly sensitized patients in Eurotransplant region. From 1989 onwards 1500 patients received transplant out of >2500 patients on AM program waiting list.
Studies showed that highly sensitized patients transplanted through AM program have a significant 10 year graft survival compared to others transplanted through regular allocation(72.8% versus 62.4%).
3. Kidney Paired Donation(PKD) :
living donor kidney transplant has a better long term graft survival and the procedure can be done preemptive .
Highly sensitized patients can go through PKD program to find an HLA compatible donor.
This PKD was first initiated in South Korea 30 years ago.
Types of exchange combinations include:
a. Direct exchange.
b. Circular exchange between 3 or more couples .
c. Domino exchange made possibly by an non-direct anonymous donor with the final donor donating to a patient on the deceased donor waiting list.
The outcomes of this transplant program are excellent and comparable to outcomes of non-sensitized patients transplantation.
4. Desensitization:
it can be used with KPD where the prospective donor has a lower HLA barrier than the original donor .
Desensitization protocols include :
High dose IVIG.
Low dose IVIG with plasmapheresis
Rituximab
Bortezomib (proteasome inhibitor)
Eculizomab (complement C5 inhibitor)
Ides(IgG-degrading enzymes derived from streptococcal pyogens).
What are the challenges?
1-HLA sensitization.
-HLA is highly polymorphic .The likelihood of finding a fully matched unrelated donor is extremely rare.
-Screening for HLA antibodies and subsequently unacceptable antigen definition with the advent bead-based luminex assays depends on the interpretation and expertise .
– The interpretation of these assays is affected by many factors like; antibody titre, antibody affinity, competition for shared epitopes on different beads, complement factors and immune complex interference, and irrelevant antibody reactivity against denaturated HLA molecules.
2- Priority points in regular allocation
The New- Kidney allocation system (KAS), which use a point system for patient with > 20% c PRA increases the chance to offer an organ transplantation . Although there is an increased rate of favorable transplantation ,the increased number of organ shipped over longer distances, thereby increasing cold ischemia time .
3- The acceptable mismatches approach
It is based on the positive identification of acceptable antigens, to which the patient has made no antibodies. It is relying on Luminex SAB analysis, combined with epitope analysis. Once acceptable antigens are defined, these are added to the HLA type of the patient, creating an extended HLA type on which matching is performed.
AM program;
If an organ donor with an HLA type compatible with this extended HLA type is reported to Eurotransplant, the kidney is immediately offered to the AM patient with mandatory shipment to the respective recipient centre. It associated with better 10-year survival rate than regular allocation program. Patients with a very low chance to get a suitable offer in their original population, may increase their chance through national and international organ exchanges. It is cost-effective way of transplanting highly sensitized patients.
4- kidney paired donation;
It depends on the definition of unacceptable antigen, too little versus too many
Increase the possibility to get compatible donors by including compatible couples in the program, and by creating trans-border KPD programs. Highly sensitized patients are not transplanted at a similar rate to other patients, they accumulate in the KPD pool, making it increasingly difficult to run successful match rounds.
5-Desensitization;
The results of desensitization remain controversial.
No standardized protocol.
Summarise the recommendations and reflect on your practice.
1-More allocation programs will introduce a sliding scale for increase priority based sensitization level .
2-Acceptable mismatch programs will expand to other donor population to facilitate transplantation of the more difficult to transplant patients .
3- kidney paired donation has the potential to be expanded , both in term of donor population ,as well as the type of patient-donor couples included.
4-Sensetization due to transplantation should become a relatively infrequent complication with the introduction of HLA epitope matching
5-Novel agent may allow for more rapid desensitization , although residual plasma cell and B memory cell activity needs to be addressed .
6- highly sensitized patients will always be part of the kidney transplant waiting list due to immunization by pregnancy and blood transfusion .
My own practice ;
Only small group of patients underwent desensitization in our country . Our experience in Paired kidney donor is through direct exchange ( in small number of patient ).
What are the challenges?
1-HLA sensitization:
HLA system is highly polymorphic which keep getting full matched donor very difficult for example within Euro-transplant from period 2008 -2017 only 11% of patients received zero-mismatched kidney.
2-Exposure to foreign antigen through blood transfusion, pregnancy and previous organ transplant led to development of new DSA due to activation of memory cells.
3- Factors that interpret the SAB assay e.g. prozone effect, antibody titer ,antibody affinity, competition for shared epitopes on different beads, complement factors and immune-complex interference.
Possibilities to increase rate of transplantation in highly sensitized patients:(Recommendation).
A-Priority point in regular allocation:
To provide points for highly sensitized patients in kidney allocation system like regional allocation for them and national allocation for those with cPRA >100% although this lead to increase number of transplantation in highly sensitized patients but due to distance factor , cold ischemia also increased and DGF rate increased also.
Allocation of organ to highly sensitized patients based on absence of unacceptable antigens led o decreased long term graft survival.
B-The acceptable mismatch approach:
Special euro-transplant program for highly sensitized patients that depends on identification of acceptable antigens which recipients not react against and no antibody produced which need to be proven by extensive laboratory testing.(Luminex and HLA matchmaker).
This led to decreasing waiting time on the list, with better 10-yrs graft survival than those on regular allocation system.
C- Kidney Paired donation:
KPD has a great feedback on living kidney transplant , in this program initial match by virtual then physical match done, has many form couple, or more than circular exchange but still highly sensitized group need more facilities to increase their chance to find compatible donor which can be increased by including the compatible couples in the program for better matching or to cross relatively lower ABO blood group and increase donor pool by keep KPD international.
D-Desensitization:
Role to keep negative cross-match before transplantation which when used with PKD to choose DSA load level lower than original donor.
There are many agents used for desensitization e.g. IVIG ,PEX with or without Rituximab ,Borteozomib also used in some trials.
Ides immunoglobulin degradation derived from streptococcus pyrogens.
Its promising but need more randomized control trials.
Reflect on your practice:
-Decrease causes of sensitization for CKD patients specially blood transfusion.
-Highly selection for matched living transplantation which has better graft survival .
-Desensitization for low level HLA antibody (IVIG&PEX).
-Try to establish KPD between at least two incompatible donor-recipient pairs.
-Unfortunately KAS ,PKD program and acceptable mismatch approach costly programs and still not available in our practice here.
III. Transplantation in highly sensitised patients: Challenges and Recommendations
What are the challenges?
– Definition of unacceptable antigens, using Luminex SAB, for highly sensitized recipients is subject to laboratory expertise & interpretation.
– SAB MFI is a sensitive but a crude method of defining antibody level or strength.
– Confounding factors in interpreting SAB results include:
i.prozone effect
ii.antibody titre & affinity
iii.irrelevant antibody reactivity against
denatured HLA molecules
iv.complement factors & immune complex
interference
v.comptition for shared epitopes on different
beads
– Prolonged waiting list time.
– Susceptible to removal from the list.
– Very low likelihood of finding a suitable donor.
– Increased mortality & morbidity while on dialysis.
– Transplanting truly high sensitized(cPRA )patients dependent on centre policy regarding acceptable antigens.
– Increased cold ischemia time due to shipment of organs for long distances.
– Long term graft survival data are not available.
– In the new KAS there is increased rate of zero HLA mm. This will likely increase the chance of HLA immunization in case of graft loss.
– Breadth of unacceptable antigens in allocation systems will preclude transplantation in many cases.
– Less than 15% of highly sensitized patients succeed to find acceptable organ in KPD program.
– highly sensitized patients accumulate in KPD pool making it difficult to run successful match runs.
– Increase risk of AMR in transplants carried after desensitization.
– Controversial results in studies looking into the benefits of desensitization compared to remaining on waitlist.
– A large single center study showed that there is no survival benefit of desensitization compared to remaining in waitlist.
================================================ Summarise the recommendations and reflect on your practice.
Recommendations:
– Introduction of HLA epitope matching to decrease frequency of sensitization.
– Introduction of new strategies to address residual plasma cells & memory cells activity
– Expand KPD programs
– Expansion in acceptable mismatch programs
– Expansion in the use of sliding scale in allocation systems for prioritization of highly sensitized patients
Reflection on my practice:
In our transplant centre we are doing less than 80 transplants annually. All are live related donations.
We are not transplanting highly sensitized patients due to logistic issues. We are sending such patients for KPD to another centre in the country; this centre is doing around 200 transplants yearly. They are doing only small number of KPD transplants.
Renal transplantation offers the highest survival benefit for ESRD patients when compared to other modalities of renal replacement therapies.
Challenges in desensitization
Desensitization offers a good transplant opportunity and survival advantage for highly sensitized recipient who has a very low likehood for getting a transplant (living or deceased) due to positive cross-match.The goal of desensitization is to remove preformed DSA that cause positive cross-match with the donor.Three main treatment options for desensitization:Plasmapharesis, IVIG, and Rituximab, with the combination of low dose IVIG and plasmapheresis, is the most commonly used protocol
Although Desensitization was found to improve short-term graft and patient survival, long-term survival may be reduced due to rejection, increase risk of infection and malignancy from aggressive immunosuppression, moreover it is expensive. Thus desensitization should be limited to transplant recipients with no living donor who are highly sensitized that are in the top of the waiting list in KAS so cannot find deceased offer and are expected to be waitlisted for long time.
Also, Desensitization cannot be applicable in all patients it is indicated only in patients with positive FXM due to DSA provided that MCS< 250 and RIS <17 if MCS > 250 or RIS > 17 this donor should be excluded
Challenges in Kidney Paired Donation (KPD)
KPD is the process of exchange of kidneys between living donor-recipient pairs due to ABO or HLA incompatibility, so allows recipients to receive a better-matched kidney.
The first challenge is that only 15% of highly sensitized transplant recipient with CPRA ≥ 98% has a chance to find a compatible donor, and recipients with blood group O are the most difficult to transplant
Highly sensitized patients will continue to be part of the transplant wait list due to pregnancy, blood transfusion & prior transplant
There has been an increase in cold ischemia times with a resultant increase in delayed graft function DGF rates as the organ is being shipped over long distances in new KAS.
Relatively poor 10-year graft survival rate in those who received kidney through KAS.
Although KPD programs are hugely successful, patients that are highly sensitized ( with => 97% cRF calculated Reaction Frequency ) have a significantly lower chance to get a suitable donor.
Less number of zero-mismatch HLA in KAS, which may increase sensitization in case of graft failure.
The highly sensitized patients are not transplanted at a similar rate to other patients, and they accumulate in the KPD pool, making it increasingly difficult to run successful match rounds.
Determining a DSA level that is amenable to desensitization is required.
< 15% of highly sensitized patients are able to get compatible donor in PKD program.
After desensitization, the transplanted kidney is at increased risk of early & late ABMR
Summarize the recommendations and reflect on your practice.
The solution to these challenges lies in a step-wise approach:
1) Avoid sensitization: Prevention is always better than cure. So avoidable sensitization events like blood transfusion should be concentrated upon.
2) Use HLA matching based on B cell epitopes, to transplant patients with a kidney not having immunogenic epitopes for the specific recipient, helping in reduction in sensitization due to previous transplant, if the graft fails.
3) Use potential live donors with or without KPD program:
a. Patient specific approach is important in this.
b. ABO incompatible transplant can be performed for highly sensitized patients in KPD
c. Addition of compatible pairs in KPD can further increase chances of getting a kidney for highly sensitized patients.
d. Referring these highly sensitized patients to certain centers with high experiences in managing these difficult cases.
e. Use the acceptable mismatch program, especially by searching for donors outside their own donor pools, by national and international collaborations.
f. Desensitization, even for non-HLA antibodies, helps in increasing transplant rates in such patients.
Our practice:
We have a living donor program at our center. We have performed a 2-3 transplants after desensitization. Although, at national level, many centers are doing transplants after desensitization and the chances of success of such highly sensitized patients, varies from center to center.
The following are some of the difficulties associated with transplantation in highly sensitized patients:
-An increase in the number of patients who are sensitized or severely sensitive as a result of sensitizing events (like pregnancy, previous transplants and blood transfusions).
-A high level of HLA polymorphism, reduces the likelihood of obtaining a kidney with no mismatches.
Because of the high sensitivity of Luminex-single antigen bead testing, increased identification of antibodies in the recipient (depending on various aspects such as prozone effect, antibody levels, antibody affinity, epitope sharing, as well as antibody activity against denatured HLA) has resulted in a reduction in the likelihood of finding an acceptable donor.
The absence of clear rules has led to different transplant facilities having their own policies when it comes to treating patients with severe organ rejection.
The new Kidney Allocation System (KAS) in the United States gave higher priority to such patients, increasing their transplant rates from 2.5 per cent to 13.4 per cent and decreasing wait times from >19 years to 3.2 years. However, it still has many challenges, including a. increased cold ischemia times, resulting in delayed graft function, though with no effect on 6-month graft survival. b. increased cold ischemia times, leading to increased delayed graft function, though with no effect on 6-month
b. Graft survival is much lower during a 10-year period.
When there is a decrease in the rate of zero-mismatch, there is an increase in the likelihood of HLA immunization in the event of graft loss.
Although the kidney paired donor program (KPD) for a negative crossmatch kidney has demonstrated results comparable to non-sensitized patients, there are several obstacles with KPD, including the following: Inconsistent statistics about the outcomes of such individuals following transplantation from different facilities (US cohort pointing towards better outcomes than remaining on wait-list, while the UK cohort shows no survival benefits).
Recommendations:
-Eurostam is a project that aims to increase the chances of finding an acceptable graft for patients who have a very low chance of finding a suitable donor due to the presence of antibodies against common HLA antigens in the Eurotransplant donor population by expanding the donor pool to different national and international allocation programs and increasing the chances of finding an acceptable graft for patients who have a very low chance of finding a suitable donor due to the presence of antibodies against common HLA antigens in the Eurotrans.
-The use of a point system to prioritize highly sensitive patients in the allocation system, similar to what was done in the KAS system, allows for a reduction in waiting time.
If a donor’s HLA type is not compatible with an acceptable mismatch program, the program will be terminated. Acceptable mismatch programs have had positive outcomes in Eurotransplant, with improved 10-year donor graft survival and cost-effectiveness. They have also reduced the waiting time for transplants.
— The use of new desensitization agents such as Bortezomib, Ecluzimab, and IdeS was investigated, with preliminary results for IdeS being favourable.
The results of certain research indicated that a desensitization regimen was advantageous to graft survival, which was in contrast to the findings of other investigations.
reflect on your practice.
1-Expand KPD programs in addition to desensitisations to improve the chances of highly sensitised patients on dialysis. we have already a program but a limited number only those who agree to proceed for paired donation.
2- Improving the national system for kidney allocation will help to expand transplantation.
Challenges to transplant in highly sensitized patients: 1-highly sensitized patients having cPRA or virtual (vPRA )or CRF is more than or equal 85–100%.
2-To increase transplanting of highly sensitized patients and decrease waiting time and mortality. 3-polymorphic HLA system which is a strong barrier against finding fully match unrelated donor . 4-previous events of sensitization like pregnancy, blood transfusion and prior transplantation. 5-depending on individual lab interpretations for the detection of an acceptable Ags. 6-new kidney allocation system as to increase rate of of transplanting highly sensitized patients and give them higher priority in the system so rate increase from 2.4 to 13.4% in first year of implementation 7-patient group with 99.9%-100% cPRA is transplant at the lowest level even with new system. 8- improve the outcome regarding graft survival in highly sensitized patients. 9-increasing the chance of receiving compatible organ offer for recipient in AM program is hard or difficult to be achieved. 11-in KPD highly sensitized population with CRF . or more than 97%,diffult to transplant. 12-transplantation with living donor for highly sensitized patients through KPD not be fully utilized. 13-most of studies for out come of transplant after desensitization are small studies,so existence of of large studies is crucial to add more result about desensitization. RECOMMENDATION : 1-avoid sensitization events such as blood transfusion . 2-transplant from living donor with or without paired kidney program. 3-acceptable mismatch added to HLA type of the patient forming extended HLA type is associated with better graft survival and more cost effective. 4-HLA matching based on B cell epitopes aiming to prevent DSA formation. 5-desensitization is for HLA and non HLA antibodies to increase success rate of transplantation,
In my country there is no KPD program or other programs we depend on living donor transplantation
And desensitization.
What are the challenges?
Adopt a step wise approach:
1. Use of available living donors whenever possible
2. Regular allocation systems like KAS.
3. Acceptable mismatch (AM) . Acceptable mismatch antigen approach (eurotransplant) identify the acceptable antigens to which the patient has no antibodies. This was done through CDC in the past but recently it has been done through single antigen lines SALs in flow cytometry. This prove to be cost effective ,3/5 the patients were transplanted, shorter waiting time on the waiting list with improved 10-year graft survival.Performing matching on Extended HLA type will combining the defined acceptable antigens to HLA type of the patient . Those who are having less chance in acceptable mismatch , search of donors should be from outside their population. EUROSTAM is a project funded by the European union to implement wide AM programme to get benefit from the variation in antigens prevalence in different populations. But this needs further workup in the ethical and legal prospective.
4. PKD: Kidney paired donation to overcome the incompatibilities in living donations.there are several modalities: direct exchange, circular exchange or domino exchange. The later provide a chance , each time, for one on the deceased donor waiting list. Kidney paired donation was faced with the small number of eligible donors esp for highly sensitized with PRA more than or equal to 97%. This can be overcome by indwelling of multicentre PKD. Acceptable antigens when too little can end with appositive final cross match which may disrupt the paired donation round.if unacceptable antigens are high , this will make finding a compatible donor.this xan be solved by using patient specific approach for relevant HLA.inclusion of compatible pairs increae the chance for finding a better match and give a chance for highly sensitized patients to find an acceptable donor. Use of ABO incompatible pairs also increase the donor pool. Utilization of trans-border KPD programms increases the donor pool.combineg PKD with desensitization .this need definition of DSA level that can be subjected to desensitization.high level are refractory to desensetzaion and are associated with poor outcome.
5. Desensitization: through the traditional protocols or through the use of new drugs such as bortezomib ,eculizumab,IdeS
reflect on your practice
In Sudan, we adopted the PKD through direct exchange mainly. Desensitization protocols which depend on plasma exchange, IVIg and rituximab are used but at a low rate due to the high costs.
Transplantation in highly sensitised patients: Challenges and Recommendations
Highly sensitized patients are those who have HLA antibodies that react to ≥ 85 –100% of the donors in their donor population (c PRA, v PRA, c RF)
They have prolonged waiting time and a high mortality rate on dialysis.
Challenges: a- HLA related
1- Regarding HLA sensitization:
HLA is highly polymorphic so; the likelihood of finding a fully matched unrelated donor is extremely rare.
2- Screening for HLA antibodies and subsequently unacceptable antigen definition with the advent bead-based luminex assays depends on the interpretation and expertise of the individual laboratories as there is no universal standardization.
3- The interpretation of these assays is affected by many factors like; prozone effect, antibody titre, antibody affinity, competition for shared epitopes on different beads, complement factors and immune complex interference, and irrelevant antibody reactivity against denaturated HLA molecules.
4- By using these sensitive assays many patients may be classified as highly sensitized, and therefore decrease their chance to receive an organ offer through regular allocation.
Recommendations: take into consideration the following in HLA ABs
1- Accurate classification of serum HLA antibodies for the definition of unacceptable antigens is essential.
2- Per-patient assessment with an individualized threshold for positivity.
3- correlation to previous sensitizing events.
4- HLA epitope analysis
5- the chance of the patient receiving a transplant.
Priority Points in regular allocation recommendation:
1- highly sensitised patients should give higher priority in the regular allocation system.
2- New- Kidney allocation system (KAS), which use a point system for patient with > 20% c PRA.
3- Further priority by regional allocation for c PRA of 98%, and national allocation to those with c PRA of 100%
Transplantation of highly sensitized patients in the New KAS (challenges)disadvantages:
1- it is dependent on the centre’s policies for the definition of unacceptable antigen
2- cold ischemia time increased, with an ultimate increase in delayed graft function rates.
3- Long term effect needs to be determined.
4- Relatively poor 10-year graft survival rates, based on unacceptable antigens.
5- The rate of zero HLA mismatches significantly declined in the new KAS, increasing the chance of HLA immunization in case of graft loss.
The Acceptable Mismatch approach strategy:
It is based on the positive identification of acceptable antigens, to which the patient has made no antibodies. It is relying on Luminex SAB analysis, combined with epitope analysis. Once acceptable antigens are defined, these are added to the HLA type of the patient, creating an extended HLA type on which matching is performed. If an organ donor with an HLA type compatible with this extended HLA type is reported to Eurotransplant, the kidney is immediately offered to the AM patient with mandatory shipment to the respective recipient centre.
Advantages of AM program:
1- Better 10-year survival rate than regular allocation program.
2- Using allocation based on acceptable antigens is better than allocation based on avoidance of unacceptable antigens.
3- Very cost-effective way of transplanting highly sensitized patients.
4- Patients with a very low chance to get a suitable offer in their original population, may increase their chance through national and international organ exchanges.
Kidney paired donation program
In this program; HLA and/ or ABO-incompatible patient-donor couples are entered into dedicated match rounds to find the highest number of compatible combinations.
Highly sensitized patients are not transplanted at a similar rate to other patients, they accumulate in the KPD pool, making it increasingly difficult to run successful match rounds.
It depends on the definition of unacceptable antigen, too little versus too many
Increase the possibility to get compatible donors by including compatible couples in the program, and by creating trans-border KPD programs.
Desensitization
With this strategy transplant of HLA incompatible kidneys with a negative crossmatch become possible.
The results of desensitization remain controversial. No standardized protocol.
Expert commentary
1- Prevention of sensitization is important.
2- 2- HLA matching based on B cell epitopes has allowed for transplanting HLA mismatched organs that do not bear immunological epitopes for the specific patient, preventing DSA formation.
The challenges facing transplantation in highly sensitized patients (cPRA 85-100%) are:
1) the hypersensitized patients are those who have antibodies against HLA antigens in the donor population,in the community. These antibodies are acquired through pregnancy, blood transfusion and previous organ transplant. It’s usually reflected as cPRA, virtual PRA, calculated reaction frequency cRF
2) Those donors whom the recipients developed antibody against, they would be excluded due to their unacceptable HLA antigens.
3) The hypersensitized patients would be waiting for long time before getting an acceptable HLA antigens donors, exposing them to the high mortality risk associated with hemodialysis.
4) Identifying the HLA antibodies in the patients properly would make up the map for unaccptible antigens . Therefore the methods used to detect the antibodies intensity and affinity ,the current Single antigen bead SAB Luminex study is highly sensitive in detecting the HLA antibodies. Concerns related to HLA antibodies detected by SAB assay:
1) Prozon effect,Antibody titer and Antibody affinity.
2) competition on shared epitops in different beads.
3) Complement binding.
4) immune complexes interference.
5) irrelevant Antibody activity against denatured HLA molecules.
Therefore individualization of the results of HLA antibodies are essentially recommended.
Methodes to overcome the immunologic barrier in highly sensitized patients.
1) Priority point in regular allocation :
KAS resulted in improved rate of kidney transplant for highly sensitized patients.
Regional allocation for cPRA of 98% and national allocation for those with cPRA of 100%.
The draw backs related to this strategy are prolonged cold ischemia time with its consequent high risk of delayed graft function, in addition to poor 10 years graft survival
2) The acceptable mismatch approach:
The acceptable mismatch antigens are those HLA antigens against which the patient has no antibodies identified by CDC and SAB assays.
This method was adopted by Eurotransplant ,and it showed that allocation by acceptable mismatch is superior to the allocation based on the avoidance of unacceptable antigens.
3)kidney Paired donation KPD:
Depend on virtual cross matching of different life donors and physical cross match of the couple afterwards showed an excellent result.
4) Desensitization protocol:
Is to remove the preformed HLA antibodies from the patient s plasma and convert the positive flow cytometric assay to negative reaction. Performed by plasma pheresis ,and adminstration of IVIG and Rituximab to deplete the sensitized clone of B lymphocytes against HLA antigen.
It’s indicated for those patients who failed to get transplantation by other methodes discussed earlier.
The outcome of this method is still controversial with debatable long term prognosis..
In our practice ,we are looking for compatable HLA antigens with negative CDC.We don’t have PKD or desensitization protocol.
Challenges to transplant in highly sensitized patients:
1) challenge to transplant in highly sensitized patients with cross match negative donor
2) successful transplant of highly sensitized patients and decrease waiting time and mortality.
3) finding fully match unrelated donor due to high level of HLA polymorphism.
4) unavoidable sensitization inform of allo antibodies, such as pregnancy and previous blood transfusion which are associated with strong immunization .
5) highly sensitized patients with in acceptable antigens their detection depend on expertise interpenetration of individual laboratory by lemunix Ag bead (SAB) and its affect by many factors.
6) new kidney allocation system as to increase rate of highly sensitized patients and give them higher priority in the system so transplant
rate increase from 2.4 to 13.4% in first year of implementation..
7)patient group with 99.9%-100% cPRA is transplant at the lowest level even with new system.
8)to improve relatives poor 10 years group survival rate for highly sensitized with a
obscene of unacceptable antigens.
9)avoidance of transplant highly sensitized with acceptable HLA mismatch and donor organ.
10)increasing the chance of receiving compatible organ offer for recipient in AM program is hard or difficult to be achieved.
11)in KPD highly sensitized population with CRF . or more than 97%,diffult to transplant.
12)transplantation with living donor for highly sensitized patients through KPD not be fully utilized.
13)most of studies for out come of transplant after desensitization are small studies,so existence of of large studies is crucial to add more result about desensitization.
SUMMARY OF RECOMMENDATION AND REFLECT YOUR PRACTICE
1-try to avoid sensitization such as blood transfusion .
2-transplant from living donor with or without paired kidney program.
3-acceptable mismatch added to HLA type of the patient forming extended HLA type is associated with better graft survival and more cost effective.
4-HLA matching based on B cell epitopes aiming to prevent DSA formation.
5-desensitization is for HLA and non HLA antibodies to increase success rate of transplantation,
in our center only available program living donor transplantation ,KPD and other program still not available.,
desensitization is done but unfortunately the out come is unfavorable.
0
Transplantation in highly sensitised patients: Challenges and Recommendations
What are the challenges?
KAS:
Increase cold ischemia in KAS.
Poor 10 YEARS graft survival.
Risk of immunization in case of graft loss, less chance of HAL -A, HAL-B and HLA-DR
zero mismatch.
Acceptable mismatch approach:
25% have less chance due to uncommon HLA in Eurotransplant donor population
KPD:
Small number of donor participate in KPD.
Large number of high sanitized in KPD lead to accumulate of patient and less chance to
have match round.
͘ Desensitization:
Increase risk of ABMR, both early and late.
Summarize the recommendations and reflect on your practice:
Highly Sensitized patient should be always part of translation list.
Minimalize sensitization by organ transplant itself.
HLA matching based in B cell epitope, allow for transplanting HLA mismatch organ not
bear immunologic epitopes to the patient, preventing DSA antibodies formation.
Making use of LRD.
Increase chance of regular allocation.
Include patient in special program like AM program.
Finally desensitization.
KPD are expanding in term of type and population of donors.
Novel agent may allow rapid desensitization.
Reflection to our practice:
Expansion of KPD.
Use of new agent for sensitization.
include patient in special program.
Challenges in transplantation of highly sensitized patients include:
1) Increased number of sensitized and highly sensitized patients due to sensitizing events (like pregnancy, previous transplants and blood transfusions).
2) High HLA polymorphism, leading to decreased chance of finding a zero-mismatch kidney.
3) Advent of luminex- single antigen bead testing, with its high sensitivity, has led to increased identification of antibodies in the recipient (depending on various aspects like prozone effect, antibody levels, antibody affinity, epitope sharing as well antibody activity against denatured HLA) further leading to lower chances of finding an acceptable donor.
4) Due to lack of uniform guidelines, different transplant centers have individual policies for transplanting such patients.
5) Although the new Kidney Allocation System (KAS) in US gave higher priority to such patients, increasing their transplant rates from 2.5% to 13.4% and decreasing wait times from >19 years to 3.2 years, it still has many challenges like:
a. Increased cold ischemia times leading to increased delayed graft function, though without any effect on 6-month graft survival.
b. Relatively poorer 10-year graft survival
c. Decreased rates of zero-mismatch, leading to increased chances of HLA immunization in case of graft loss.
6) The kidney paired donor program (KPD) for a negative crossmatch kidney have shown results similar to non-sensitized patients but there are challenges with KPD including:
a. Only <15% of the highly sensitized patients are able to get a kidney in KPD
b. Patients with cRF≥97% have a very low chance of getting a kidney through KPD.
c. It is challenging to define unacceptable antigens for including the patient in KPD program.
7) Desensitization has been used as a modality for rendering sensitized patients transplantable, with (by lowering the HLA barrier with respect to the original donor) or without KPD, with good long-term outcomes. The challenges faced include:
a. No guidelines for protocol of desensitization to be followed have been formulated, probably due to low number of cases and small number of centers performing such transplants.
b. Conflicting data regarding transplant outcomes of such patients from different centers (US cohort pointing towards better outcomes than remaining on wait-list, while the UK cohort shows no survival benefits)
8) The acceptable mismatch program, despite showing excellent graft survival and cost-effectiveness, has certain challenges like:
a) Presence of uncommon HLA type and antibodies against common HLA types in population is seen in 25% of the patients decreasing their chances to <0.015% to get a donor kidney. Hence the donor pool needs to be increased for such patients, by having national and international collaborations.
The solution to these challenges lies in a step-wise approach:
1) Avoid sensitization: Prevention is always better than cure. So avoidable sensitization events like blood transfusion should be concentrated upon.
2) Use HLA matching based on B cell epitopes, to transplant patients with a kidney not having immunogenic epitopes for the specific recipient, helping in reduction in sensitization due to previous transplant, if the graft fails.
3) Use potential live donors with or without KPD program:
a. Patient specific approach is important in this.
b. ABO incompatible transplant can be performed for highly sensitized patients in KPD
c. KPD with desensitization can be performed
d. Addition of compatible pairs in KPD (bolstering their chances to get a better matched kidney) can further increase chances of getting a kidney for highly sensitized patients.
e. International collaboration for KPD will further increase their chances.
4) Use the acceptable mismatch program, especially by searching for donors outside their own donor pools, by national and international collaborations.
5) Desensitization, even for non-HLA antibodies, helps in increasing transplant rates in such patients.
6) Enlarging donor pools with national and international collaboration.
Our practice:
We have a living donor program at our center. We enter such patients in KPD program, but it is very difficult to get a donor for them. We have performed a few transplants after desensitization. Although, at national level, certain transplant centers have collaborated to increase the donor pool and the chances of transplantation of such highly sensitized patients, we have not contributed to the program.
Renal transplantation offers better outcomes as compared to other modalities. Sensitization can develop due to blood transfusion, pregnancy and previous transplants. Those with cPRA>20 are labelled as sensitized and constitute 20% of transplant recipients in United kingdom. Patients with cPRA>85 % are called as highly sensitized and constitute 85% of the UK recipients and remain on waiting list for long times. Such patients who cannot find suitable donor have following options.
1– Stay on Haemodialysis
2- Try to find suitable living donor through KPD
3-Wait for suitable deceased donor and enrol in KAS. In UK waiting time has reduced from 19 years to 3 years.
4- To adopt desensitization protocols to make transplantation possible in highly sensitised patients.
Challenges in transplantation in highly sensitized recipients.
Repeated rejections leading to poor graft survival
Complication of immunosuppression like infections and malignancy
Applicable in only those with positive FXCM due to DSA if Mean channel shift <250 or RIS <17
Challenges in KPD
Those with negative Virtual cross match can have positive wet crossmatch
Those with blood group O and cPRA >98 have great difficulty in finding a donor
Challenges in KAS
Prolonged cold ischemia time
Antibodies to common HLA antigen may be present and such cases suitable donor may not be present locally and patient may have to find donor in another country.
Those with cPRA >98 have vary less chance of finding a suitable offer.
Recommendations
In highly sensitized patients , adopting the desensitization protocols and paired kidney donation may improve graft outcome and survival.
Effect on my current practice
In my current practice we are only doing live related renal transplantation and with current resources I think there is no room for PKD and KAS
The challenges:
Highly sensitized patients have antibodies against almost all frequent HLA antigens in donor population and probability of having compatible living donor is low even with KPD.
Sensitization occur due to pregnancy, blood transfusion or prior transplant so they will always be part of waiting list.
Donors with unacceptable antigens are excluded to avoid hyper-acute rejection leading to difficulties in finding compatible donors and prolonged waiting time on dialysis which is associated with higher mortality rates.
Transplantation of highly sensitized patients based on absence of unacceptable antigens is associated with poor 10-year graft survival.
Increasing rate of transplantation in highly sensitized patients through giving them priority in allocation system increase clod ischemia time as organs are shipped over long distance resulting in increased rate of delayed graft function.
Patients with uncommon HLA type in donor population have low chance to find HLA match and mostly have antibodies against common HLA types in donor population.
Patients with high level HLA antibodies may be refractory to desensitization and is associated with inferior outcomes.
Transplants after desensitization are at increased risk of early and late AMR.
Results of studies comparing benefits of desensitization versus benefits of remaining on waiting list are controversial.
Recommendations:
Immunological risk assessment should be individualized with consideration of previous sensitizing events, HLA epitope analysis, SAB assays results to determine truly relevant HLA antibody specificity and probability of receiving a transplant.
Highly sensitized patient should have higher priority in regular allocation system to decrease waiting time and to increase transplant rate.
Allocation according to acceptable antigens is more beneficial than that according to unacceptable antigens.
Acceptable mismatch (Antigens against which patient had made no antibodies) added to HLA type of the patient forming extended HLA type is associated with better graft survival and is more cost effective.
Searching for compatible donor outside donor population in patients with extremely low chance to receive organ in original donor population.
KPD program with inclusion of compatible pairs searching for better match to enlarge the potential donor pool.
combination of KPD and desensitization to facilitate transplantation.
Prevention of sensitization by organ transplant through HLA matching based on B cell epitopes aiming to prevent DSA formation.
A step wise approach is the optimal strategy starting with potential living donor, increase priority in regular allocation, special program as acceptable mismatch program and finally desensitization protocols.
In our practice,
We don’t have allocation program or PKD
Only living donor transplant
Desensitization with plasmapheresis and IVIG is used in sensitized patients who can afford the expenses and fails to find compatible donor.
We minimize blood transfusion in CKD patients to avoid sensitization
Recommendations to transplant highly sensitized patients ;
1.Priority points in regular allocation ; The new kidney allocation system(KAS) in USA ; a) cPRA >20% ; point system & sidling scale
b)cPRA > =98% ; regional allocation
c) cPRA >=100%; National allocation[13,5]
Transplant rate increased from 2% to 13% in the first year after implementation[16]
Median waiting time was reduced from 19 years to 3 years[17]
2.The Acceptable Mismatch approach in Europe ; Based on acceptable antigens[21]
More than 1500 transplant since 1989
Excellent graft survival & very cost effective[28,29]
3.Kidney paired donation ; This approach is utilized in living kidney transplantation when direct donation is impossible due to ABO/ HLA incompatibility
Started in South Korea 30 years back because they have shortages of living donation and they don’t have deceased donor transplant[30]
Transplant outcomes in this program is comparable to outcomes of non-HLA sensitized patients[32,34]
4.Desensitization ; Removal of HLA antibodies and prevention of its production
Achieved by combination of the following ;[52,53,75,58,61,62]
a) Phasma pheresis
b) IVIG
C) Rituximab
D) Bortezomib
E) Ecluizumab
F) Ides = IgG- degrading enzyme derived from streptococcus pyogenes
5.Combined desensitization & KPD
New ideas which requires ethical,legal, and logistical barrier to be put be overcome between national and international program to help those patient who are still cannot make their way to transplantation ;
a) Europe-wide AM programs
b)Trans-border KPD programs
Challenges ;
My practice ;
The HLA system is highly polymorphic, and every human being has its own HLA-fingerprint.
The immune system is not educated about non self HLA molecules, that’s why foreign molecules induces immune response. Sensitization of recipients occur through pregnancies, blood transfusion and previous transplantation.
The advances in HLA typing, crossmatching techniques and antibody screening techniques have increase the number of sensitized patients , recognizing unacceptable antigens. In the other hand, defining the specificity of antibodies (DSA vs non-DSA), and their strength and also binding capacity also facilitate some high risk sensitized patients.
The development of paired exchange kidney program, kidney allocation policies and also desensitization protocols also had a great impact in transplantation of sensitized recipients. The kidney allocation system resulted in increased transplant rated among sensitized patients with c-PRA > 20. In one year after implementation of KAS, the transplantation of highly sensitized pts c-PRA>99 increased by more than 11%.
The implementation of acceptable HLA antigens to which the patient has no antibodies against, using extensive laboratory testing, will increase the chance to get renal offer. The highly sensitized patients who received offer through the acceptable mismatch program have better overall survival rate comparing to counterparts transplanted via other allocation system. Despite this advance, around 25 % of patients have very low chance to get compatible offer and stay in the waiting list for a long period.
Transplantation from living donor is superior to DDK. Paired exchange program through direct, circular or domino kidney exchange improved the access to living donation with better and more compatible HLA and ABO match. The results of this program are excellent and comparable with transplantation among non-senstized patients. Despite this program, highly sensitized patients are still waiting for a long periods in the waiting list. Improving local and national Paired exchange program into international program could help many patients to find acceptable offer.
Desensitization is a preceding step, when proceeding with paired exchange program , as most of highly sensitized patient not only has HLA Mismatches but also preformed antibodies which will hazard any transplantation. The development of desensitization protocols using plasmapheresis/IVIG/B cell depleting agents/Bortezomib/Complement inhibitors , improve the chance to get more compatible and less risky transplantation. Patients with positive CDC or flowcytometry crossmatch before desensitization, are likely to get kidney offer after desensitization and negative crossmatch. Ides – a streptococcal derived IgG degrading enzyme, given as desensitization agent has been reported to be effective in managing sensitized patients with very promising results.
HLA matching transplantation should be considered to be done on the allele and epitope levels , to avoid sensitization from the transplantation itself. Highly sensitized patient should also be transplanted using different programs of paired exchange, allocation systems, acceptable matches and desensitization.
Challenges :
RECOMMENDATIONS ;
Reflection on my practice :
currently while still not having allocation or KPD programs , nothing can be reflected from this point of view .
In my practice, our program is a live donor program, we don’t have a PKD program, and for sensitized patients who are amenable to desensitization, we use PP+IVIG+-Rituximab.
What are the challenges?
1- incompatible pairs are entered into dedicated match rounds to find the highest number of compatible combinations.
2- initial match rounds are generally based on virtual cross matching with a physical cross match performed for every pair thereafter.
3- logistically, there are several types of exchange combinations as :
a- direct exchange between 2 pairs.
b- circular exchange between 3 or more pairs.
c- domino exchange by an non-directed anonymous donor with the final donor donating to a patient on the deceased donor waiting list.
Summarise the recommendations and reflect on your practice :
Challenges
-The increasing number of HLA sensitised cases on the transplantation waiting list
– HLA is polymorphic rendering it difficult to attain a fully matched donor
-HLA sensitisation is acquired through pregnancy , blood transfusion and previous transplantation,in fact each one has different immunisation intensity .
-Highly sensitised cases are those having c PRA >85-100%
– The luminex single antigen bead assay output MFI is very sensitive and is influenced by different factors which can overestimate hypersensitivity in some cases.
-The increase of transplanting of highly sensitised patients is associated with increased cold ischemia time of organs shipped for long distances , increasing the possibility of delayed graft function
– The more the zero HLA A B C mismatch the more the HLA immunisation leading to graft loss
Recommendations
-To prioritize highly sensitised patients in the allocation system as done in KAS using a point system which enabled reducing waiting time
-In Eurotransplant , Acceptable mismatch programs define acceptable antigens based on Luminex and epitope analysis forming an extended HLA type to which a donor will be offered if compatible to it ,it had favourable outcomes with better 10 y graft survival, cost effective and reduced the waiting time too.
-EUROSTAM project aimed at widening the donor pool to different national and international allocation program increasing the chance of finding an acceptable graft for the group of patients with very low chance to find a suitable donor due to having antibodies against common HLA antigens in the Eurotransplant donor population
-Kidney paired donation (KPD) program is beneficial to highly sensitised patients with access to an incompatible living donor it can be processed either by direct ,circular or domino exchange method, inspite of it’s successful outcomes the chance is low for highly sensitised cases to find an acceptable donor through KPD, this can be solved by widening the donor pool by creating transborder KPD program as well as combining it with desensitisation protocol.
– DSA level amenable for desensitisation need to be addressed .
-Desensitisation protocol usually includes either high or low dose of IVIG with plasmapheresis with or without Rituximab meanwhile still transplanted grafts are susceptible to early and late AMR.
– New desensitisation agents as Bortezomib , Ecluzimab , and IdeS were used ,while the IdeS preliminary results were favourable.
-Some studies showed that desensitisation regimen had beneficial effects on graft survival which was contradictory to other studies.
-A stepwise approach can be the best policy for highly sensitised patients starting by making use of the potential living donor , increasing their chance in allocation programs, involving them in programs as AM program , KPD program as well as combining it with desensitisation protocols.
Etiology and impact of high sensitization:
· Many sensitizing events as pregnancy, blood transfusion and previous transplant leads to development of anti HLA antibodies.
· Sometimes spontaneous sensitization by viral infections, vaccinations can play a role.
· Those with cRA≥ 20% are considered sensitized and cPRA ≥85 % is considered highly sensitized.
· Determination of unacceptable antigens which are contraindication to transplantation.
· In KAS, usually highly sensitized ones take priority points.
· After failed PKD in living donor and KSA in deceased ones to find suitable donor especially in those with cPRA ≥ 98% and in case of very long waiting list, we are obligated to use desensitization protocols as (PEX, rituximab or IVIG) to remove preformed DSA and convert cross match from positive to negative.
Challenges in transplanting highly sensitized recipients:
Challenges in desensitization
Challenge in KPD and KSA
Recommendations:
In our local practice
· Unfortunately, such highly sensitized patients are let to die on dialysis.
· I don’t know how to apply these protocols in my practice.
Still there is waited list for long time of sensitised patients which are accounted 20% of total transplant and 5% of highly sensitised patients.
Those patients have antibodies against allograft.
These antibodies develops due to exposure to pregnancy and transfusion immunization.
HLA antibody detected by CDC and cPRA > 20% considered unacceptable antigen.
Recommendation:
Highly sensitised patients who are waited for long time better put them in priority of allocation system; by this ways recently there’s increase number of transplanted patients from deceased donor and decrease waiting list from 19 years to 3.2 years but there’s challenges for patients with cPRA > 99% better avoid to transplant.
Despite decrease rate of waiting list but kidney allocation system based on avoidance of unacceptable mismatch.
Acceptable mismatch approach:
first identify of acceptable antigen .
it’s HLA antigen which are no match antibody .
this is detected by CDC / single antigen assay and MIF.
this is a chance about 25% to get transplant of sensitised patients who are waited list .
They recommended to Kidney paired donation.
Transplant with living donor is associated with superior long term graft survival.
Types of exchanges:
1. Direct exchange between 2 couples
2. Circular exchange between 3 or more couples
3. Donor donation to patients on deceased donor waiting.
Transplant outcome with cross match negative donor by kidney paired donation are excellent and give same results of transplant outcome of non sensitised patients.
Several ways to increase chance of successfully transplant in highly sensitised patients in kidney paired donation.
1. Compatible pairs in the program
2. Cross the relatively lower ABO groups and increase possibilities of HLA compatible match
3. Combination of Kidney paired donation with desensitisation strategies are used to allow for transplant of seemingly incompatible pairs.
Desensitisation:
Many reports show high level of HLA antibodies are refractory to desensitisation.
Most desensitisation protocol are high dose of IV Ig or low dose Iv Ig associated with plasma exchange plus rituximab.
Despite this protocol still there risk of early and late ABMR occur.
Recent years novel agents have been introduced such as proteosome inhibitors ( bortezomib ) C5 inhibitors eculizumab
This agents not show significant benefits in patients with DSA level high.
Another agents still under study Ig G degradation enzymes derived of streptococcus pyrogens.
Recommendation:
Desensitisation protocol in combination kidney paired donation help to minimize list of patients waited for transplant and help to improve outcome of graft survival in sensitised patients.
This study describes the introduction of Eurotransplant and its impact on the promotion of transplants in Europe, comparing it with other modalities in the world.
As in other parts of the world, the classification of highly sensitized patients originates from blood transfusions, immunization, and activation of humoral humanity, whether due to underlying disease or infections. Screening with crossmatch positivity is similar.
Unlike the Americans, who use a cPRA above 80% to consider the patient sensitized, Europe uses a cut-off of 85%. Regardless, patients above 99.95% cPRA still have a lot of difficulty having an organ available. The more sensitized the patient, the greater the area of expansion to search for the organ, which directly impacts the time of cold ischemia. These protocols for highly sensitized patients increased transplantation from 2.4 to 13.4% and decreased waiting time from 19 to 3.2 years. There is still the challenge of quality and standardization of exams for correct classification of cases.
Kidney paired donation (KPD) has become an alternative option to find an HLA-compatible donor. Associated with the Acceptable Mismatch (AM) program, if an organ is offered to Eurotransplant, the kidney is immediately offered and prioritized at the transplant center where the recipient waits. This combination of programs (Eurotransplant and AM) improved graft survival in highly sensitized patients at ten years when compared to the traditional model (72.8 vs 62.4%). In addition to good results, it is a very cost-effective program.
Kidney Paired Donation transplants have grown significantly to include subpopulations and more advanced laboratory techniques have included patients with positive Crossmatch who initially were virtually negative. The expansion to include ABO mismatch has increased HLA match compatibility.
The possibility of desensitization is practically mandatory in this profile of patients with high cPRA, in an attempt to reduce the ability of humoral immunity to promote rejection.
The lack of standardization of techniques such as plasma exchange associated with immunoglobulins in the most varied doses, rituximab (anti-CD20 blocking the maturation of B lymphocytes but unable to restrict antibody-producing plasma cells), bortezomib (high cost but blocking the action of plasma cells), eculizumab (blocking complement complex formation). Recently changes in Streptococcus pyogenes lead to IgG degrading proteins, preventing the antibody from promoting a local humoral response.
HLA matching based on humoral response (B cell epitopes) has been shown to allow for transplanting HLA mismatched organs that do not bear immunogenic epitopes for the specific patient, preventing DSA formation.
Renal transplantation offers the highest survival benefit for ESRD patients when compared to other modalities of renal replacement therapies.
Exposure to sensitizing events like pregnancy, blood transfusion and previous HLA mismatched transplant leads to the development of HLA antibodies.
Patients with c PRA≥ 20% are considered sensitized (constitute 20% of UK transplant recipients), and patients with cPRA ≥85 % are considered highly sensitized (constitute 5% of UK transplant recipients)
Highly sensitized transplant recipients are extremely difficult to find a suitable living donor and usually are maintained for a long time in the waiting list for deceased donor.
Highly sensitized transplant candidate who cannot find a suitable donor has one of the following possibilities:
1- Keeping the patient on hemodialysis which is associated with higher mortality
2-Try to find compatible living kidney donor, it may be difficult but because of KPD (local or preferred national) any recipient who have a living donor even if ABO or HLA incompatible can exchange the donor with another pairs
3- Wait for a compatible deceased donor and this will take a very long time, but because of improvement in the kidney allocation system (in UK it is called acceptable mismatch program -AM) waiting time is reduced from > 19 years to around 3 years
4- Desensitization to render incompatible donor possible for transplantation
Challenges in Finding deceased donor offer through KAS
Challenges in desensitization
Challenge in Kidney Paired Donation (KPD)
Recommendations
In my practice
Thanks
How this article will change your practice?
Week 5
Journal 3
There is accumulation of highly sensitised patients on the transplant waiting list.
These patients have antibodies against most commonly found HLA types present in the donor pool.
Patients are considered sensitised when having an HLA antibody profile that reacts to > 85%-100% of donors in the donor population.
Within eurotransplant among patients awaiting transplant around 20% are sensitised and 5% are highly sensitised.
Within eurotransplant between 2008- 2017 only 11% of patients received a zero mismatched kidney when only considering HLA-A and HLA-B on the broad and HLA-DR on the split antigen level.
Luminex SAB is very sensitive but crude and its interpretation is affected by-
prozone effect
antibody titre
antibody affinity
competition for shared epitopes on different beads, complement factors
Immune complex interference
Irrelevant antibody reactivity against denatured HLA molecules.
Centres unacceptable antigen listing policies may lead to listing intermediately sensitised patients as highly sensitised.
Increased no of organs shipped over long distances increasing cold schema time and DGF rates.
With the new KAS the rate of zero HLA A,B, DR and zero DR mismatches significantly declined increasing the chance of HLA immunisation in case of graft loss.
Definition of DSA levels amenable to desensitisation is needed.
Conflicting outcomes of benefit vs no benefit from studies comparing desensitization vs remaining on dialysis ,getting deceased donor or KPD.
Residual plasma cells and memory B cell activity needs to be addressed.
Summarise the recommendations and reflect on your practice.
A)Priority points in regular allocation
Point system with a sliding scale is used for patients with >20% cPRA.
Regional allocation for patients with cPRA of 99% and national allocation to those with a cPRA of 100%.
B) Acceptable mismatch approach
Based on positive identification of acceptable antigens, which are defined as HLA antigens to which the patient has made no antibodies.
Once acceptable antigens defined they are added to the HLA type of the patient creating an extended HLA type on which matching is performed.
C) EUROSTAM project- Europe wide AM program
D) Kidney paired donation –
Direct exchange, circular exchange or dominos exchange can be done.Less than 15% of highly sensitised patients can find a compatible pair in a KPD match run, especially patients with cRF >97%.Hence for such patients international or multi centre KPD programs are needed.one can include compatible pairs to increase chance of successful transplantation in KPD.Also crossing the ABOi barrier can increase the possibility of a HLA compatible match.combining KPD with desensitisation is a third option to increase transplantation rates in highly sensitised.
E) Desensitisation –
Desensitisation with KPD is needed to be considered.
Some protocols for desensitisation
High dose ivig
Low dose ivig with plasmapheresis
Both with/ without rituximab
Newer agents –
Bortezomib
Eculizumab ‘
Ides
kidney paired donation was not done in our unit .
desensitisation was not carried out,CDC used to be done and if negative transplanted and if positive rejected.
it was mainly a live related transplant program
highly sensitized transplant recipients should be managed in countries experienced in transplantation of these types of patients since PKD, deceased donor allocation system, and desensitization are complex techniques that requires coordination between centers; computer-based matching system and shipping of organs which is not available in all countries