Kidney paired exchange and desensitization: Strategies to transplant the difficult to match kidney patients with living donors
Kidney paired donation in conjunction with desensitization strategies considered to be a novel approach to transplantation in highly sensitized patients.
Kidney paired donation
· Involved the exchange of donors between two incompatible donor/recipient pairs. It was first performed in south Korea 1991.
· A more compatible match with less overall immunosuppression is the motive behind establishment and development of kidney exchange programs.
· KPD program can be single center or multi-center registry.
· The advantage of single center over multi-center registry is:
a. the simplification of logistics and the presence of the donor/recipient pair in the same region or center.
b. a single HLA laboratory with decisions made by a single program.
· Overall match rates are approximately 50–60% in a large KPD registry with more than 1000 pairs.
· The blood group of the pair(donor/recipient) has a significant impact on the match finding. Sensitized patients with blood group O, have a match rate as low as 15%.
· KPD can be extended to enlarge the donor population poll via non-directed donation and non-simultaneous extended altruistic donor-NEAD (domino linear chain of transplant). This is very helpful in increasing the match rate when there’s ABOi. Desensitization
· The aim of goal of Desensitization therapy is to reduce the antibody level so the flow cytometry cross- match is negative or lower than a pre-determined cutoff, thereby preventing hyper acute rejection.
· Desensitization protocols generally use plasmapheresis along with infusions of IVIG and RTX to lower the titers of HLA antibodies in the candidate.
· Side effects of PP: coagulopathy, hypocalcemia, thrombocytopenia, hypotension, pheresis catheter related infection beside rebound increase in the level of antibody.
· IVIG modulates the allo-immune response in different ways:
a. Inhibition of T- and B-cell proliferation.
b. Inhibition of cytokine production.
c. Inhibition of dendritic cell maturation.
d. Induction of B cell apoptosis.
e. It provides the advantages of repleting normal immunoglobulins, therefore reducing the risk of infection associated with PP.
· IVIG potential adverse reactions: headache, HS-like reaction and venous thrombosis.
· IVIG approaches in desensitization: one of 2 approaches
a. alternate day plasmapheresis followed by low-dose IVIG (used in living donor transplant candidates).
b. high dose IVIG with rituximab.
· RTX is CD 20 monoclonal antibody that eliminate premature and mature B cell from the circulation:
a. results in a substantial elimination of B-cell populations.
b. induce a modest decrease in anti-HLA antibodies in a fraction of patients.
c. Side effects: very small but increased risk of JC virus infection and development of Progressive multifocal leukoencephalopathy.
· Bortezomib has been shown to provide significant and sustained reductions in anti-HLA antibody levels when used in combination with other therapies such as plasmapheresis and IVIG.
· The modified protocol of adding rituximab and splenectomy to plasmapheresis and IVIG did not decrease AMR rates in the past. Splenectomy was eventually replaced by anti-CD20 treatment, and post-transplant antibody removal via plasmapheresis was performed routinely in addition to pre-transplant treatments.
KPD and desensitization can be combined together as a novel strategy for transplanting highly sensitized patients with extreme difficulty in finding a suitable matching donor. KPD and desensitization are not a competing strategies.
Nandita Sugumar
2 years ago
Summary
Highly sensitized patients have few suitable options when it comes to donor selection.
Viable options for these patients include KPD, desensitization and recently deceased donor priority listing.
Kidney paired donation is exchange of donors between two incompatible pairs such that they are now compatible. ABO incompatibility plays a major role in adding donors to this database.
Desensitization is done using plasmapheresis, IVIG, Rituximab, Bortezomib.
Routine post transplant plasma exchange may be of good benefit.
Combining desensitization with KPD can increase the chances of good outcome post transplant.
Relaxing restrictions on unacceptable antigens can help in matching sensitized patients.
Further studies are needed to assess impact of KPD and desensitization.
ahmed saleeh
2 years ago
non-blood type-O, sensitized patients with O-donors have a much greater chance of finding a match within the registry than sensitized O-recipients with blood-type A donors. Conversely, sensitized O-patients paired with an A-donor have less chance of finding a successful match and will need to rely on other means such as desensitization.
The donorpool canalsobeenriched by includingABO/HLA compatible pairs
Risks of participating in a KPD pool for the compatible pair include delay of surgery as they wait for a match and the possibility of receiving an inferior graft. Potential benefits would be for those that need or may benefit from a better HLA match.
The two most common methods used to deplete antiblood group antibodies are plasmapheresis and/or blood group-specific immunoadsorption. Some protocols institute routine post-transplant therapeutic plasma exchange (TPE) in an effort to keep titers b8 during the first weekpost-transplant .
The challenge remains in selection of the appropriate patients to optimize successful matching. Mathematical algorithms based on donor/recipient blood type, sensitization status, and pool size can determine the probability of successful matching in a KPD
Combining desensitization with KPD as a complimentary modalitywillincreasethechancesoffindingacompatibledonor
MICHAEL Farag
3 years ago
1. Introduction Unfortunately many living donor recipient pair transplantations are not feasible because of ABO incompatibility, HLA mismatch/donor specific antibody, or donor/recipient age and size discrepancies. The majority of patients awaiting kidney transplant are sensitized to human leukocyte antigens, for this reason, highly sensitized kidney transplant candidates experience longer wait times and have a higher chance of being removed from or dying on the transplant waiting list.
Two strategies to address these barriers to living donor kidney transplantation are Kidney Paired Donation (KPD) and desensitization which can be used individually and in combination.
2. Kidney paired donation The exchange of donors between two incompatible donor/recipient pairs so that two compatible transplants could be performed. If multiple institutions within a country combine their registries, they can theoretically enable more matches. Possible kidney paired donation chains. (A) Traditional exchange between two incompatible pairs. (B) Closed loop chain of 3+ pairs where the last donor donates to the first recipient. (C) Non Directed Donor (NDD) initiated chain where a bridge donor may be used to start another chain or the last donor can terminate the chain by donating to a waitlist recipient. 3. Desensitization The goal of therapy is to reduce the antibody level so the flow cytometry crossmatch is negative or lower than a pre-determined cutoff, thereby preventing hyper acute rejection. Desensitization protocols generally use plasmapheresis along with infusions of intravenous immunoglobulin (IVIG) and rituximab to lower the titers of HLA antibodies in the candidate. Plasmapheresis works by removing alloantibodies from the circulation. Aside from coagulopathy, side effects commonly seen with plasmapheresis include hypocalcemia, thrombocytopenia, hypotension, and pheresis catheter-related infection and sepsis. An obstacle to this method is rebound increases in antibody levels. This occurs as a result of re-equilibration between the intravascular and interstitial compartments, as well as ongoing antibody synthesis by plasma cells.
IVIG has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, and to induce B-cell apoptosis. IVIG provides the advantage of repleting normal immunoglobulins, thereby providing a theoretical advantage of reducing the infectious risk associated with plasmapheresis. Potential adverse reactions that can be seen with IVIG administration include headache, hypersensitivity-like reactions, and venous thrombosis. IVIG-based desensitization is currently conducted using one of two approaches: alternate day plasmapheresis followed by low-dose IVIG (used in living donor transplant candidates) and high dose IVIG with rituximab
Rituximab It is a CD20 specific chimeric murine-human monoclonal Ab.
It depletes CD20 expressing B cells via complement-mediated cytotoxicity and apoptosis. Rituximab has also been shown to induce a modest decrease in anti-HLA antibodies in a fraction of patients — particularly those with low-level antibodies. There is a very small but increased risk of JC virus-induced progressive multifocal leukoencephalopathy associated with Rituximab. The newest agents added to the armamentarium for desensitization are therapies that target plasma cells. Bortezomib has been shown to provide significant and sustained reductions in anti-HLA antibody levels when used in combination with other therapies such as plasmapheresis and IVIG
4. KPD versus desensitization The view of KPD and desensitization as competing strategies for matching suitable incompatible donors/recipient pairs is incorrect. The success of both strategies has been well established over the past decade and data supporting a combination strategy continue to emerge
kumar avijeet
3 years ago
The paucity of kidney transplant as compared to number of people needing a kidney is the result of limited amount of organs available. Unfortunately many potential recipient- donor pairs are either ABO or HLA incompatible. Presence of DSAs lead to hyperacute rejection, ABMR, and Graft loss.
2 main strategies to overcome this barrier–
1) Kidney paired donation programs.
-started off as exchange of donors in between 2 incompatible pairs so that 2 compatible transplants could be performed.
– now also includes even 3 or more pairs.
-ABOi , HLAi, Graft size or age incompatible pairs also included.
-single centre registries , national registries, and also international registries have been encouraged.
2) DESENSITIZATION
-Immunomodulating therapies that reduce or eliminate DSAs
-Therapies available- Plasmapheresis, IVIG, Rituximab, Bortezomib. And their combinations.
-Challenges faced are- the high cost, antibody rebound, and poor outcomes.
– Reliance over live donor transplantation is more, as patients will need to be at top of the deceased waiting list due to the high cost and Ab rebound.
3) COMBINATION OF KPD PROGRAM AND DESENSITIZATION
The idea is to find pairs that are less incompatible, or where the recipient has lower level of DSAs to the newly matched recipient, do that DESENSITIZATION strategy is more amenable .
Ahmed Omran
3 years ago
Renal transplantation is considered the best option for ESRD patients , but there is shortage of deceased donors and living donor transplantation has several limitations including ABO incompatibility ,HLA mismatch/DSA and donor/ recipient age & size non matching.
Strategies used to overcome the obstacle to living donor transplantation: PKD, desensitization or combination of both. PKD:
Started before >30 years ago for exchange donor between incompatible donor/recipient, so compatible transplant can be undertaken. .It is important where living donor is the only available option for transplantation. In UK, USA, Canada & Australia there are combined registries from different institutions in same country resulting in offering more compatible transplantation. Some programs match ABO incompatible donor/recipient to increase match rate. USA PKD is a unique program use multiple single & multiple registries that operate independent of each other.
It is better to use one HLA lab and decision made by single program and standard practice. The complexity of PKD increased to involve 3 or 4 pairs which require complicated mathematical algorithms.
Highly sensitized patients ; c PRA> 98% had better chance to have compatible donor by PKD. Desensitization:
Different desensitization protocols which aim to remove or minimize Abs and convert positive crossmatch to negative , using PP,IVIG, and rituximab.
PP had many side effects including coagulopathy, hypotension, hypocalcemia, thrombocytopenia and CV line related infections with rebound Abs levels.
IVIG can modulate immune response through different mechanisms: It inhibit T cells & B cells proliferation, cytokine production, maturation of dendritic c cells, induce B cells apoptosis. IVIG can be used with PP on alternate day with low dose in living donor transplantation or high dose with rituximab. Rituximab can eliminate B cells population & induce moderate reduction in HLA Abs especially in case of low levels of DSA.
Bortezumib targets plasma cells.
There is clear survival advantage of desensitization in living donor transplantation when compared to patients remaining on dialysis especially in patients with positive FCXM ;also in Negative FCXM but positive CDC.
Considering desensitization cost & rebound phenomenon of Abs it is preferred to implement desensitization for patients who are on the top of waiting list.
Highly sensitized patients has 15% chance to get matched donor in PKD program .Combination of desensitization with PKD can lead to better chance of finding compatible donor with better graft and patients outcomes.
Tahani Ashmaig
3 years ago
☆Kidney paired exchange &desensitization: Strategies to transplant the difficult to match kidney patients with living donors
¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤
☆Introduction:
▪︎ Many living donor recipient pair transplantations are not feasible because of ABO incompatibility, HLA mismatch/donor specific antibody, or donor/recipient age, size discrepancies and sensitization to HLA.
▪︎ Two strategies to address these barriers to living donor kidney transplantation are:
1) Kidney Paired Donation (KPD)
2) Desensitization (alone or in combination
Kidney paired donation (KPD)).
KPD:
_____
▪︎lnvolve the exchange of donors between two incompatible donor/recipient pairs.
▪︎ Is essential in developing countries where living donation is the primary means
▪︎ Used in ABO incompatible pairs.
▪︎ Despite the success of larger multi-center registries, single center KPD programs still exist.
☆The advantage of single center registry over a multi-center registry:
_________________________
1) Simplification of logistics
2) The use of a single HLA laboratory with decisions made by a single program
▪︎KPD can involve three or more pairs. This requires sophisticated mathematical algorithms to best match patients for transplant.
▪︎ KPD now commonly involves highly sensitized recipients age and graft size mismatch pairs, and those pairs that are borderline compatible but will benefit from a better HLA match.
▪︎The highly sensitized patient has been defined as patients with a calculated panel reactive antibody (cPRA) greater than 95% but some KPD registries show that those with cPRA between 50 and 96% had equivalent match rates as those less than 50%.
▪︎Patients greater than or equal to 97% were less likely to find a match overall.
▪︎Sensitized pts and/or blood type O have match rates as low as 15%.
▪︎ The donor pool can be enriched by including ABO/HLA compatible pairs.
☆Risk of KPD pool for the compatible pair :
1) Delay of surgery as they wait for a match 2) Possibility of receiving an inferior graft.
3. Desensitization stratigies:
_________________________________
▪︎ Adopted to increase transplant rates in highly sensitized pts with low match rates.
▪︎ Immunomodulation therapies are administered to eliminate or reduce
HLA antibody levels.
▪︎The goal of therapy is to reduce the antibody level so the flow cytometry crossmatch is negative or lower than a pre-determined cutoff.
▪︎ Desensitization protocols generally use plasmapheresis along with infusions of intravenous immunoglobulin (IVIG) and rituximab.
▪︎ Due to the plasmapheresis cost and other reasons, IVIG is used.
▪︎IVIG has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, and to induce B-cell apoptosis.
▪︎IVIG provides the advantage of repleting normal immunoglobulins,so reduce the infection risk.
☆ IVIG-based desensitization approaches:
_______________________________
1) Alternate day plasmapheresis followed
by low-dose IVIG (used in living donor
transplant candidates).
2) High dose IVIG with rituximab.
▪︎ Rituximab depletes CD20 expressing B cells and decrease anti-HLA antibodies in patients with low-level antibodies.
▪︎ Bortezomib is used in combination with other therapies such as plasmapheresis and IVIG.
▪︎Desensitization followed by living donor kidney transplantation give a clear benifit (compared to staying on dialysis).
4. KPD versus desensitization:
________________________________
▪︎ Both strategies are successed.
▪︎Data supporting a combination strategy continue to emerge
▪︎ The challenge remains in selection of the appropriate patients to optimize successful matching.
▪︎Mathematical algorithms based on donor/recipient blood type, sensitization status, and pool size can determine the probability of successful matching in a KPD
▪︎Cross matching and solid phase assays against the determine the degree of desensitization needed.
▪︎The highly sensitized patient has a match rate as low as 15% in KPD
pools.
▪︎Combining desensitization with KPD as a complimentary modality will increase the chances of finding a compatible donor.
▪︎ The updated national kidney allocation system (KAS) initiated by the Organ Procurement and Transplant Network (OPTN) on December 4th 2014 is designed to improve transplant rates of the most highly sensitized patients with cPRA ≥98%.
▪︎The role of desensitization in the setting of the new KAS remains unclear. Highly sensitized patients may have their cPRA decreased thus giving them less priority on the deceased donor waitlist. Conversely, those with antibodies against common HLA antigens will have difficulty being matched regardless of the cPRA.
▪︎Desensitization still play a critical role in highly sensitized patients but these patients will have to be carefully chosen according their HLA antibody profile.
▪︎Another strategy in matching sensitized patients is to relax restrictions on unacceptable antigens. This will allow for low level DSAs whose role in allograft rejection remains unclear.
5. Conclusions:
________________
▪︎ The best option for highly sensitized patients is to be transplanted at a center
with access and expertise in KPD, desensitization and deceased donor priority. The center should then be able to analyze each patient’s immunological profile and determine the best strategy for transplant.
▪︎Future studies are needed to assess its overall impact on KPD and desensitization
Mohamed Essmat
3 years ago
A highly sensitized transplant candidate who has ABO or HLA incompatible donor should be evaluated for desensitization, exchange the donor with other pairs or both. *KPD is the process of exchange of kidneys between living donor-recipient pairs due to ABO or HLA incompatibility. It’s worth to say that only 15% of highly sensitized transplant recipient with cPRA ≥ 98% has a chance to find a compatible donor. *The goal of desensitization is to remove preformed DSA that cause a positive cross match with the donor and is associated with hyper acute rejection with immediate loss of the graft upon transplantation. The 3 main lines available for desensitization include plasmapheresis, IVIG, Rituximab *The Combination of desensitization and PKD may be the only way of living transplantation for a highly sensitized patient who can’t find suitable pair. Regarding my own practice; no cadaveric experience, no kidney allocation system but we implement desensitization accordingly.
Nasrin Esfandiar
3 years ago
To overcome against HLAi and ABOi living TX, KPD and desensitization protocols are emerged.
Highly sensitized recipients experience prolonged waiting times.
1- KPD:
Exchange of donors with other pairs to do a compatible TX.
This program is done by joining multiple institution registries in a country.
The first one was in the Netherlands called Dutch KPD. NKP is the largest
KPD program in the world with more than 300 active donors.
But there are single center registries too.
For example, in Johns Hopkins hospital KPD program in combination with desensitization is performed for highly sensitized patients.
Frequency of blood groups may impacts the chance of finding a match using KPD programs.
To solve this problem NDDS (non-directed donors) is used.
Australian KPD program used ABOi TX to reach a better HLA matching but the outcome of this program have to be determined.
Some centers deceased donors to increase KPD program.
2- Desensitization:
By using plasmapheresis in combination with IVIG and rituximab, the titer of DSA is lowered to reach a negative flow cytometry or reaching a pre-determined out off.
Plasmapheresis removes antibodies but could have rebound increase again IVIG inhibits B and T cell proliferation and cytokine production but may be associated with hypersensitivity reaction.
Rituximab eliminates B cell and bortezomib targets plasma cell with sustained reduction in DSA levels.
Higher pre-transplant DSA titers could result in AMR.
In some centers ABOi TX using anti-CD20 and post-TX plasmapheresis in addition to pre-TX ones was performed with deleting splenectomy.
But only patients low titer anti-ABO Abs can have successful ABOi TX and keeping titer < 8 during the first post–TX week is important.
3- KPD vs desensitization:
A combination strategy is emerging
In this strategy exchanging of donors lowers the need to desensitization.
New KAS program in 2014 was invented to increase chance of TX for the highly sensitized ones with CPRA ≥ 98%
Another strategy is to lower restriction on unacceptable antigens.
Ahmed Abd El Razek
3 years ago
Introduction
Living kidney donation has become a standard of practice. The outcomes of living donor kidney transplants are significantly better than those of deceased donor grafts. Unfortunately many living donor recipient pair transplantations are not feasible because of ABO incompatibility, HLA mismatch/donor specific antibody, or donor/recipient age and size discrepancies.
The presence of DSAs in highly sensitized recipients is associated with hyper acute rejection, antibody-mediated rejection (ABMR), and graft loss so, they experience longer waiting times and have a higher chance of being removed from or dying on the transplant waiting list. Therefore, Kidney Paired Donation (KPD) and desensitization can be used individually and in combination as good solutions.
Kidney paired donation
The idea is based on the exchange of donors between two incompatible donor/recipient pairs so that two compatible transplants could be performed with the advantage of avoiding the cost of desensitization while offering a more compatible match with less overall immunosuppression and serious infectious complications. Better immunological match will also result in improved long term graft survival.
Desensitization
Immunomodulation therapies aimed to reduce the antibody level so the flow cytometry cross match is negative or lower than a pre-determined cutoff, thereby preventing hyper acute rejection.
Desensitization protocols generally are plasmapheresis along with infusions of intravenous immunoglobulin (IVIG) and rituximab.
Plasmapheresis side effects commonly include coagulopathy, hypocalcemia, thrombocytopenia, hypotension, pheresis catheter-related infection and sepsis.
IVIG has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, and to induce B-cell apoptosis.
Rituximab is a CD20 specific human monoclonal Ab. It depletes CD20 expressing B cells via complement-mediated cytotoxicity and apoptosis. Side effects include risk of JC virus-induced progressive multifocal leukoencephalopathy.
Most studies showed that a clear survival benefit for desensitization followed by living donor kidney transplantation (compared to staying on dialysis).
However, acute antibody-mediated rejection rates were higher. A modified protocol adding rituximab and splenectomy to plasmapheresis and IVIG did not decrease AMR rates.
Baseline anti-blood group antibody titers seem to be the strongest predictor of early antibody-mediated rejection in ABO incompatible transplants.
Conclusions
Highly sensitized patients are considered to be a challenge for transplant centers. Several options have become available mainly KPD and desensitization.
Future studies are needed to assess its overall impact on KPD and desensitization.
In our center practice, we perform desensitization for highly sensitized recipients .Our main protocol consists of plasmapheresis and rituximab guided by the CDC, flowcytometry, calculated PRA
Wee Leng Gan
3 years ago
Transplantation of the difficult to match kidney patients with living donors.
The combination of both kidney paired donation (KPD) and desensitisation increase the successful rate of living donor transplantation in highly sensitised recipients. However, calculated panel reactive antibody (cPRA) of more than 95% remain technically challenge for transplantation with match rates as low as 15% in KPD pools. On the other hand, ABO incompatibility of donor / recipient pair significantly affect the probability to get match transplant even in KPD registry. For instance, sensitised non-blood type-O, recipients with O blood-donors have greater chance of finding a match than sensitised O-recipients with blood-type A donors. On the other hand, sensitised O-patients paired with an A-donor have less chance of finding successful match.
Following are the strategies for successful living donor transplantation for highly sensitised recipients. Non-directed donors (NDD) should be recruited to start linear domino chains of transplants to increase the proportion of blood group O donor. Besides, ABO HLA compatible pairs should be enriched in the donor pool in KPD. Matching ABO incompatible yet HLA compatible pairs allowing more successful transplants which include highly sensitise kidney transplant recipients. Furthermore, lowering the threshold for unacceptable antigens at transplant centres has boost up the transplant rate in the highly sensitised recipients.
Desensitising protocol is crucial to eliminate HLA antibody levels for successful transplantation especially among highly sensitised recipients. Most of the desensitising protocol include plasmapheresis along with infusions of intravenous immunoglobulin (IVIG) and rituximab. Bortezomib is a newer agent target at plasma cell in transplant medicine for desensitisation to induce effective reduction of HLA antibody level. Routine therapeutic plasma exchange in the first week following transplantation may ensure good graft survival among highly sensitise recipients. However, it still remain controversial for the optimum antibody titre is acceptable before and after ABO incompatible renal transplantation.
Combining KPD and desensitisation increase the probability of finding compatible donor especially among highly sensitised recipients. The updated national kidney allocation system (KAS) has improve transplant rates among highly sensitised recipients with cPRA more than 98% .
Revision of unacceptable antigen listing among transplant centres allow more highly sensitised recipients for transplantation. This will permit for lower level of donor specific antibodies ( DSA ) whose role in allograft rejection remains unclear. The transplant centres are responsible for the determination of acceptable antibody level.
In my opinion, the novel approach by combining the KPD and effective desensitisation protocol is the key for the better outcome among highly sensitise recipients in living donor transplantation. However, we need to personalise the management of difficult to match recipients with living donors by studying the immunological profile and determine the best strategy based on our patient circumstances and the transplant centre facilities.
Drtalib Salman
3 years ago
Paired kidney donation is cheap safe and good option for highly sensitized patient ,suitable and cost effective for developing country
Drtalib Salman
3 years ago
Summarise this article and reflect on your practice ?
Unfortunately many living donor recipient pair transplantations are not feasible because of ABO incompatibility, HLA mismatch/donor specific antibody, or donor/recipient age and size discrepancy , majority of patients awaiting kidney transplant are sensitized to human leukocyte antigens (HLA) ,two strategies to address these barriers are Kidney Paired Donation (KPD) and desensitization.
Paired Donation (KPD), performed in 1991 at a single center in South Korea where kidney transplantation relies heavily on living donation because of the lack of an established deceased donor program.
The highly sensitized patient remains particularly challenging. Generally, this has been defined as patients with a calculated panel reactive antibody (cPRA) greater than 95% but more recent data from the Australian and Canada KPD registries show that those with cPRA between 50 and 96% had equivalent match rates as those less than 50%. Those patients greater than or equal to 97% were less likely to find a match overall.
Desensitization immunomodulation therapies are administered to transplant candidates as a means to eliminate or reduce HLA antibody levels in order to enable transplantation the goal of therapy is to reduce the antibody level so the flow cytometry crossmatch is negative or lower than a pre-determined cutoff, thereby preventing hyper acute rejection.
Most studies on desensitization outcomes are small, non-randomized, not adequately powered, and have a relatively short follow-up time. Montgomery et al. reported one of the first long-term experiences with alternate day plasmapheresis and low dose IVIG. They demonstrated a clear survival benefit for desensitization followed by living donor kidney transplantation (compared to staying on dialysis).
While initial experience with ABO incompatible renal transplants resulted in hyperacute rejection, the 1970s were notable for extended survival of some of the A2 kidneys transplanted into blood group O patients who were receiving conventional immunosuppression
Splenectomy was eventually replaced by anti-CD20 treatment, and post-transplant antibody removal via plasmapheresis was performed routinely in addition to pre-transplant treatments. Subsequent studies reported comparable results with conventional immunosuppression and antibody removal, with omission of splenectomy and rituximab.
The highly sensitized patient has a match rate as low as 15% in KPD pools , Combining desensitization with KPD as a complimentary modality will increase the chances of finding a compatible donor.
reflect on my practice ?
we need more RCT or more study and consensus on desensitization protocol.
Sucharita Chakraborty
3 years ago
SUMMARY
The paucity of kidney transplant as compared to number of people needing a kidney is the result of limited amount of organs available. Unfortunately many potential recipient- donor pairs are either ABO or HLA incompatible. Presence of DSAs lead to hyperacute rejection, ABMR, and Graft loss.2 main strategies to overcome this barrier–>
1) Kidney paired donation programs.
-started off as exchange of donors in between 2 incompatible pairs so that 2 compatible transplants could be performed.
– now also includes even 3 or more pairs.
-ABo incompatible, HLA incompatible, Graft size or age incompatible pairs also included.
-single centre registries , national registries, and also international registries have been encouraged.
2) DESENSITIZATION
-Immunomodulating therapies that reduce or eliminate DSAs
-Therapies available- Plasmapheresis, IVIG, Rituximab, Bortezomib. And their combinations
– Each centre has its own desensitization protocol
-Challenges faced are- the high cost, antibody rebound, and poor outcomes.
– Reliance over live donor transplantation is more, as patients will need to be at top of the deceased waiting list due to the high cost and Ab rebound.
3) COMBINATION OF KPD PROGRAM AND DESENSITIZATION
The idea is to find pairs that are less incompatible, or where the recipient has lower level of DSAs to the newly matched recipient, do that DESENSITIZATION strategy is more amenable and hence give better Graft survival.
REFLECT ON PRACTICE-
We do not have well established national registries for KPD program, but it may be considered at the state level atleast.
Desensitization protocols are in practice in few centres, but it is considered only as the very last step .
Reem Younis
3 years ago
-Approximately 100,000 people are waiting for a deceased donor kidney transplant but only 17,878 solitary kidney transplants were performed in 2015 in the United States. . To offset this disparity, living kidney donation has become a standard of practice at most transplant centers in the United States.
-The outcomes following living donor kidney transplants are significantly better than those of deceased donor grafts .
– Many living donor recipient pair transplantations are not feasible because of ABO incompatibility, HLA mismatch/donor specific antibody, or donor/recipient age and size discrepancies.
-Two strategies to address these barriers to living donor kidney transplantation
are Kidney Paired Donation (KPD) and desensitization which can be used individually and in combination. Kidney paired donation
-It is involved the exchange of donors between two incompatible donor/recipient
pairs so that two compatible transplants could be performed.
-A more compatible match with less overall immunosuppression is ideal because the most common cause of death in their posttransplant population is infectious complications.
-If multiple institutions within a country combine their registries,
they can theoretically enable more matches. This has been accomplished
in countries such as the United Kingdom (U. K), Canada,
Netherland, Australia and the United States (U.S.).
– Dutch KPD success has been well published and attributed to its use of a national oversight committee and a single central HLA laboratory.
-The Dutch KPD has served as the model for other national multicenter KPD registries that followed in the UK, Canada and Australia.
-The first U.S. KPD exchange took place in the year 2000, three years prior to the
initial KPD exchange in the Netherlands. Since then it has grown to
over 500 transplants a year .
-National Kidney Registry (NKR) in 2007, has facilitated more than 1898 transplants since its inception and has over 300 active donors in its pool, making it the largest paired exchange donor pool in the world .
– Likely more important is the use of a single HLA laboratory with decisions made by a single program as opposed to multiple programs with their own individual HLA laboratory and standards of practice.
-This advantage is clearly seen in the Johns Hopkins Hospital KPD program where they have combined desensitization with KPD for a number of years in order facilitate transplant of highly sensitized individuals.
-Traditionally, pairs were entered into the registry because of ABO incompatibility but the use of KPD now commonly involves highly sensitized
recipients age and graft size mismatch pairs, and those pairs that are borderline compatible but will benefit from a better HLA match.
-The highly sensitized patient has been defined as patients with a calculated panel reactive antibody (cPRA) greater than 95% but more recent data from the
Australian and Canada KPD registries show that those with cPRA between 50 and 96% had equivalent match rates as those less than 50%. Those patients greater than or equal to 97% were less likely to find a match overall .
-Overall match rates are approximately 50–60% in a large KPD registry with more than 1000 pairs.
-Highly sensitized patients are less likely to find a compatible match they will have longer waiting times and will accrue in the KPD pool.
-Non-blood type-O, sensitized patients with O-donors have a much greater chance of finding a match within the registry than sensitized O-recipients with
blood-type A donors.
-Sensitized O-patients paired with an A-donor have less chance of finding a successful match and will need to rely on other means such as desensitization.
-A potential strategy to match these patients through KPD is to increase the proportion of O-donors. This can be accomplished by using non-directed donors (NDDs) to start linear domino chains of transplants otherwise known as non-simultaneous extended altruistic donor (NEAD) chain . NDDs presumably have a similar blood type distribution to the general public with approximately 45–57% having blood type-O depending on ethnicity .
– The donor pool can also be enriched by including ABO/HLA compatible pairs
-Risks of participating in a KPD pool for the compatible pair include delay of surgery as they wait for a match and the possibility of receiving an inferior graft.
-Potential benefits would be for those that need or may benefit from a better HLA match.
-KPD benefits reach beyond living paired donation as NDD’s can contribute to chains and the deceased donor list simultaneously.
-Highly sensitized patients will still suffer from low match rates even with an increase in the donor/recipient pool. Desensitization
– Immunomodulation therapies are administered to transplant candidates as a means to eliminate or reduce HLA antibody levels to enable transplantation.
-The goal of therapy is to reduce the antibody level so the flow cytometry crossmatch is negative or lower than a pre-determined cutoff, thereby
preventing hyper acute rejection .
-Desensitization protocols generally use plasmapheresis along with infusions of intravenous immunoglobulin (IVIG) and rituximab to lower the titers of HLA antibodies in the candidate.
-Side effects commonly seen with plasmapheresis include hypocalcemia, thrombocytopenia, hypotension, and pheresis catheter-related infection and sepsis.
– An obstacle to this method is rebound increases in antibody levels as a result
of re-equilibration between the intravascular and interstitial compartments,
as well as ongoing antibody synthesis by plasma cells.
– IVIG has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, and to induce B-cell apoptosis. Potential adverse reactions that can be seen with IVIG administration include headache, hypersensitivity-like reactions, and venous thrombosis.
-IVIG-based desensitization is currently conducted using one of two approaches: alternate day plasmapheresis followed by low-dose IVIG (used in living donor transplant candidates) and high dose IVIG with rituximab.
-Rituximab is a CD20 specific chimeric murine-human monoclonal Ab.
It depletes CD20 expressing B cells via complement-mediated cytotoxicity
and apoptosis . CD20 is expressed early in B lymphocyte ontogeny
in immature bone marrow-resident pre-B cells up to the point of
initiation of plasma cell differentiation in secondary lymphoid tissues.
-This broad expression of CD20 in multiple immature and mature B cell
populations results in a substantial elimination of B-cell populations
by rituximab .
– Rituximab has also been shown to induce a modest decrease in anti-HLA antibodies in a fraction of patients — particularly those with low-level antibodies . -There is a very small but increased risk of JC virus-induced progressive multifocal leukoencephalopathy associated with Rituximab .
-Bortezomib has been shown to provide significant and sustained reductions in anti-HLA antibody levels when used in combination with other therapies such as plasmapheresis and IVIG .
-There is a clear survival benefit for desensitization followed by living donor kidney transplantation (compared to staying on dialysis) in recipients who were flow cytometric cross-match negative, flow cytometric cross-match positive but cytotoxic crossmatch negative, and cytotoxic crossmatch positive .
-Despite high transplant rates and 100% one-year graft survival, acute antibody-mediated rejection rates were high .
– A modified protocol adding rituximab and splenectomy to plasmapheresis
and IVIG did not decrease AMR rates .
-The high cost of desensitization and the tendency for antibody rebound after treatment require that the candidates be near the top of the waiting list, so that it is realistic for them to receive organ offers soon after treatment .
– The optimal desensitization protocol before transplant and the best maintenance immunosuppression program post-transplant remain to be determined.
-Improved ABO incompatible outcomes with splenectomy at the time of transplant led to splenectomy being a required component of pioneering Japanese ABO incompatible programs that began in the late 1980s but it was considered to be high risk for antibody mediated rejection, viral infections,
and decreased graft survival.
-Splenectomy was e replaced by anti-CD20 treatment, and post-transplant antibody removal via plasmapheresis was performed routinely in addition to pre-transplant treatments.
-The two most common methods used to deplete anti blood group antibodies are plasmapheresis and/or blood group-specific immunoadsorption.
KPD versus desensitization – Thesuccess of both strategies has been well established over the past decade
and data supporting a combination strategy continue to emerge.
-The challenge remains in selection of the appropriate patients to optimize successful matching.
– The highly sensitized patient has a match rate as low as 15% in KPD
pools .
Combining desensitization with KPD as a complimentary modality will increase the chances of finding a compatible donor.
-The updated national kidney allocation system (KAS) initiated by the Organ Procurement and Transplant Network (OPTN) on December 4th 2014 is designed to improve transplant rates of themost highly sensitized patientswith cPRA ≥98% .
-Highly sensitized patients may have their cPRA decreased thus giving them less priority on the deceased donor waitlist.
-Another strategy in matching sensitized patients is to relax restrictions on unacceptable antigens. This will allow for low level donor specific antibodies whose role in allograft rejection remains unclear .
-In sudan ,we mainly focus on KPD and in limited cases.
Shereen Yousef
3 years ago
Summary of the article
Kidney transplantation is the best treatment for ESRD patients, living kidney donation has become a standard of practice at most transplant centers in the United States.
The outcomes of living donor kidney transplants are significantly better than those of deceased donor grafts .
But there are many obstacles to living doner transplantation as ABO incompatibility, HLA mismatch/donor specific antibody, or donor/recipient age and size discrepancies .
Most of awaiting kidney transplant are sensitized to HLA DSAs which is associated with poor out come they usually have longer wait time to find compataibile doner.
Kidney Paired Donation (KPD) and desensitization are used to over come this obstacles.
■Kidney paired donation
It allows finding more compatible donor and decrease the load of heavy immunosuppression and its complications mainly infections.
It includes exchange of donors between two incompatible donor/recipient pairs so that two compatible transplants could be performed .
multiple single center KDP registries have been developed worldwide in countries such as India, Romania and Turkey.
It is essential in developing countries as desensitization are not easily accessible because of poor socioeconomic conditions.
The first established national registry originated from the Netherlands where all seven transplant centers combined to form The Dutch National Living Donor.
Which was a model for other national multicenter KPD registries that followed in other countries .
In the years following the first KPD exchange, multiple multi-center registries were born .
-The advantage of single center registry over a multi-center registry is the simplifications as donor and recipient are at the same institution. And the use of a single HLA laboratory with decisions made by a single program as seen in the Johns Hopkins Hospital KPD program they have combined desensitization with KPD .
KPD involves ABO incompatibile pair, highly sensitized recipients, age and graft size mismatch pairs, and those pairs that are borderline compatible but will benefit from a better HLA match.
The highly sensitized defined as patients with a calculated panel reactive antibody (cPRA) greater than 95% .
Recipients with cPRA between 50 and 96% had equivalent match rates as those less than 50%.
■Desensitization
The goal of therapy is to reduce the antibody level so the flow cytometry cross-match is negative or lower than a pre-determined cutoff to prevent hyper acute rejection.
Desensitization protocols usually involve combinatiòn of plasmapheresis along +IVIG and rituximab to lower the titers of HLA antibodies.
*Plasmapheresis works by removing alloantibodies from the circulation.
An obstacle to this method is rebound increases in antibody levels.
*IVIG modulates the alloimmune response via several mechanisms ,it inhibits T-and B-cell proliferation, cytokine production, maturation of dendritic cells, and induce B-cell apoptosis.
one of two approaches are currently in practice: alternate day plasmapheresis followed by low-dose IVIG (used in living donor transplant candidates) and high dose IVIG with rituximab .
*Rituximab :It depletes CD20 expressing B cells via complement-mediated cytotox-icity and apoptosis .
CD20 is expressed in immature and mature B-cell so rituximab results in elimination of B-cell populations.
Rituximab also dcrease in anti-HLA antibodies in some patients .
*Bortezomib: target plasma cells provides significant and sustained reductions in anti-HLA antibody levels when used in combination with other therapies such as plasmapheresis and IVIG.
Protocols of desensitization are not standard and studies on desensitization outcomes are small, non-randomized, not adequately powered, and have a relatively short follow-up time.
■KPD versus desensitization
Combination of both strategies proved to be successful .
The highly sensitized patient has a match rate as low as 15% in KPD pools Combining desensitization with KPD as a complimentary modality will increase the chances of finding a compatible donor.
■Conclusions
several options have become available for Highly sensitized patients including KPD, desensitization and most recently deceased donor priority listing.
these patients is better to be transplanted at experienced centres with strategies providing a multi-modality approach to transplant.
Future studies are needed to assess its overall impact on KPD and desensitization.
Ban Mezher
3 years ago
Renal transplantation is the best treatment option for patients with ESRD, but the shortage of available deceased donor was a big obstacle. So living transplantation can overcome this shortage. Living donor transplantation das several limitation:
ABO incompatibility
HLA mismatch/DSA
donor/ recipient age & size discrepancy.
There are 2 strategies used to overcome over the barrier to living donor transplantation: PKD, desensitization or combination of both.
PKD:
This program start before >30 years ago for exchange donor between incompatible donor/recipient, so compatible transplant can be done.It is essential in countries where living donor is the only available option for transplantation. In UK, USA, Canada & Australia there are combined registries from different institutions in same country leading to offering more compatible transplantation. Some programs match ABO incompatible donor/recipient to increase match rate. USA PKD is a unique program use multiple single & multiple registries that operate independent of each other.
It is better to use single HLA lab & decision made by single program & standard practice. Over years the complexity of PKD increased to involve 3 or 4 pairs which require complicated mathematical algorithms.
Now, highly sensitized patients ( cPRA> 98%) had better chance to had compatible donor by PKD. PKD benefit can reach beyond :
living paired donation as NDD can involve deceased donor from waiting list
better match results improve survival
desensitization to reduce threshold of unacceptable antigens.
Desensitization:
Large number of highly sensitized patients including patients with retransplantation leading to development of different desensitization protocols which aim to eliminate or reduce Abs & convert positive crossmatch to negative one, through PP+IVIG+ rituximab.
PP had many side effects as coagulopathy, hypotension, hypocalcemia, thrombocytopenia & CV line associated infections in addition to rebound in Abs level.
IVIG can modulate immune response through different mechanisms. It inhibit T cells & B cells proliferation, cytokine production, maturation of dendritic c cells, induce B cells apoptosis. IVIG can be used with PP on alternate day with low dose ( living donor transplantation) or high dose with rituximab. Rituximab can eliminate B cells population & induce moderate reduction in HLA Abs especially in patients with low level of DSA.
Bortezumib is a new agent used in sensitization protocols, It target plasma cells.
There is clear advantage( survival) of desensitization strategies in living donor transplantation when compared to patients staying on dialysis especially in patients with positive FCXM & Negative FCXM but positive CDC.
Due to cost of desensitization & rebound phenomenon of Abs it is better to use desensitization for patients who are on the top of waiting list.
Highly sensitized patients has 15% chance to get matched donor in PKD pool, so combining desensitization with PKD can increase the chance of finding compatible donor with good graft & patients outcome.
CARLOS TADEU LEONIDIO
3 years ago
VI. Kidney paired exchange and desensitization: Strategies to transplant the difficult to match kidney patients with living donors
Summarise this article and reflect on your practice
INTRODUTION
The majority of patients awaiting kidney transplant are sensitized to human leukocyte antigens (HLA). The presence of DSAs has been associated with hyper acute rejection, antibody-mediated rejection (ABMR), and graft loss. For this reason, highly sensitized kidney transplant candidates experience longer wait times and have a higher chance of being removed from or dying on the transplant waiting list.
KIDNEY PAIRED DONATION
It has proven to be essential in developing countries such as India where living donation is the primary means of kidney transplantation and options such as desensitization are not easily accessible because of poor socioeconomic conditions. In fact, a more compatible match with less overall immunosuppression is ideal because the most common cause of death in their post-transplant population is infectious complications.
If multiple institutions within a country combine their registries, they can theoretically enable more matches. The advantage of single center registry over a multi-center registry is the simplification of logistics when both the donor and recipient are at the same institution. Likely more important is the use of a single HLA laboratory with decisions made by a single program as opposed to multiple programs with their own individual HLA laboratory and standards of practice.
However, highly sensitized patients will still suffer from low match rates even with an increase in the donor/recipient pool. Other strategies such as desensitization and/or owering the threshold for unacceptable antigens will have to be adopted to increase transplant rates in this subset of patients.
DESENSITIZATION
An increasing population of highly sensitized patients including those seeking repeat kidney transplants has led to the development of several desensitization strategies. Immunomodulation therapies are administered to transplant candidates as a means to eliminate or reduce HLA antibody levels in order to enable transplantation. The goal of therapy is to reduce the antibody level so the flow cytometry crossmatch is negative or lower than a pre-determined cutoff, thereby preventing hyper acute rejection. Desensitization protocols generally use plasmapheresis along with infusions of intravenous immunoglobulin (IVIG) and rituximab to lower the titers of HLA antibodies in the candidate.
Plasmapheresis works by removing alloantibodies from the circulation. IVIG is a blood product derived from the gamma globulin fraction of plasma from thousands of donos and has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, and to induce B-cell apoptosis. Rituximab is a CD20 specific chimeric murine-human monoclonal, responsible for a substantial elimination of B-cell populations and has also been shown to induce a modest decrease in anti-HLA antibodies in a fraction of patients — particularly those with low-level antibodies.
The high cost of desensitization and the tendency for antibody rebound after treatment require that the candidates be near the top of the waiting list, so that it is realistic for them to receive organ offers soon after treatment. The optimal desensitization protocol before transplant and the best maintenance immunosuppression program post-transplant remain to be determined.
KPD VERSUS DESENSITIZATION
The view of KPD and desensitization as competing strategies for matching suitable incompatible donors/recipient pairs is incorrect. The success of both strategies has been well established over the past decade and data supporting a combination strategy continue to emerge. The highly sensitized patient has a match rate as low as 15% in KPD pools, combining desensitization with KPD as a complimentary modality will increase the chances of finding a compatible donor. An example is to match a sensitized recipient to a donor that is more compatible than the patient’s original donor. This new match will have fewer antibodies against the KPD donor and thus a better chance at successful desensitization. This strategy has been utilized at several centers with emerging success.
CONCLUSION
Highly sensitized patients continue to be a challenge for transplant centers. Over the years, several options have become available including KPD, desensitization and most recently deceased donor priority listing. The best option for these patients is to be transplanted at a center with access and expertise in all of the aforementioned strategies provid[1]ing a multi-modality approach to transplant. The center should then be able to analyze each patient’s immunological profile and determine the best strategy for transplant. It is clear that the new deceased donor allocation system giving priority to those patients ≥98% cPRA is increasing the rate of transplantation in this group. Future studies are needed to assess its overall impact on KPD and desensitization
Mohamed Saad
3 years ago
Kidney paired exchange and desensitization: Strategies to transplant the difficult to match kidney patients with living donors. Introduction:
Kidney transplantation is the best modality for those with end stage renal disease, living kidney transplant has better outcome than deceased kidney transplant but there are many causes of incompatibility
Such as ABO incompatibility, HLA mismatch/donor specific antibody, or donor/recipient age and size discrepancies which keep the highly sensitized kidney transplant candidates experience longer wait times and have a higher chance of being removed from or dying on the transplant waiting list for that PKD /desensitization or both together considered to override these difficulties. A-Kidney paired donation:
It depends on the exchange of donors between two incompatible donor/recipient pairs so that two compatible transplants could be performed and this allow better matched transplantation with good survival and less immunosuppression.
The national Dutch KPD reported a transplant success rate of 49% within the first two years of its adoption which increase the donor pool.
Despite the success of larger multi-center registries, single center KPD programs still exist specially when combined with desensitization.
KPD in its simplest form is an exchange of donors between two incompatible pairs such that now they are compatible . The complexity has grown over time, regularly involving three or more pairs.
Those that are sensitized and/or are blood type O have match rates as low as 15% and so the become on waiting list or long time.
KPD allowing better matching for better outcome but still highly sensitized patients suffer to find compatible donor so we can use another strategy like desensitization or lowering the threshold for unacceptable antigens. B- Desensitization:
Its target to reduce the antibody level so the flow cytometry cross-match is negative or lower than a pre-determined cutoff to prevent hyper-acute rejection.
Desensitization protocols are center dependent but generally PEX,IVIG + or – Rituximab are used.
Plasmapheresis works by removing alloantibodies from the circulation, but the obstacle to this method is rebound increases in antibody levels The side effects commonly seen with plasmapheresis include hypocalcemia, thrombocytopenia, hypotension, and apheresis catheter-related infection and sepsis.
IVIG has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, and to induce B-cell apoptosis. IVIG provides the advantage of repleting normal immunoglobulins so not led to infection.
Two approaches: alternate day plasmapheresis followed by low-dose IVIG and high dose IVIG with rituximab.
Rituximab is anti CD20 monoclonal antibody used to deplete B-cell but associated with increased risk of JC virus-induced progressive multifocal leukoencephalopathy .
Bortezomib has been shown to provide significant and sustained reductions in anti-HLA antibody levels when used in combination with other therapies such as plasmapheresis and IVIG.
Standard protocol of desensitization shown good result and survival benefit from it.
A modified protocol adding rituximab and splenectomy to plasmapheresis and IVIG did not decrease AMR rates specially with high HLA antibody titer.
The two most common methods used to deplete anti-blood group antibodies are plasmapheresis and/or blood group-specific immunoadsorption. C-KPD versus desensitization:
They are not competing strategy but complementary for highly sensitized patients to select good matching by KPD and desensitization for lower titer of HLA DSA antibodies.
By using KPD with desensitization together increase the chance of good donor matching with recipients with high c PRA and by relaxing the restrictions on unacceptable antigen.
Many studies shown mean follow up at 23 months showed 100% graft and patient survival. Conclusion:
Still transplantation of highly sensitized patients is an obstacle and need more facility and collaboration between KPD and new protocols of desensitization. Reflect on your practice: –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.
Hinda Hassan
3 years ago
Highly sensitized patients whose with cPRA ≥95% remain a challenge in kidney transplantation so strategies as Kidney paired exchange and desensitization are considered .Kidney paired exchange is the exchange of donors between at least two incompatible donor-recipient pairs such that they are now compatible. Desensitization is the removal of circulating DSA to prevent graft rejection.
Combination of both KPD and desensitization is a promising strategy in this population of patients. One factor which affect finding a match within a KPD registry is theblood group of the pair especially if they have different blood groups. To improve this, more donors with o group are recruited, non-directed donors to start linear domino chains of transplants( non-simultaneous extended altruistic donor chain) and the use of ABO/HLA compatible pairs. The latter was associated with more risks of delaying of surgery and the possibility of receiving an inferior graft. Using deceased donor kidney to initiate a KPD chain will help to initiate living donor transplants that would not have happened otherwise and would remove more patients from the deceased donor waiting list which will increase the availability of deceased donor kidneys. Desensitization use plasmapheresis , intravenous immunoglobulin and rituximab. Side effects of plasmapheresis include hypocalcemia, thrombocytopenia, hypotension, and pheresis catheter-related infection and sepsis. A rebound increases in antibody levels are noted in this method due to ongoing antibody synthesis and re-equilibration between the intravascular and interstitial compartments. IVIG inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, to induce B-cell apoptosis with less risk of infection due to repletion of normal immunoglobulins. Side effects include headache, hypersensitivity-like reactions, and venous thrombosis. There are two approaches: 1. Alternate day plasmapheresis followed by low-dose IVIG (used in living donor transplant candidates) 2. High dose IVIG with rituximab.
Bortezomib provide significant and sustained reductions in anti-HLA antibody levels when used in combination with other therapies such as plasmapheresis and IVIG. The two most common methods used to deplete anti-blood group antibodies are plasmapheresis and/or blood group-specific immunoadsorption. The challenge remains in selection of the appropriate patients to optimize successful matching. Mathematical algorithms were suggested to determine the probability of successful matching in a KPD to predict who will likely benefit from desensitization. Combining desensitization with KPD as a complimentary modality will increase the chances of finding a compatible donor.
In Sudan both modalities are used but we focus mainly on PKD at it is less expensive than desensitization. combining both modalities is faced with many challenges including the lack of pool of donors to initiate PKD and the sole dependence on direct donation in PKD.
Jamila Elamouri
3 years ago
Summary of the article:
It is so difficult to find a suitable living donor therefore, these patients are usually remaining on the waiting list for a long time. Highly sensitized patients are those who have c PRA >95%. It is challenging to transplant them. Kidney paired Donor exchange(KPD) and desensitization are strategies used to facilitate transplantation in those sensitized patients. Paired kidney donation:
1- exchange of donors between two incompatible donor/recipient pairs so that two compatible transplants could be performed. (direct-paired exchange)
2- Exchange of donors between 3 or more pairs (closed-loop KPD) in which the last donor donate to the first recipient.
3- Non-Directed Donor (NDD) initiated chain where a bridge donor may be used to start another chain or the last donor can terminate the chain by donating to a waitlist recipient. Domino exchange
4- ABO-type affect the KPD, O-sensitized patients paired with an A-donor have less chance to get a suitable match. Including ABO/HLA compatible pairs can increase the donor pool in the KPD although ABO incompatibility is the main reason to enter the KPD.
5- KPD recently extends beyond living donors. NDD, s can contribute to the chain and the deceased donor list simultaneously.
6- KPD not only proved donor but also better immunologic match that affects the longe term graft survival.
7- KPD is suitable in counters with high infectious complication due to low socioeconomic status and the cost also represent an important issue there.
8- Even with KPD the highly sensitized patients remain very difficult to provide suitable donor, only 15% have a chance to find a suitable donor. As well; O-blood type recipients have low chance to find a good donor Desensitization:
It temporally removes DSA from the circulation and allows for transplantation against negative cross match.
Although rebound increase of these antibodies can occur post-transplantation leading to acute ABMR.
It depends on the use of plasmapheresis to remove these antibodies from the circulation in combination with other agents that affect antibody-producing cells like IVIG, Rituximab, and bortezomib. Historically splenectomy had been used. Combination of KPD and desensitization: this will increase the possibility of the sensitized recipient being transplanted.
In my centre:
Desensitization has been used with success, although occasionally due to decreased resources. I faced one case. Paired kidney donors for two couples are in our strategy and discussed with the patients and their families, but I do not apply due to the patient’s fairness.
We have no allocation program and we do not use deceased donors yet.
nawaf yehia
3 years ago
Kidney transplantation is the standard of care for those with end stage renal disease .
Deceased kidney donor transplantation has some limitation in regard to organ supply , its acceptance in some cultures and having inferior outcomes , so living kidney donation has become a standard of practice at many transplant centers worldwide .
Unfortunately many living donor recipient pair transplantations are not feasible because of :
*ABO incompatibility
* HLA mismatch/donor specific antibody
* donor/recipient age and size discrepancies
sensitized patients have higher incidence of hyperacute rejection , ABMR & graft loss , therefore have lower chances to get transplanted . Two strategies to address these barriers to living donor kidney transplantation are Kidney Paired Donation (KPD) and desensitization which can be used individually and in combination
Kidney paired donation
The KPD strategy, as originally proposed & applied over 30 years ago in South korea, itinvolved the exchange of donors between two incompatible donor/recipient pairs so that two compatible transplants could be performed .
It has proven to be essential in developing countries such as India where living donation is the primary means of kidney transplantation and options such as desensitization
are not easily accessible because of poor socioeconomic conditions In fact, a more compatible match with less overall immunosuppression is ideal because the most common cause of death in their posttransplant population is infectious complications
the program can be extended to be national like the Dutch KPD that served as the model for other national multicenter KPD registries
KDP possible scenarios currently include :
A) Traditional exchange between two incompatible pairs.
(B) Closed loop chain of 3+ pairs where the last donor donates to the
first recipient.
(C) Non Directed Donor (NDD) initiated chain where a bridge donor may be used to start another chain or the last donor can terminate the chain by donating to a waitlist recipient.
Traditionally, pairs were entered into the registry because of ABO incompatibility but the use of KPD now commonly involves highly sensitized recipients age and graft size mismatch pairs, and those pairs that are borderline compatible but will benefit from a better HLA match. The highly sensitized patient remains particularly challenging (those that are sensitized and/or are blood type O have match rates as lowas 15% ) and as the number of sensitized patients accumulates in a pool themore difficult it will be to initiate chains . KDP programs tend to have disproportionately large numbers of O recipients
and A-donors and disproportionately low numbers of A recipients and O-donors , also
sensitized O-patients paired with an A-donor have less chance of finding a successful match and will need to rely on other means such as desensitization and also by using the NDDs ( Non Directed Donors ) to increase group O donors to the group O recipients .
It has recently been proposed to use deceased donor kidney to help initiate a KPD chain; similar to that of an NDD initiated KPD chainwhere the last live donor on the chain donates to the deceased donor waiting list . This has the potential to initiate living donor transplants that would not have happened otherwise. In addition, it will remove more patients from the deceased donor waiting list which will
increase the availability of deceased donor kidneys
Desensitization
sensitization occurs mainly in pregnancy , blood transfusion & previous organ transplantation . Or such cases desensitization aims to reduce the antibody level so the flow cytometry crossmatch is negative or lower than a pre-determined cutoff, thereby
preventing hyper acute rejection . Desensitization protocols generally use plasmapheresis along with infusions of intravenous immunoglobulin (IVIG) and rituximab to lower the titers of HLA antibodies in the candidate.
Plasmapheresis works by removing alloantibodies from the circulation. An obstacle to this method is rebound increases in antibody levels ,as well as ongoing antibody synthesis by plasma cells .
IVIG has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of
dendritic cells, and to induce B-cell apoptosis. IVIG provides the chance of repleting normal immunoglobulins, thereby providing a theoretical advantage of reducing the infectious risk associated with plasmapheresis.IVIG-based desensitization is currently conducted using one of two approaches:
1- alternate day plasmapheresis followed by low-dose IVIG (used in living donor transplant candidates)
2- high dose IVIG with rituximab
Rituximab depletes Bells population by targeting CD20
Bortezomib targerts plasma cells
Most studies on desensitization outcomes are small, non-randomized, not adequately powered, and have a relatively short follow-up time.
Montgomery et al. reported one of the first long-term experiences with alternate day plasmapheresis and low dose IVIG. They demonstrated a clear survival benefit for desensitization followed by living donor kidney transplantation (compared to staying on dialysis) .
The high cost of desensitization and the tendency for antibody rebound after treatment require that the candidates be near the top of the waiting list, so that it is realistic for them to receive organ offers soon after treatment .
Baseline anti-blood group antibody titers seem to be the strongest predictor of early antibody-mediated rejection in ABO incompatible transplants. Masterson and colleagues demonstrated that selected patients with low anti-blood group antibody titers can successfully undergo ABO incompatible transplants using conventional immunosuppression alone . The two most common methods used to deplete antiblood
group antibodies are plasmapheresis and/or blood group-specific iimunoadsorption . however , kidney transplants of blood group A2 into group O recipents had extended survival with conventional immunosuppression as the A2 antigen is less expressed in tissues .
KPD + Desensitization is increasingly being recognized to be successful . The challenge remains in selection of the appropriate patients to optimize successful matching. Mathematical algorithms based on donor/recipient blood type, sensitization status, and pool size can determine the probability of successful matching in a KPD .
Predicting who will likely benefit from desensitization is more difficult.
Cross matching and solid phase assays against the donor will assess the donor specific antibody specificity and quantity. This will determine the degree of desensitization needed. The highly sensitized patient has a match rate as low as 15% in KPD pools . Combining desensitization with KPD as a complimentary modality will increase the chances of finding a compatible donor. An example is to match a sensitized recipient to a donor that is more compatible than the patient’s original donor. This new match will have fewer antibodies against the KPD donor and thus a better chance at successful
desensitization.
Although cPRA is used as a surrogate to sensitization level , those with antibodies against common HLA antigens will have difficulty being matched regardless of the
cPRA.
Conclusions
Highly sensitized patients continue to be a challenge for transplant centers.Over the years, several options have become available including KPD, desensitization and most recently deceased donor priority listing or a combination
The center should then be able to analyze each patient’s immunological profile and determine the best strategy for transplant. It is clear that the new deceased donor allocation system giving priority to those patients ≥98% cPRA is increasing
the rate of transplantation in this group.
Future studies are needed to assess its overall impact on KPD and desensitization.
reflection on practice :
there are no KPD , deceased kidney donation nor ABO incompatible transplantation in our country
Abdulrahman Ishag
3 years ago
Summarise this article and reflect on your practice.
Definition of highly sensitized patient;
Patients with a calculated panel reactive antibody (cPRA) greater than 95% are defined as highly sensitized patients .Those patients greater than or equal to 97% were less likely to find a match. The new deceased donor allocation system giving priority to those patients ≥98% cPRA is increasing the rate of transplantation in this group.
Strategies to transplant the difficult to match kidney patients with living donors
Two strategies to address these barriers to living donor kidney transplantation are Kidney Paired Donation (KPD) and desensitization which can be used individually and in combination.
Kidney paired exchange donation ;
KPD in its simplest form is an exchange of donors between two incompatible pairs such that now they are compatible . The complexity has grown over time, regularly involving three or more pairs .
The blood type of the donor/recipient pair significantly impacts the likelihood of finding a match within a KPD registry. The non-blood type-O, sensitized patients with O-donors have a much greater chance of finding a match within the registry than sensitized O-recipients with blood-type A donors. Conversely, sensitized O-patients paired with an A-donor have less chance of finding a successful match and will need to rely on other means such as desensitization .
Non-directed donors NDDs;
A potential strategy to match these patients through KPD is to increase the proportion of O-donors. This can be accomplished by using non-directed donors (NDDs) to start linear domino chains of transplants otherwise known as non-simultaneous extended altruistic donor (NEAD) chain .Presumably have a similar blood type distribution to the general public with approximately 45–57% having blood type-O depending on ethnicity.
The donor pool can also be enriched by including ABO/HLA compatible pairs. While part of their motivation to participate in KPD maybe altruistic, compatible pairs may benefit by obtaining a better quality or better matched kidney.
Risks of participating in a KPD pool for the compatible pair include delay of surgery as they wait for a match and the possibility of receiving an inferior graft.
The benefits of KPD have shown to be substantial and its potential has yet to be maximized as algorithms evolve. Its benefits reach beyond living paired donation as NDD’s can contribute to chains and the deceased donor list simultaneously. A better immunological match will result in improved long term graft survival and less economical strain with the use of less immunosuppression.
Desensitization:
The goal of therapy is to reduce the antibody level so the flow cytometry cross match is negative or lower than a pre-determined cutoff, thereby preventing hyper acute rejection.
The high cost of desensitization and the tendency for antibody rebound after treatment require that the candidates be near the top of the waiting list, so that it is realistic for them to receive organ offers soon after treatment . The optimal desensitization protocol before transplant and the best maintenance immunosuppression program post-transplant remain to be determined.
Desensitization protocols generally use plasmapheresis along with infusions of intravenous immunoglobulin (IVIG) and rituximab to lower the titers of HLA antibodies in the candidate.
1-Plasmapheresis;
Works by removing alloantibodies from the circulation.
Side effects commonly seen with plasmapheresis include hypocalcemia, thrombocytopenia, hypotension,and pheresis catheter-related infection and sepsis.
2-IVIG ;
is a blood product derived from the gamma globulin fraction of plasma from thousands of donors.
IVIG has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, and to induce B-cell apoptosis.
IVIG provides the advantage of repleting normal immunoglobulins, thereby providing a theoretical advantage of reducing the infectious risk associated with plasmapheresis.
Potential adverse reactions that can be seen with IVIG administration include headache, hypersensitivity-like reactions, and venous thrombosis.
IVIG-based desensitization is currently conducted using one of two approaches: alternate day plasmapheresis followed by low-dose IVIG (used in living donor transplant candidates) and high dose IVIG with rituximab .
3-Rituximab;
It is a CD20 specific chimeric murine-human monoclonal Ab. It depletes CD20 expressing B cells via complement-mediated cytotoxicity and apoptosis .
Rituximab has also been shown to induce a modest decrease in anti-HLA antibodies in a fraction of patients particularly those with low-level antibodies .
There is a very small but increased risk of JC virus-induced progressive multifocal leukoencephalopathy associated with Rituximab .
4-Bortezomib ;
It targets plasma cells. Bortezomib has been shown to provide significant and sustained reductions in anti-HLA antibody levels when used in combination with other therapies such as plasmapheresis and IVIG.
5-Splenectomy ;
was eventually replaced by anti-CD20 treatment .
KPD versus desensitization;
The highly sensitized patient has a match rate as low as 15% in KPD
pools . Combining desensitization with KPD as a complimentary
modality will increase the chances of finding a compatible donor.
Reflect on your practice:
KPD and Desensitization for ABO incompatibility programs are not available in our center .
Mahmud Islam
3 years ago
With the increased number of patients waiting for transplantation considering alternatives to finding matched donors should be considered. the alternatives are:
**Kidney paired donation
**Desensitization
kidney paired donation can be done among more than two couples to find the best match. despite that, still, it is difficult to match most of patients so still we need desensitization
For desensitization: plasmapheresis, Rituximab, and IVIG is utilized
Plasmapheresis works by removing alloantibodies from the circulation. It has side effects like coagulopathy, hypocalcemia, adverse reaction like hypotension and catheter-related issues like infection etc.
IVIG was shown to inhibit both T and B cells proliferation, modulate the immune system, inhibit the maturation of dendritic cells and induce T and B cell apoptosis. It also inhibits cytokine production
Rituximab depletes B cells which express CD20 by this was decreasing antibody production. It replaced splenectomy.
ABO-incompatible transplantation is risky costly and difficult. most common used methods are plasmapheresis and immune-adsorption.
In Turkey, there is wide use of deceased donors. many centers have paired kidney exchange. some centers do as many as 4 pairs. since more than 15 years no ABO incompatible transplant is done (because of cost). the government insurance covers transplantation from A to Z but not ABO incompatible transplants. ABO-incompatible transplants are replaced with kidney paired donation. desensitization is reserved for those with high PRA in some centres
saja Mohammed
3 years ago
kidney pair donation program: (KPD)started since1991 in developing countries like Korea and India limited to local centers then gradually expanded to multicenter , national base registry and innovation of Kidney exchange program in many countries worldwide , such program improved the matching and allow for better compatible and HLA matched donation its ideal for living transplant program in developing countries especially when there is no access to desensitization or DD programs also the low socio-economic status with high rate of infection so such program allowed for less intense immunosuppression use such program should be encouraged in our setting as we are dealing mainly with LD transplant program, this will improved the access for better matched donors and limit access to commercial transplantation . Available protocol for PKD, including:
1- Two Paired donation that allow exchange between HLA incompatible donor to recipient
2- Closed loop chain KPD, 3 pairs with one NDD
3-NDD initiated KPD chain with bridge donor can initiated the chain or last donor can donate for waitlisted recipient. NDD can increase the access to blood group O donors with better ABO /HLA compatible pairs Risk with KPD program that still sensitized patients will be difficult to get match donor and delay in the surgery time, in addition risk of receiving an inferior graft.
Recently extended the registry of KPD to the DD list similar to NDD-KPD chain when the last living donor in the chain NDD can donate to the waiting DD
This will further expand the pool of better match donors with less cost, less immunosuppression, better use of resources and better graft survival and outcome
KPD still of limited benefit for highly sensitized patients with CPRA >95%, access to matched donor reported in < 10%
Alternative will be desensitization alone or the combination of both for better match and less DSA exposures in order to increase rate of transplantation in such specific group.
Desensitization protocol:
Limited use for highly sensitized recipients with target to remove HLA specific DSAs and convert the FXCM to negative in order to get access for transplantation , used alone or in combination with KPD ,different protocols , based on local center resources and experiences , available resources and expertise , risk of infection coagulopathy with PP and depleting agents
By principles by desensitization we are targeting the DSA removal by plasmapheresis and further reduction of DSA production by using immunomodulating agent like IVIG with pleotropic effect as inhibit T and B cells proliferation, reduce cytokines expression, induce B cells apoptosis followed by B cells depleting agents to prevent further production of DSA like rituximab or plasma cells depleting agent bortezomib
Based on available limited evidence from underpowered studies, standardized desensitization protocol no yet performed with doubtful benefits as its associated with higher rate of AMR due to the DSA rebound post-transplant in addition its use limited by cost, over suppression and risk of infections, malignancy.
Combination of both KPD and desensitization will further expand the access for better HLA matched donor in highly sensitized groups.
Our kidney donor pool from living related donors no access to DD, no KPD program started yet but we are planning to start KPD this will allow for better match with less cost and less access to commercial transplantation, desensitization I will individualize its use.
Last edited 3 years ago by saja Mohammed
Weam Elnazer
3 years ago
Donation of kidneys in pairs
This refers to the exchange of donors between two incompatible donor/recipient pairings in order to execute two compatible transplants.
Over time, the level of difficulty has increased, with three or more pairs of players frequently involved.
The use of complex mathematical algorithms is required in order to optimally match patients for transplantation. Transplant facilities that participate in national registries must conduct transplants at the same time in order to avoid donor reneging and causing a break in the chain.
Pairs were traditionally entered into the registry because of ABO incompatibility, but the use of KPD is increasingly common among highly sensitized recipients, those with age and graft size mismatches, and those who are borderline compatible but will benefit from a better HLA match, according to the National Kidney Foundation.
Desensitization
During immunomodulation therapy, transplant candidates’ HLA antibodies are eliminated or reduced in order to allow for the transplantation of a healthy organ.
To prevent excessive acute rejection, the objective of treatment is to decrease antibody levels to the point where the flow cytometry cross-match is negative or lower than a pre-determined threshold.
Plasmapheresis, in combination with intravenous immunoglobulin (IVIG) and rituximab infusions, is commonly used in desensitization programs to reduce the titers of HLA antibodies in candidates.
Plasmapheresis
Alloantibodies are removed from the circulation as a result of this treatment.
an adverse effect of the medication:
Coagulopathy
hypocalcemia
thrombocytopenia
hypotension
as well as infection and sepsis caused by apheresis catheter.
Because of the high expense of desensitization and the likelihood of antibody rebound following treatment, applicants must be at the head of the waiting list in order to get organ offers as soon as possible after therapy.
In response to subsequent findings of improved ABO-incompatible outcomes associated with splenectomy at the time of transplant, splenectomy became a mandatory component of the pioneering Japanese ABO-incompatible programs that began in the late 1980s and were implemented throughout the country.
Because ABO-incompatible transplantation was considered to be associated with a significant risk of antibody-mediated rejection, viral infections, and poor graft survival, it was not routinely performed in the past.
As anti-CD20 therapy became more widely available, splenectomy became less common, and post-transplant antibody elimination by plasmapheresis became commonplace in addition to pre-transplant therapies. Several follow-up studies found that standard immunosuppression and antibody elimination, with the exclusion of splenectomy and rituximab, produced results that were equivalent.
Anti-blood group antibody titers at the time of the transplant appear to be the most reliable predictor of early antibody-mediated rejection in ABO-incompatible transplants.
KPD and desensitization should not be seen as competing techniques for matching acceptable incompatible donor/recipient couples, as this is wrong. Over the past decade, the effectiveness of both tactics has been well established, and new evidence supporting a combined strategy is continually emerging.
In KPD Pools, the match rate for the highly sensitive patient might be as low as 15 per cent in some cases. The use of desensitization in conjunction with KPD as a complementary therapy will boost the likelihood of finding a donor who is compatible. The matching of a sensitized recipient to an organ donor who is more compatible with the patient than the patient’s initial donor is an example. There will be fewer antibodies against the KPD donor in this new match, which will increase the likelihood of effective desensitization.
Reflect on practice:
we have paired exchanges in our centre(the limited number we have done). I found it is an excellent option for highly sensitised and ABO-incompatible.
Mohamed Mohamed
3 years ago
VI. Kidney paired exchange and desensitization: Strategies to transplant the difficult to match kidney patients with living donors Summarise this article and reflect on your practice.
Introduction There is a big gap between the need for & the actual number of kidney transplants; and it is clear that this is due to limited amount of organs available. Although living kidney donation has become a common practice at many centers, however many such transplants fail to proceed due to:
– ABO incompatibility
– HLA mismatch
– DSA or
– Donor/recipient age & size discrepancies Highly sensitized transplant candidates spend longer times on waitlists & are more likely to die or being removed from the list before finding a suitable donor. KPD & desensitization are strategies to surmount the immunological barriers; & can be used either individually or in combination. Kidney paired donation It is a good option in developing countries where living donation is the primary means of transplantation & where access to desensitization is not easy regarding poor socioeconomic conditions. More matches can be enabled by combining multiple registries within a country , which is the case in countries like UK, Canada, Australia & USA. Some programs also match ABO-i pairs to increase their match rate. Single center KPD programs still exist despite the success of larger multi-center registries. The highly sensitized patient, defined as cPRA >95%, remains particularly challenging. Those with cPRA=>97% are less likely to find a match overall. Overall match rates are roughly 50–60% in a large KPD registry with > 1000 pairs. Those that are sensitized &/or are ABO type O have match rates as low as 15%. Non-ABO type-O, sensitized patients with O-donors have a greater chance of finding a match within the registry than sensitized O-recipients with ABO-type A donors. In contrast, sensitized O-patients paired with an A-donor have less chance of a successful match & will need to look for other means such as desensitization. The proportion of O-donors can be increased in such programs by the use of non-directed donors (NDDs) to expand the chains of transplants; also known as non-simultaneous extended altruistic donor (NEAD) chain. The donor pool can also be increased by including ABO/HLA compatible pairs. Disadvantages of KPD include:
– delay of surgery while waiting for a match
– possibility of receiving an inferior graft. The use of deceased donor kidney to help initiate a KPD chain has recently been proposed; it is similar to that of an NDD initiated KPD chain where the last live donor on the chain donates to the deceased donor waiting list. This will likely initiate living donor transplants that would not have happened otherwise. It will also remove more patients from the deceased donor waiting list & thus will increase the availability of deceased donor kidneys. Even with an increase in the donor/recipient pool a subgroup of highly sensitized patients will still suffer from low match. They can benefit from other strategies such as desensitization and/or lowering the threshold for unacceptable antigens. Desensitization It aims to reduce the antibody level so the FCM-XM is negative or lower than a pre-determined cutoff, thus preventing hyper acute rejection. Protocols use PP plus IVIG & rituximab to lower the titers of HLA antibodies. PP removes alloantibodies from the circulation. S/E commonly seen include:
– coagulopathy
– hypocalcemia
– thrombocytopenia
– hypotension and
– catheter-related infection & sepsis.
– rebound increases in antibody levels occurs IVIG modulates the alloimmune response via several mechanisms:
– inhibit T- & B-cell proliferation, cytokine production, maturation of DCs, & induce B-cell apoptosis. IVIG replete normal immunoglobulins, thus theoretically reduces the infectious risk associated with PP. Potential S/E of IVIG:
– headache
– hypersensitivity-like reactions, and
– venous thrombosis. Rituximab depletes CD20 expressing B cells via CDC & apoptosis. It results in a substantial elimination of B-cell populations Rituximab can increase the risk of JC virus-induced progressive multifocal leukoencephalopathy. Bortezomib, when combined with PP & IVIG, provide significant & sustained reductions in anti-HLA antibody levels. The high cost of desensitization & the tendency for antibody rebound after treatment require that the candidates be near the top of the waiting list so as to receive organ offers soon after treatment. The optimal pre-transplant desensitization protocol & the best maintenance IS remain to be determined. Masterson et al showed that selected patients with low anti-ABO antibody titers can successfully undergo ABO-i transplants using conventional IS alone. The methods used to deplete anti-ABO antibodies are PP &/or blood group-specific IA. It is unclear what minimum titer is acceptable before & after ABO-i transplantation. KPD versus desensitization It is not correct to view these strategies as competing for matching suitable incompatible donors/recipient pairs. There are data supporting a combination strategy. Mathematical algorithms determine the probability of successful matching in a KPD. Predicting who will likely benefit from desensitization is more difficult. The highly sensitized patient has a match rate as low as 15% in KPD pools. Combining desensitization with KPD will increase the chances of finding a compatible donor. An example is to match a sensitized recipient to a donor that is more compatible than the patient’s original donor. This new match will have fewer antibodies against the KPD donor & thus a better chance at successful desensitization. The updated national KAS initiated by the OPTN in 2014 is meant to improve transplant rates of the most highly sensitized patients with cPRA ≥98%. Desensitization will likely play a critical role in highly sensitized patients, however these patients will have to be carefully chosen according their HLA antibody profile. Relaxing restrictions on unacceptable antigens is also another strategy in matching sensitized patients. This will allow for low level DSAs. The individual center would then determine the level of antibody reactivity they are comfortable with. Raising this threshold will increase the number compatible donors; not only in the KPD pool but also from available deceased donors. Desensitization goals will also be easier to reach. Conclusions Highly sensitized patients continue to be a challenge for transplant centers. Several options have become available including KPD, desensitization & most recently deceased donor priority listing. The best option for these patients is to be transplanted at a center with access & expertise in all of the strategies providing a multi-modality approach to transplant. The new deceased donor allocation system, which gives priority to patients with ≥98% cPRA, is increasing the rate of transplantation in this group. Future studies are needed to assess its overall impact on KPD & desensitization.
Reflection on my practice: Desensitization is rarely done in our center; the local program is generally not supporting transplantation of highly sensitized patients due logistic issues. KPD is in its early infancy in our country. There is a modest experience in only one center. No published data. No deceased donation transplant program in our country. No ABO-i transplantation in our country. Surely the inormations gained from this article will help us in planning for our future in this setting.
summary of Kidney paired exchange and desensitization: Introduction:
Living donor kidney transplant outcome are significantly better than those of deceased donor graft but it is difficult to have living donor recipient pair transplant because of ABO incompatibility HLA mismatch donor specific Ab or donor /recipient age ,size discrepancies .
DSA formation is result in :
1) Hyperacute rejection
2) ABMR and graft loss
To overcome barriers for living donor kidney transplant are:
1) Kidney pared donation
2) Desensitization
3) Combination PKD +desensitization. KPD
More compatible match with less over all immunosuppression which is deal as post transplant cause of death is infection.
Multiple institutions within a country combine their registry and enable more match.
Despite the success of large multi-centre registries ,single centre PKD program still exist.
In order to facilitate transplant of highly sensitized patients combined KPD programme and desensitized patients.
KPD it is an exchange of donor between two incompatible pairs such that now they are compatible .
Patient pairs were entered into the registry because:
1) ABO incompatible
2) Highly sensitized recipient age and graft size mismatch pairs
3) Border line compatible but will benefit from better HLA match
Highly sensitized patients defined as patients with (cPRA) greater than 95%.
Over all match rate are approximately 50—60% in a large KPD registry .
The blood type of donor/recipient pair impact the like hood of finding a match within a KPD registry specially group O recipient and A donor .
Non blood group type sensitized patients with O donor have a much greater chance of finding match with registry than sensitized O recipient and blood group A donor .
Sensitized O patients paired planed with a donor have less chance of finding successful match.
So strategy-to match O recipient through PKD increase the O donor so can be through non-direct donors(NIDS) to start linear dominos chains of transplant .
To help in initial a KPD chain has really proposed use deceased donor kidney .
NIDD has potential to initiate living donor transplant that would not have happened other wise ,so will remove more patients from the deceased donor waiting list which will increase the available of deceased donor kidney.
Abetter immunological match will result in improved long term graft survival and less economic status with use of less immunosuppression .
Desensitization use to lowering the threshold to unacceptable antigens will have adapted to high transplant rate in slim patients. Desensitization:
In order to enable transplant for highly sensitized patients administrated immunomodulation therapy is necessary .
Goal of therapy is to reduce HLA Ab level in order so flow cytometry crossmatch is -ve prevent hyperacute rejection .
Desensitization protocol generally use plasmapheresis with IVIG and rituximab to lower titre of HLA Abs
S/E of plasmapheresis:
1) Decrease ca
2) Decrease ph
3) Hypotension
4) Catheter related infection and sepsis
5) Rebound increase in antibody level
IVIG modality alloimmune response via several mechanism:
1) -ve Tand B cell proliferation
2) -ve cytokins production
3) -ve maturation of dendritic cells
4) B-cell apoptosis
IVIG replating normal immunological so decrease risk of infection with plasmapheresis.
S/E of IVIG:
1) Headache
2) Hypersensitivity like reaction
3) Venous thrombosis
IVIG based sensitization :is currently conduct using one of two approaches:
1) Alternative day plasmapheresis followed by low dose IVIG
2) High dose IVIG with rituximab
Rituximab depleted CD20 expression B cells via complement-mediated cytotoxicity and apoptosis
Rituximab induce modest decease in anti HLA level Abs
S/E of rituximab:
Risk of JC virus leading to progressive multilucoencephalopathy .
New desensitization agents:
Bortezomib is reduce anti-HLA Abs level when used in combination with plasmapheresis or IVIG.
Although most of studies on desensitization use small but clear survival benefit of desensitization followed by living donor kidney transplant.
Despite high rate of transplantation 100% one year graft survival, acute Ab-mediated rejection rate were high .
Adding rituximab to IVIG and plasmapheresis and splenectomy did not decrease AMR.
There is suggestion that increase level of DSA associated with AMR
In pioneering Japanese ABO incompatible program begin 1980 report that improved ABO incompatible outcome with splenectomy but splenectomy replace by antiCD20.
It remain unclear what minim titre is acceptable before and after ABO incompatible kidney transplant. Kidney paired donation versus desensitization
Combined approach of KPD and desensitization selection of appropriate patient to optimize successful matching mathematical algorisms based on
Donor /recipient blood type ,sensitization, statistical pool size can determine the probability of successful matching in KPD.
Combined class with KPD as complementary modality will increase the chance of function a compatible donor.
New match have few antibodies against the KPD donor and thus has better chance at successful desensitization .
With the new allocation system deceased system donor match wait time will be short and may provide abetter HLA match than in KPD pool with or without desensitization.
The role of desensitization in the setting of new KAS remain unclear.
Desensitization play crucial role in highly sensitized patients but these patients still have to be carefully.
Chosen according their HLA antibody profile.
Matching sensitized patients is to relax restriction on acceptable antigens. Conclusion
Transplantation of highly sensitized patients still running challenge.
There are options available for highly sensitized patients include :KPD ,desensitization and deceased donor priority listing.
Highly sensitized patients should be transplant at centre with access and expertise in approach in transplant.
The centre should be able to analyse each patient immunological profile and determine the best strategies for transplantation.
New deceased donor allocation system gives priority to those patients equal or >98 cPRA is high rate of transplant in this group.
For the studies need to access its overall impact on KPD and desensitizing.
Reflect in my practize
KPD program and ABO incompatible transplant is not availble in our center.
for desensitation they use Rituxmab in our center,graft survival out come is variable .
Zahid Nabi
3 years ago
This paper has again raised concerns about another important question of devising strategies how to transplant highly sensitized patients who other wise carry a very little chance to find an appropriate well matched donor.
Two strategies to address these barriers to living donor kidney transplantation are Kidney Paired Donation (KPD) and desensitization which can be used individually and in combination.
KPD was first performed in 1991 at a single center in South Korea where kidney transplantation relies heavily on living donation because of the lack of an established deceased donor program .
The best way would be if If multiple institutions within a country combine their registries, they can theoretically enable more matches. This has been accomplished in countries such as the United Kingdom (U. K), Canada, Netherland, Australia and the United States .
KPD in its simplest form is an exchange of donors between two in- compatible pairs such that now they are compatible however it gets complex if majority of sensitized pools carry’s blood group O and most of donors belong to another blood group.
Inspite of all this highly sensitized patients will still suffer from low match rates even with an increase in the donor/recipient pool. Other strategies such as desensitization and/or lowering the threshold for unacceptable antigens will have to be adopted to increase transplant rates in this subset of patients.
Different desensitization protocols have been adopted by different centers and different modalities used are as follows
Plasmapheresis works by removing alloantibodies from the circulation Aside from coagulopathy, side effects commonly seen with plasmapheresis include hypocalcemia, thrombocytopenia, hypotension, and pheresis catheter-related infection and sepsis.
IVIG is a blood product derived from the gamma globulin fraction of plasma from thousands of donors.
IVIG modulates the alloimmune response via several mechanisms but it is not known which mechanisms are important in mediating anti-humoral effects in humans . IVIG has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, and to induce B-cell apoptosis. IVIG provides the advantage of repleting normal immunoglobulins, thereby providing a theoretical advantage of reducing the infectious risk associated with plasmapheresis.
Rituximab was originally approved for the treatment of B-cell lymphomas. It is a CD20 specific chimeric murine-human monoclonal Ab. It depletes CD20 expressing B cells via complement-mediated cytotoxicity and apoptosis . Rituximab has also been shown to induce a modest de- crease in anti-HLA antibodies in a fraction of patients particularly those with low-level antibodies .
The newest agents added to the armamentarium for desensitization are therapies that target plasma cells. Bortezomib has been shown to provide significant and sustained reductions in anti-HLA antibody levels when used in combination with other therapies such as plasmapheresis and IVIG .
The highly sensitized patient has a match rate as low as 15% in KPD pools. Combining desensitization with KPD as a complimentary modality will increase the chances of finding a compatible donor.
The best option for these patients is to be transplanted at a center with access and expertise in all of the aforementioned strategies providing a multi-modality approach to transplant.
Mohamed Ghanem
3 years ago
The outcome of living kidney transplantation is better than deceased kidney transplantation however many pairs are not compatible due to ABO Incompatibility, presence of DSA or high HLA mismatch, and inappropriate size of the donor’s kidney
So this lead to overcoming these problems through two strategies: kidney paired donation and desensitization Kidney paired donation:
Exchange of donors of two pairs or more noncompatible donor /recipient pairs with a result of matching donor-recipient pairs so early transplantation, less use of desensitization, decrease the need for immunosuppression.
combining KPD with desensitization protocols facilitates transplantation of highly sensitized patients
Highly sensitized patients represent the main problems of the waiting list in KPD with 68 % of waiting list were having c-PRA > 80 % since 2012
KPD has many problems first due to many recipients with blood group O and paucity of donors with blood group O
many donors with group A with less number of recipients with group A
So we can overcome these problems by including ABO-incompatible transplantation
Deceased donors now can be involved in KPD to extend the donors pool and start the chain of KPD
Importance of KPD: transplantations of patients with ABO-incompatible pairs, good immunological match, less economic needs for desensitization, early transplantation for highly sensitized patients on the waiting list. Desensitization
Decrease or elimination of antibodies levels to enable highly sensitized patients for earlier transplantation and prevent hyperacute rejection
many strategies used for desensitization
first plasmapheresis by removing antibodies from the circulation
secondly, IVIG blocks antibodies as it inhibits both B cell and T cells decrease cytokine production and induce B cell apoptosis with less risk of immunosuppression of plasmapheresis
Third Rituximab is a chimeric monoclonal antibody against CD20 of B cells lymphocytes with a modest decrease of antibodies
fourthly new agents like Bortezomib target plasma cells with a significant decrease in antibodies.
With many protocols with plasma pheresis with low dose IVIG on alternate days
another protocol of High dose IVIG in addition 2 doses of rituximab
and modified protocol with plasmapheresis , Rituximab, IVIG and splenectomy, however, didn’t show a better decrease of alloantibodies reduction with more risk of infection KPD and desensitization :
Combining two strategies improve significantly transplantation of highly sensitized patients with increased chance of finding a suitable donor
reflect on your practice: unfortunately, KPD programs are not available in our center however desensitization protocols improve significantly transplantation of highly sensitized patients ABO-incompatible transplantation is not allowed in our country
Mohammed Sobair
3 years ago
Sensitization and ABO incompatibility, age and size discrepancies of donors are the
main barriers to transplant, strategies such as KPD and desensitization have been
developed to overcome this.
KPD:
Start long time, good for areas where deceased donor program is not established.
And when desensitization are not easily accessible because of poor socioeconomic
conditions.
It is the exchange of donors between at least two incompatible donor-recipient pairs
such that they are now compatible. Complexity has grown over time, regularly involving
three or more pairs.
This requires sophisticated mathematical algorithms to best match patients for
transplant. Transplant centers involved in national registries must perform transplants
simultaneously to prevent donor reneging and disruption of the chain.
Traditionally, pairs were entered into the registry because of ABO incompatibility but the
use of KPD now commonly involves:
Highly sensitized recipients.
Age and graft size mismatch pairs.
Pairs that are borderline compatible but will benefit from a better HLA match.
If multiple institutions within a country combine their registries, they can theoretically
enable more matches.
Programs such as the UK and Australia match ABO incompatible pairs to increase their
match rate.
Match rates are approximately 50–60% in a large KPD registry with more than 1000
pairs.
Those that are sensitized and/or are blood type O have match rates as low as 15%.
The number of sensitized patients accumulates in a pool the more difficult it will be to
initiate chains. The blood type of the donor/recipient pair significantly impacts the
likelihood of finding a match within a KPD registry.
Non-blood type-O, sensitized patients with O-donors have a much greater chance of
finding a match within the registry than sensitized O-recipients with blood-type a donors.
Conversely, sensitized O-patients paired with an A-donor have less chance of finding a
successful match and will need to rely on other means such as desensitization.
A potential strategy to match these patients through KPD is to increase the proportion of
O-donors.
By using non-directed donors (NDDs) to start linear domino chains of transplants
otherwise known as non-simultaneous extended altruistic donor (NEAD) chain.
Australian KPD program has matching ABO incompatible yet HLA compatible pairs. This
overall does not increase the donor/recipient pool but allows for more possible matches
to be made allowing for more transplants to occur and possibly the inclusion of more
highly sensitized recipients.
Use deceased donor kidney to help initiate a KPD chain; similar to that of an NDD
initiated KPD chain where the last live donor on the chain donates to the deceased
donor waiting.
Desensitization:
The goal of therapy is to reduce the antibody level so the flow cytometry crossmatch is
negative or lower than a pre-determined cutoff.
Desensitization protocols generally use:
Plasmapheresis.
Intravenous immunoglobulin (IVIG).
Rituximab.
Side effectsof PE:
Coagulopathy, hypocalcemia, thrombocytopenia, hypotension, and apheresis catheter-
related infection and sepsis.
Potential adverse reaction OF IVIGs:
Include headache, hypersensitivity-like reactions, and venous thrombosis.
Rituximab SIDE EFFECT:
There is a very small but increased risk of JC virus-induced progressive multifocal
leukoencephalopathy associated with Rituximab.
KPD versus desensitization:
A novel approach is the combination of both KPD and desensitization.
Conclusions:
Highly sensitized patients continue to be a challenge for transplant centers.
Several options have become available including KPD, desensitization and most
recently deceased donor priority listing.
The best option for these patients is to be transplanted at a center with access and
expertise in all of the aforementioned strategies providing a multi-modality approach to
transplant.
Reflect on your practice:
Expansion of KPD, we are still using single center program.
Use of new agent for sensitization medication i.e. bortezomib
Sahar elkharraz
3 years ago
Highly sensitised patients remain a large problem to get suitable donor for successfully transplant.
Highly sensitised defined as cPRA >97%. they are difficult to find matching.
Recently with start the program of kidney paired donation provide a better matching kidney also used for patients who are ABO incompatible to exchange with compatible donor to maintain kidney transplant with negative cross match.
This program not used for compatible matching because there’s risk of surgery delays and risk of inferior graft.
Non blood group type O sensitised patients with O donor have greater chance of transplant.
In contrast sensitised patients who are O type paired with A donor have less chance to find successful match.
For sensitised patients with cPRA >20 or more but less than 95% are get benefits from kidney allocation system with desensitisation protocol and they get successful transplant and reduce list of waiting.
But still highly sensitised patients not get benefits from kidney allocation system and kidney paired donation because there’s less chance to get suitable donor and many of them dying on dialysis while they still on waiting list.
The program of national kidney registry help sensitised patients to get suitable donor and decrease waiting list.
Desensitisation protocol using for highly sensitised patients despite it’s costy but helps to reduce immunity response and decrease risk of rejection.
Using IV Ig whether low dose or high dose help to reduce all risk ABMR.
Immunoglobulin derived from human plasma immune globulin and it’s action reduce B cell and T cell activation reduce maturation of dentric cells and reduce cytokines production and Increase B cell apoptosis.
it is side effects are hypersensitive and viral infection and venous thrombosis
High dose Iv Ig used with plasma exchange as alternative days
plasma exchange help to remove allantibodies but there’s risk of rebounding of antibodies after equilibrium between intravascular and interstitial cell.
it’s side effects hypotension and hypocalcemia and bleeding tendency and infection related catheter.
or low dose with rituximab
Rituximab are CD30 inhibitors lead to depletion of B cell activation
In the past patients with highly sensitised patients do splenectomy at the time of transplant.
Now rituximab used in state Splenectomy.
Bortezomib another regimen using in highly sensitised patients for removal anti HLA antibodies and can using in combination with plasmapheresis and rituximab.
Combination of kidney paired donation with desensitisation protocol help to improve survival of transplant and decrease percentage of waiting list.
In our centre they do only ABO compatible
there’s no KPD or kidney allocation system
MOHAMMED GAFAR medi913911@gmail.com
3 years ago
Many patients with ESRD on RRT or still CKD stage 5 have living kidney donors which are non comaptible to them.
These patients with different ages may go through very hectic and complaicted transplant journey using very aggresive immunosuppresion protocols to be transplanted.
The comaplications of these such trasplantion are diveres, ranging from ABMR , TCMR, cABMR with risk of early and late graft loss.
on the on the other hand using aggresive immunsuppresion protocls for these patients increases the risk of infections and malignacies post transplantion.
Hence paired kidney exchange will be the ultimate soultion for these kind of patients .
The unmatched donors with their recipents with their HLA typing and cPRA will enter a cpmuterized programm that automatically give them the best HLA match with comapatibilty.
The higher the number of the donors and the recipents the faster the match.
Regardless of the era of PKD programm evolving everywhere in many centers around the globe , some patients which are highly senstized with cPRA more than 95% dont have a comaptible match.
Hence the desentization is a good choice for them comapred being on RRT.
Aggresive desntization protocols are used for these ptients to reverse their cross match to be come negative .
DESENTIZATION STRATIGES,
PLAMAPHARESIS ,
Remove antibodies from the blood .
Has alot of comaplication like cathere realted infection, hypocalcemia, thrombocytopenia , in some cases sepsis.
Rebound increse in antibodies may occur post plasmapharesis, and it is very difficult to keep the patients on these procedures due to its cost and complications .
2.IV IGG,
Inhibits B &T cell proliferation, cytokine prduction and maturation of dendritic cells.
Induce B cell apopotosis.
Risk of allergy and hypersensitivty like reaction may occur during adminstration.
May be used as low dose protoclos for living kidney transplant and high dose for cadveric kidney transplant.
3. Rituximab ,
Causes CD20 expression depletions on B cells by complement mediated cytotoxicity.
Rituximab has also been shown to induce a modest de- crease in anti-HLA antibodies in a fraction of patients — particularly those with low-level antibodies .
CONCLUSION,
The PKD is the best option for the highly sensitzed patients with positive cross mtach.
The larger the pool of donors and the recipent the faster the track and better match.
Desentiztion startigies should be in parellel with PKD for these patients with positive cross mtach and no avialble PKD in their home town.
Amit Sharma
3 years ago
· Summarise this article and reflect on your practice
Kidney transplantation is the best form of treatment for ESRD patients. Living donor transplants have better results than deceased donor transplants. The transplant wait-list has high number of sensitized patients who can be transplanted either using kidney paired donation (KPD) or desensitization.
KPD was initially performed in South Korea amongst 2 pairs of incompatible pairs for getting 2 compatible transplants. It is an important tool especially in countries with poor access to desensitization. The Dutch KPD program led to 49% transplant rate among the highly sensitized, following which, other countries like UK, Australia and US also started KPD program. KPD program in US, be in single center or multi-center registry, has also shown increased transplant rates. Programs have used ABO incompatible pairs to increase their match rates. KPD is offered to patients with ABO incompatibility, highly sensitized pairs with age and graft size mismatch or borderline compatible pairs who can benefit with a better HLA match. A KPD can be either between 2 pairs, closed loop chain with 3 or more pairs, or a non-directed donor-initiated chain. Analysis of data revealed that 50-60% of patients receive a match in large KPD program but the patients with cPRA≥97% had lower chances to find a match, especially with blood group O showing only 15% match rate. Those with O group donor had higher chances to get a match while O group recipients had low chances to get a donor in KPD. So, to increase their chances, the proportion of O donors need to be increased, either by living non-directed donors or adding ABO/ HLA compatible pairs in the KPD program, or even using a deceased donor to start a KPD chain. This way, KPD helps in getting a better immunological match, lower costs and less immunosuppression leading to lower infection risk and better graft outcomes.
Desensitization is a tool to reduce the antibody levels so that a transplant can be performed. Various protocols have been used for desensitization. These include: 1) Plasmapheresis: It involves antibody removal, but is associated with unintended side-effects like coagulopathy, hypocalcemia, thrombocytopenia, hypotension, infections etc. Rebound in antibody levels happens after plasmapheresis which led to search of other methods of desensitization. 2) IVIG: It modulates alloimmune response by multiple mechanisms and in addition reduces risks of infections associated with plasmapheresis. Side-effects include headache, hypersensitivity reactions and venous thrombosis. IVIG use can be either low dose IVIG with plasmapheresis or high dose IVIG with rituximab. 3) Rituximab: It decreases CD20 expressing B cells as well as anti-HLA antibodies. 4) Bortezomib: It acts on plasma cells, reducing anti-HLA antibody levels when used with IVIG and plasmapheresis.
Living donor transplant after desensitization using plasmapheresis and IVIG has been shown to have survival advantage over remaining on waitlist. These patients have high rates of antibody mediated rejections (AMR), which did not decrease with adding rituximab or splenectomy. Among the patients with baseline titres <1:4 20% had subclinical AMR, with no clinical AMR. Another study using rituximab and IVIG showed 50% acute rejection with 30% AMR. By desensitization, the waiting period for transplant drastically comes down with good short-term graft results. In ABO incompatible transplants, splenectomy was used for desensitization and later on was replaced by rituximab. Newer data shows that antibody removal using plasmapheresis and routine immunosuppression without rituximab or splenectomy has similar results. ABO incompatible transplants with low baseline antibody titres can be performed even without plasmapheresis, although there is no consensus on minimum acceptable titre for transplant.
Rather than comparing KPD with desensitization, combination of the 2 strategies can be a better strategy. So, a donor who is more compatible to the recipient as compared to the original donor, having better chance of successful desensitization, can lead to better graft results. The updated KAS (Kidney Allocation System) decreased the wait-time and increased the percentage of deceased donor transplant among patients with cPRA of 100% by 10 times. By desensitization, the cPRA of the patients can go down, leading to lowering their priority in the wait-list. The restriction on the unacceptable antigens can be relaxed for highly sensitized patients to increase their chances to get a match. To conclude, it is important to assess each recipient individually and treatment modalities (be it KPD, desensitization, or a combination) be planned to get best results.
In our practice, we usually enroll the patients in KPD program. Most of the ABO incompatible transplants are able to get a donor in KPD except blood group O recipients. They require desensitization. We do not have much experience with respect to highly sensitized patients.
Wael Jebur
3 years ago
Highly sensitized patients with cPRA of more than 95% due to preformed DSAs, secondary to blood transfusion, pregnancy or prior sold organ transplant, is a hindering status ,as it would be extremely difficult to find a living or cadaveric donor without the unacceptable HLA antigens.
Those highly sensitized patients would be having prolonged waiting list time in order to have a donor with acceptable HLA antigens.
In order to overcome this immunologic barrier , two strategies were invented :
1) kidney Paired donation KPD: in which a patient with a living donor who is having an unacceptable HLA antigen,would be switched with other pairs whose donor is without the unacceptable antigens.
This strategy improved the rate of transplantation and shortened the waiting time .However highly sensitized patients remain difficult to transplant. PKD improved matching rate to less than 15%.
Therefore some patients would continue on HD for years before finding a suitable match,if ever.
2) The other modality implemented in this situation is the desenzitization protocol:
As there’s no potential acceptable HLA antigens.
Desenzitization includes Plasma pheresis to remove the circulating DSAs.
IVIG to Induce apoptosis of T and B lymphocytes, neutralization of DSAs and other less well identified effect. Rituximab is another agent used routinly in desensitization protocol to deplete B-lymphocytes clone sensitized to HLA antigen .However post transplant higher rate of AMR and inferior long term graft outcome hinder the growing enthusiasm in desensitization.
3) A third modality was to combine both PKD and Desensitization .
Therefore, PKD will get better immunologic profile donor,which will be translated into lesser immunologic risk and AMR ,ensuring better tolerance after desensitization which would be implemented simultaneously.
I never worked in a transplant center performing desenzitization protocol.
PKD is not implemented yet in our practice.
Batool Butt
3 years ago
Kidney paired exchange and desensitization: Strategies to transplant the difficult to match kidney patients with living donors
Living donor kidney transplants have better outcomes than those of deceased donor grafts. Majority of patients awaiting kidney transplant are sensitized to human leukocyte antigens (HLA).Highly sensitized kidney transplant cases had worse outcomes .KPD program and or desensitization are the strategies to facilitate such cases. Kidney paired donation: involves the exchange of donors between two incompatible donor/recipient pairs so that two compatible transplants could be performed leading to long term graft survival and less financial burden. ABO typing of donors/recipients is essential consideration for matching. The donor pool for PKD can be improved by non-directed donors (NDDs),also called non-simultaneous extended altruistic donor (NEAD) chain or ABO/HLA compatible pairs. Risk of contributing in a KPD donor pool for compatible donor is; 1. Delayed surgery as they wait for match 2. possibility of getting low quality allograft. KPD is considered to be the best option in underdeveloped countries where desensitization can’t be the option due to the cost and infectious complication. Desensitization: The goal is to reduce or remove preformed DSA so the flow cytometry crossmatch is negative or lower than a pre-determined cutoff, preventing hyper acute rejection . Desensitization should be limited to transplant recipients with no other living donor, who are highly sensitized and also cannot find the deceased offer and are expected to be waitlisted for a long time. Desensitization include: Plasmapheresis: Remove circulating antibodies but does not affect the on going production by the plasma cells. IVIG : Inhibits T & B cells, cytokine release, complement, maturation of dendritic cells & anti-idiotypic against alloantibodies. : Two approaches:alternate day plasmapheresis followed by low-dose IVIG (used in living donor transplant candidates) and high dose IVIG with rituximab. Rituximab : Anti-CD 20, induce B cell depletion through complement-dependent cellular cytotoxicity, & B cells apoptosis. Bortezomib : Plasma cell inhibitor Rituximab + Splenectomy + plasmapheresis
According to one study,29% of kidney transplant recipients after desensitization experienced AMR. Patient and overall graft survival at 24 months was 95% and 84%, respectively. KPD versus desensitization
The highly sensitized patient has a match rate as low as 15% in KPD pools .Combining desensitization with KPD as a complimentary modality will increase the chances of finding a compatible donor But more studies are needed to evaluate the overall impact on PKD & desensitization.
In my center ,Only living-related transplant recipients are being done.No kidney allocation system nor a system for KPD available.Desensitization is being done very rarely at our Centre due to cost issues.
Heba Wagdy
3 years ago
Living donor kidney transplants are associated with significantly better outcome than deceased donor transplant but it is limited by the ABO incompatibility, HLA mismatch, DSA, age and size discrepancies.
Highly sensitized patients stay on dialysis or waiting list for long time till find a compatible donor.
KPD and desensitization aim to facilitate living donor kidney transplantation. Kidney paired donation (KPD):
It includes exchange of donors between incompatible donor/recipient pairs to perform 2 compatible transplant and may involve 3 or more pairs.
It is essential in developing countries that depend on living donor kidney transplantation and desensitization is difficult due to socioeconomic conditions and associated increased risk of infection (a common cause of death post transplant).
It requires mathematical algorithms to best match patients for transplant.
Transplantation is performed simultaneously to prevent donor reneging.
It involves pairs with ABO incompatibility, highly sensitized recipients, pairs with age or size mismatch and pairs with borderline compatibility who will benefit from having a better HLA match.
Highly sensitized patients with cPRA>/= 97% are less likely to find a match and may accumulate in the KPD pool.
Blood type of donor/recipient pair has a significant impact on finding a match due to disproportionate numbers of O recipients, A donors, A recipients and O donors this may be overcome by increasing number of nondirected donors.
Inclusion of ABO/HLA compatible pairs enriches the donor pool with having the benefit of receiving better matched kidneys but with the risk of delaying the surgery till find a better match.
KPD provides better immunological match with better long-term graft survival and less economic cost. Desensitization:
Aims to decrease the antibody level so FCXM is negative or lower than predetermined cutoff. Plasmapheresis:
Removes alloantibodies from the circulation.
Side effects include coagulopathy, hypocalcemia, thrombocytopenia and catheter related infections.
Associated with rebound increase in antibody levels.
It is difficult to maintain recipients on plasmapheresis due to cost and logistical reasons. IVIG:
Modulate allo-immune response with advantage of repleting normal immunoglobulins.
Side effects include hypersensitivity like reaction and venous thrombosis.
It is either used as alternate day plasmapheresis followed by low dose of IVIG or as high dose IVIG and rituximab. Rituximab:
Anti-CD20 monoclonal antibody, depletes CD20 expressing B cells.
Decreases anti-HLA antibodies in some patients with low level antibodies. Bortezomib:
New agent in desensitization, leads to significant and sustained reduction in anti-HLA antibody levels when used with other therapies.
Studies on outcome of desensitization are small, non-randomized, not adequately powered and have short follow up time.
Studies showed that survival benefit for desensitization followed by living donor transplant compared to remaining on dialysis but with high AMR rates.
Optimal desensitization protocol and best maintenance immunosuppression are not determined yet.
ABO incompatible transplants show comparable results with conventional immunosuppression, antibody removal and rituximab, baseline anti-blood group antibody titer is strong predictor of AMR, It is depleted using plasmapheresis and/or blood group specific immunoadsorption. KPD versus desensitization:
Combining KPD and desensitization increases probability of finding a compatible donor for highly sensitized patients
Patients undergoing desensitization should be carefully chosen according to their HLA antibody profile as patients with antibodies against common HLA antigens are difficult to match regardless the cPRA.
Decreasing restrictions of unacceptable antigens will increase probability of having transplant and role of desensitization will be easily achieved.
In our practice, we have no KPD programs, only do desensitization.
Asmaa Khudhur
3 years ago
Kidney paired donation
Mean the exchange of donors between two incompatible donor/recipient pairs so that two compatible transplants could be performed.
The complexity has grown over time, regularly involving three or more pairs .This requires sophisticated mathematical algorithms to best match patients for transplant. Transplant centers involved in national registries must perform transplants simultaneously to prevent donor reneging and disruption of the chain.
Traditionally, pairs were entered into the registry because of ABO incompatibility but the use of KPD now commonly involves highly sensitized recipients age and graft size mismatch pairs, and those pairs that are borderline compatible but will benefit from a better HLA match.
Those that are sensitized and/or are blood type O have match rates as low as 15%.
Since these patients are less likely to find a compatible match they will have longer waiting times and will accrue in the KPD pool.
As the number of sensitized patients accumulates in a pool the more difficult it will be to initiate chains.
The blood type of the donor/recipient pair significantly impacts the likelihood of finding a match within a KPD registry.
such as the NKR tend to have disproportionately large numbers of O- recipients and A-donors and disproportionately low numbers of A- recipients and O-donors (Table 1) .Therefore, non-blood type-O, sensitized patients with O-donors have a much greater chance of finding a match within the registry than sensitized O-recipients with blood-type A donors. Conversely, sensitized O-patients paired with an A-donor have less chance of finding a successful match and will need to rely on other means such as desensitization.
A potential strategy to match these patients through KPD is to increase the proportion of O-donors. This can be accomplished by using non-directed donors (NDDs) to start linear domino chains of transplants otherwise known as non-simultaneous extended altruistic donor (NEAD) chain .
In theory, this will increase the number of blood type O donors to be used for dis- advantaged blood type O recipients in the KPD pool .
Possible kidney paired donation chains:
(A) Traditional exchange between two incompatible pairs.
(B) Closed loop chain of 3+ pairs where the last donor donates to the first recipient.
(C) Non Directed Donor (NDD) initiated chain where a bridge donor may be used to start another chain or the last donor can terminate the chain by donating to a waitlist recipient.
The donor pool can also be enriched by including ABO/HLA compatible pairs.
Risks of participating in a KPD pool for the compatible pair include delay of surgery as they wait for a match and the possibility of receiving an inferior graft.
Potential benefits would be for those that need or may benefit from a better HLA match.
ABO incompatible kidney transplantation outside of the KPD has been performed for several years with success in selected patients
It has recently been proposed to use deceased donor kidney to help initiate a KPD chain; similar to that of an NDD initiated KPD chain where the last live donor on the chain donates to the deceased donor waiting list .
A better immunological match will result in improved long term graft survival and less economical strain with the use of less immunosuppression.
Highly sensitized patients will still suffer from low match rates even with an increase in the donor/recipient pool.
Other strategies such as desensitization and/or lowering the threshold for unacceptable antigens will have to be adopted to increase transplant rates in this subset of patients.
Desensitization
Immunomodulation therapies are administered to transplant candidates as a means to eliminate or reduce HLA antibody levels in order to enable transplantation.
The goal of therapy is to reduce the antibody level so the flow cytometry cross- match is negative or lower than a pre-determined cutoff, thereby preventing hyper acute rejection .
Desensitization protocols generally use plasmapheresis along with infusions of intravenous immunoglobulin (IVIG) and rituximab to lower the titers of HLA antibodies in the candidate.
Plasmapheresis
works by removing alloantibodies from the circulation.
side effects :
Coagulopathy
hypocalcemia
thrombocytopenia
hypotension
and pheresis catheter-related infection and sepsis.
rebound increases in antibody levels after plasmapheresis is an obstacle . This occurs as a result of re-equilibration between the intravascular and interstitial compartments, as well as ongoing antibody synthesis by plasma cells.
IVIG :
IVIG is a blood product derived from the gamma globulin fraction of plasma from thousands of donors.
mechanism of action:
inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, and to induce B-cell apoptosis.
IVIG provides the advantage of repleting normal immunoglobulins, so reducing the infectious risk associated with plasmapheresis.
adverse reactions :
headache, hypersensitivity-like reactions, and venous thrombosis.
IVIG-based desensitization is currently conducted using one of two approaches:
alternate day plasmapheresis followed by low-dose IVIG (used in living donor transplant candidates) and high dose IVIG with Rituximab.
Rituximab:
It is a CD20 specific chimeric murine-human monoclonal Ab. It depletes CD20 expressing B cells via complement-mediated cytotoxicity and apoptosis
Rituximab has also been shown to induce a modest de- crease in anti-HLA antibodies in a fraction of patients — particularly those with low-level antibodies .
There is a very small but increased risk of JC virus-induced progressive multifocal leukoencephalopathy associated with Rituximab .
Bortezomib:
provide significant and sustained reductions in anti-HLA antibody levels when used in combination with other therapies such as plasmapheresis and IVIG.
Outcome:
Montgomery et al. reported experiences with alternate day plasmapheresis and low dose IVIG. They demonstrated a clear survival benefit for desensitization followed by living donor kidney transplantation .
However, despite high transplant rates and 100% one-year graft survival, acute antibody-mediated rejection rates were high.
A modified protocol adding rituximab and splenectomy to plasmapheresis and IVIG did not decrease AMR rates .
-higher pre-treatment DSA levels are associated with AMR.
Jordan et al. evaluated adding Rituximab to a high dose IVIG based regimen . Patient survival and allograft survival at one year were 100% and 94%, respectively. Half of the patients had acute rejection episodes of these; 30% had AMR. Most acute rejection episodes occurred within the first month post-transplant and were reversed with treatment.
The high cost of desensitization and the tendency for antibody rebound after treatment require that the candidates be near the top of the waiting list, so receive organ offers soon after treatment .
Subsequent reports of improved ABO incompatible outcomes with splenectomy at the time of transplant led to splenectomy being a required component of pioneering Japanese ABO incompatible programs that began in the late 1980s.
Because this type of transplantation was con- sidered to be high risk for antibody mediated rejection, viral infections, and decreased graft survival, ABO incompatible transplants were not commonly performed.
Splenectomy was eventually replaced by anti-CD20 treatment, and post-transplant antibody removal via plasmapheresis was performed routinely in addition to pre-transplant treatments. Subsequent studies reported comparable results with conventional immunosuppression and antibody removal, with omission of splenectomy and rituximab.
Baseline anti-blood group antibody titers seem to be the strongest predictor of early antibody-mediated rejection in ABO incompatible transplants.
It remains unclear what minimum titer is acceptable before and after ABO incompatible kidney transplantation.
Another strategy in matching sensitized patients is to relax restrictions on unacceptable antigens. This will allow for low level donor specific antibodies whose role in allograft rejection remains unclear .The transplant center then would determine the level of antibody reac- tivity they are comfortable with. By raising this threshold the likelihood of identifying an immunologically compatible donor increases not only in the KPD pool but also from available deceased donors. Desensitization goals will also be easier to reach.
Conclusions:
Highly sensitized patients continue to be a challenge for transplant centers. Over the years, several options have become available including KPD, desensitization and most recently deceased donor priority listing. The best option for these patients is to be transplanted at a center with access and expertise in all of the aforementioned strategies providing a multi-modality approach to transplant. The center should then be able to analyze each patient’s immunological profile and determine the best strategy for transplant. It is clear that the new deceased donor allocation system giving priority to those patients ≥98% cPRA is increasing the rate of transplantation in this group. Future studies are needed to assess its overall impact on KPD and desensitization.
Kidney paired exchange and desensitization: Strategies to transplant the difficult to match kidney patients with living donors
Two strategies to address barriers to living donor kidney transplantation are Kidney Paired Donation (KPD) and desensitization which can be used individually and in combination.
The KPD strategy, as originally proposed over 30 years ago, involved the exchange of donors between two incompatible donor/recipient pairs so that two compatible transplants could be performed. Traditionally, pairs were entered into the registry because of ABO incompatibility
but the use of KPD now commonly involves highly sensitized recipients age and graft size mismatch pairs, and those pairs that are borderline compatible but will benefit from a better HLA match.
The highly sensitized patient remains particularly challenging. Generally, this has been defined as patients with a calculated panel reactive antibody (cPRA) greater than 95% but more recent data from the Australian and Canada KPD registries show that those with cPRA between 50 and 96% had equivalent match rates as those less than 50%.
Those patients greater than or equal to 97% were less likely to find a match overall. The blood type of the donor/recipient pair significantly impacts the likelihood of finding a match within a KPD registry. KPD registries such as the NKR tend to have disproportionately large numbers of O- recipients and A-donors and disproportionately low numbers of A-recipients and O-donors (Table 1) [13]. Therefore, non-blood type-O, sensitized patients with O-donors have a much greater chance of finding a match within the registry than sensitized O-recipients with blood-type A donors. Conversely, sensitized O-patients paired with an A-donor have less chance of finding a successful match and will need to rely on other means such as desensitization
A potential strategy to match these patients through KPD is to increase the proportion of O-donors. This can be accomplished by using non-directed donors (NDDs) to start linear domino chains of transplants otherwise known as non-simultaneous extended altruistic donor (NEAD) chain
Risks of participating in a KPD pool for the compatible pair include delay of surgery as they wait for a match and the possibility of receiving an inferior graft. Potential benefits would be for those that need or may benefit from a better HLA match. The benefits of KPD have shown to be substantial and its potential has yet to be maximized as algorithms evolve. Its benefits reach beyond living paired donation as NDD’s can contribute to chains and the deceased donor list simultaneously. A better immunological match will result in improved long term graft survival and less economical strain with the use of less immunosuppression. Highly sensitized patients will still suffer from low match rates even with an increase in the donor/recipient pool.
Desensitization protocols generally use plasmapheresis along with infusions of intravenous immunoglobulin (IVIG) and rituximab to lower the titers of HLA antibodies in the candidate. Most studies on desensitization outcomes are small, non-randomized, not adequately powered, and have a relatively short follow-up time.
Montgomery et al. reported one of the first long-term experiences with alternate day plasmapheresis and low dose IVIG. They demonstrated a clear survival benefit for desensitization followed by living donor kidney transplantation (compared to staying on dialysis) in recipients who were flow cytometric cross-match negative, flow cytometric cross-match positive but cytotoxic crossmatch negative, and cytotoxic crossmatch positive. This larger experience was preceded by similar but smaller reports, which also had favorable outcomes. However, despite high transplant rates and 100% one-year graft survival, acute antibody-mediated rejection rates were high.
The view of KPD and desensitization as competing strategies for matching suitable incompatible donors/recipient pairs is incorrect. The success of both strategies has been well established over the past decade and data supporting a combination strategy continue to emerge
The highly sensitized patient has a match rate as low as 15% in KPD Pools Combining desensitization with KPD as a complimentary modality will increase the chances of finding a compatible donor. An example is to match a sensitized recipient to a donor that is more compatible than the patient’s original donor. This new match will have fewer antibodies against the KPD donor and thus a better chance at successful desensitization.
Highly sensitized patients continue to be a challenge for transplant centers. Over the years, several options have become available including KPD, desensitization and most recently deceased donor priority listing. The best option for these patients is to be transplanted at a center with access and expertise in all of the aforementioned strategies providing a multi-modality approach to transplant. The center should then be able to analyze each patient’s immunological profile and determine the best strategy for transplant. It is clear that the new deceased donor allocation system giving priority to those patients ≥98% cPRA is increasing the rate of transplantation in this group. Future studies are needed to assess its overall impact on KPD and desensitization.
In our hospital, we only transplant from a matched first-degree relative living donor (Palestine).
Abdul Rahim Khan
3 years ago
Kidney transplantation is the main standard of care for patients with end stage renal disease and patients who received kidney transplant have better outcome as compared to those who remain on haemodialysis. Patients who receive live related donor have better outcome as compared to those who receive donation from deceased donors. Unfortunately many related kidney transplantations or not possible due to multiple factors which include HLA incompatibility, ABO incompatibility ,extremes of age etc. the presence
The preserve presence of DSA can lead to hyper acute rejection or antibody mediated rejection. For patients who are highly sensitised the waiting time for transplantation is very long . Such patients can be considered for KPD or desensitization.
Paired kidney donation
This s basically an exchange of donation between two or more couples to achieve better matching and outcomes. Better matching can lead to less cost and less side effects from aggressive immunosuppression. It is more suitable for developing countries due to financial impacts. One strategy to have more transplants through PKD can be to increase the number of Blood group O donors which can be achieved by NDDs- non directed donors to start a linear domino chain also known as NEAD ( Non simultaneous extended altruistic donor. Disadvantage can be delay in finding suitable matches.
Desensitization
This can be achieved by –
· Plasmaphresis
· IVIG
· Rituximab
· Bortuximab
· Ides
Combined desensitization and PKD
It can increase the chance of finding a suitable donor although its role is still not established.
Conclusion
Highly sensitized patients are a challenge in transplant centres. Their options include desensitization, PKD and deceased donors priority listing. PKD can achieve a better matches transplant with less risk of desensitisation. Such highly sensitized patients should be transplanted at centres with significant expertise in handling such cases
Effect on my current Practice
At our centre we only do live related kidney transplants . PKD and KSA is not available in my country however the development of PKD approach is an area which higher attention for policy makers
Mohamad Habli
3 years ago
The majority of patients on the waiting list of kidney transplant are sensitized to HLA
Several strategies are used to address these barriers to living donor kidney transplantation:
1-Kidney Paired Donation
2- Desensitization which can be used individually and in combination with KPD.
Kidney Paired Donation
The KPD strategy involves the exchange of donors between two incompatible donor/recipient pairs so that two compatible transplants could be performed. Programs target to match ABO incompatible and HLA incompatible pairs to increase their match rate. A better immunological match will result in improved long term graft survival and less economical strain with the use of less immunosuppression.
A more compatible match with less overall immunosuppression is ideal because the most common cause of death in their posttransplant population is infectious complications.
KPD in its simplest form is an exchange of donors between two incompatible pairs such that now they are compatible. The complexity has grown over time, regularly involving three or more pairs. 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.
Low numbers of A- recipients and O-donors.Therefore, non-blood type-O, sensitized patients with O-donors have a much greater chance of finding a match within the registry than sensitized O-recipients with blood-type A donors. A potential strategy to match these patients through KPD is to increase the proportion of O-donors.
Desensitization
Several desensitization strategies developed to overcome the need of transplantation for highly sensitized recipients. 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.
Although KPD and desensitization are distinct strategies to improve the access to transplantation, both competing strategies are complementary for matching suitable incompatible donors/recipient pairs. The success of both strategies has been well established over the past decade and data support the combination strategy.
Highly sensitized patients has a match rate as low as 15% in KPD pools, but when combined with desensitization treatment, the chances of finding a compatible donor is increased.
In conclusion, KPD program and desensitization are two different strategies to increase the access of sensitized recipients to transplantation. Combination of both strategies is worth in some patients for better graft and patient survival.
Our practice
I think that KPD is feasible and economic method that can be developed and used in our
Islamic world, especially with exclusively living donor transplantation. Better matching for ABO incompatible and HLA incompatible dono/recipient pair would be solved with national and international KPD programs.
Doaa Elwasly
3 years ago
Highly sensitized kidney transplant cases suffer worse outcomes either due to being removed from or dying on the transplant waiting list.
Therefore KPD program and or desensitisation increased their chance of finding an acceptable donor.
KPD is the donor exchange between two incompatible donor/recipient pairs so that two compatible transplants could be done depending on living donors rendering more compatible matches .
A model for national multicentre KPD registries was first established by Netherland increased the chance of successful transplantation.
Then other countries followed, USA is special in having multiple single and multicenter registries independent of each others working beside governmental registries.
The advantage of single center registry over a multi-center registry is the simpler logistics and the use of a single HLA laboratory.
Highly sensitised cases having c PRA >95% remain a difficult group of patients to find a suitable donor .
Some countries registry mentioned that cases with c PRA from 50 -96% had equal match rates as those < 50%.
The accumulation of sensitized patients in a pool renders it difficult to initiate chains.
Sensitised blood group O patients have low chance of finding a match so Non direct donor (NDD)and Non simultaneous extended altruistic donor (NEAD) chain can solve this case
The Australian KPD program matches ABO incompatible but HLA compatible pairs.
It was recommended to use deceased donor kidney to start a KPD chain; similar to NDD initiated KPD chain.
KPD has many advantages as providing the NDD who can participate in chains and the deceased donor list as well improving the immunological match.
Desensitisation protocols applied to highly sensitised cases to decrease HLA antibody levels rendering FCX negative to a level preventing hyperacute rejection to occur.
The protocol includes plasmapheresis removing alloantibodies from the recipient’s blood but can lead to coagulopathy, hypotension , hypocalcemia and rebound increase of Ab levels. IVIG inhibiting T- and B-cell proliferation and cytokine release, it can cause hypersensitivity like reaction and venous thrombosis ,it is used in alternate days with plasmapheresis and with Rituximab. Rituximab depletes CD20 expressing B cells by CDC ,it’s side effect is that it can increase the risk of JC virus-induced progressive multifocal leukoencephalopathy. Bortezomib gave acceptable results when used with plasmapheresis and IVIG .
Cases with higher DSA levels prior to desensitisation are associated with higher possibility of AMR.
The expenses of desensitization and the antibody rebound possibility after treatment needs to consider cases near the top of the waiting list, so that they can have organ offers after treatment. The best desensitization protocol and the best maintenance immunosuppression program post-transplant are not established yet.
In Japan at the late 1980 ,ABO incompatible transplants were not commonly performed even with splenectomy due to the high risk for antibody mediated rejection, viral infections, and lower graft survival.
Later some studies demonstrated that low anti-blood group antibody titers can have ABO incompatible transplantation using plasmapheresis and immunoadsorption methods.
Recently it was published that combing KPD and desensitisation is better than applying each one separately, in fact choosing the cases whom will benefit the most is challenging as highly sensitised patients been offered donors with more acceptable antigens ie less immunogenic than their own donors improving the overall outcome .
Another issue is to decrease the restrictions for unacceptable antigens enabling more deceased donors to be available increasing the KPD pool.
fakhriya Alalawi
3 years ago
The majority of patients awaiting kidney transplant are sensitized to human leukocyte antigens (HLA). The presence of DSAs has been associated with hyper acute rejection, antibody-mediated rejection (ABMR), and graft loss. The highly sensitized patient remains particularly challenging. Generally, this has been defined as patients with a calculated panel reactive antibody (cPRA) greater than 95%. Those patients greater than or equal to 97% were less likely to find a match overall.
Two strategies to address these barriers to living donor kidney transplantation are Kidney Paired Donation (KPD) and desensitization which can be used individually and in combination.
Kidney paired donation (KPD)
KPD in its simplest form is an exchange of donors between two incompatible pairs such that now they are compatible. The complexity has grown over time, regularly involving three or more pairs. A potential strategy to match these patients through KPD is to increase the proportion of O-donors. This can be accomplished by using non-directed donors (NDDs) to start linear domino chains of transplants otherwise known as non-simultaneous extended altruistic donor (NEAD) chains. It has recently been proposed to use a deceased donor kidney to help initiate a KPD chain; similar to that of an NDD initiated KPD chain where the last live donor on the chain donates to the deceased donor waiting list.
Highly sensitized patients will still suffer from low match rates even with an increase in the donor/recipient pool.
Desensitization
The goal of therapy is to reduce the antibody level so the flow cytometry crossmatch is negative or lower than a pre-determined cut-off, thereby preventing hyperacute rejection. Desensitization protocols generally use plasmapheresis along with infusions of intravenous immunoglobulin (IVIG) and rituximab to lower the titers of HLA antibodies in the candidate.An obstacle to this method is rebound increases in antibody levels.
Bortezomib as the newest agent has been shown to provide significant and sustained reductions in anti-HLA antibody levels when used in combination with other therapies such as plasmapheresis and IVIG.
A modified protocol adding rituximab and splenectomy to plasmapheresis and IVIG did not decrease AMR rates. Splenectomy was eventually replaced by anti-CD20 treatment, and post-transplant antibody removal via plasmapheresis was performed routinely in addition to pre-transplant treatments.
KPD versus desensitization
A combination strategy of both techniques (KPD & desensitization) continues to emerge with a high success rate. Cross-matching and solid phase assays against the donor will assess the donor-specific antibody specificity and quantity. This will determine the degree of desensitization needed. Combining desensitization with KPD as a complementary modality will increase the chances of finding a compatible donor.
Conversely, those with antibodies against common HLA antigens will have difficulty being matched regardless of the cPRA. It is likely that desensitization will still play a critical role in highly sensitized patients but these patients will have to be carefully chosen according to their HLA antibody profile
Conclusion: A highly sensitized patient can be paired with a better immunological match in the KPD pool and subsequently desensitized to a lesser degree. Other strategies such as lowering the threshold for unacceptable antigens will have to be adopted to increase transplant rates in this subset of patients.
mai shawky
3 years ago
Available options to highly sensitized recipients:
PKD:
o Exchange donors between 2 or mor couples to find the most suitable matching.
o Preferred in developing countries to avoid cost of desensitization and decrease cost of immune-suppression, and infections.
o Transplant must be done simultaneously to avoid declining and disruption of the chain.
o ABO typing of donors/recipients is essential consideration for matching.
o The donor pool for PKD can be improve by non-directed donors (NDDs) ,also called non-simultaneous extended altruistic donor (NEAD) chain or ABO/HLA compatible pairs.
o Disadvantages are delayed surgery as they wait for matched donor and possibility of getting low quality allograft
KSA: with prioritization of highly sensitized recipients.
Desensitization available options:
1. Plasmapheresis ; Remove circulating DSA but re-bound is common.
2. IVIG: bind DSA.
3. Rituximab ; Anti-CD 20, deplete B cells.
4. Bortezomib: anti CD22, plasma cell inhibitor and therefore, reducing antibody production by these cells
5. Ides (IgG degrading enzyme of strept pyogens)
· Combined desensitization with PKD (hybrid approach) will increase the chances of finding a compatible donor.
· However, the role of desensitization in KAS is not clear
· Decrease restrictions on unacceptable antigen as not every DSA are clinically significant or reflected on graft outcome.
Our practice:
We are exclusively living-donor transplant, due to religious issues.
PKD and KSA is not utilized or available in Egypt.
However, I think application of PKD can be applied without much economic constrains.
Ibrahim Omar
3 years ago
Summarise this article and reflect on your practice :
due to the severe short supply of donated organs, the number of kidney transplantations per year is still unfortunately low.
even with available live donors, transplantation may not be done due to the problem of incompatibility and highly sensitized patients continue to be a challenge for transplant centers.
this problem of incompatibility has been partially resolved with kidney paired donation (KPD) and desensitization.
however, even with these 2 therapeutic options, patients with cPRA more than 95 % remain difficult to undergo transplantation.
this article was regarding current progress in KPD and desensitization.
KPD :
1- it was 1st performed in 1991 in south Korea. later it was successfully done in many world-wide centers.
2- the probability of successful matching can be determined by mathematical matching based on donor/recipient blood type, sensitization status and pool size
3-despite so, the highly sensitized patient has a match rate of only 15 % in KPD pools.
desensitization :
1- it is difficult in those with high antibody titre.
2- predicting who will benefit from it is difficult.
3- combination with KPD increase the rate of successful cases.
finally, the best option for the highly sensitized patients is transplantation at centers with experiences in all strategies with providing of multimodality approaches.
future studies are needed to assess the overall impact on KPD and desensitization.
Huda Al-Taee
3 years ago
Kidney Paired Donation:
Proposed 30 years ago, based on the exchange of donors between 2 incompatible donor/recipient pairs so that 2 compatible transplants could be done. It was first performed in Korea, since then, multiple single-center KPD registries have been developed worldwide.
If multiple institutions within a country combine their registries, they can enable multiple matches. In the years following the first KPD exchange, multiple multi-center registries were born such as the Alliance for paired donation in 2001, the national kidney registry in 2007 which made the largest paired exchange donor pool in the world, the new England kidney exchange in 2005, and the UNOS KPD in 2010.
The complexity of KPD has grown over time involving three or more pairs. transplant centres involved in the national registries should perform transplants simultaneously to prevent donor reneging and disruption of the chain.
Traditionally, pairs were entered into the registry because of ABO incompatibility but the program now involves highly sensitized recipients’ age and graft size mismatch pairs.
The highly sensitized patient remains a challenge, this had been defined as patients with cPRA> 95%, and those with cPRA>97% were less likely to find a match overall.
The blood group of the donor/recipient pair significantly impacts the likelihood of finding a match within a KPD registry, and those who are sensitized and/ or blood group O have a match rate as low as 15%. In general, there is a disproportionately large number of O recipients and A donors, and disproportionately low numbers of A recipients and O donors. A potential strategy to match these patients is to increase O donors through the use of non-directed donors to start linear domino chains of transplants otherwise known as non-simultaneous extended altruistic donor chains. The donor pool can be enriched by the use of HLA/ABO compatible pairs as this will offer better quality or better-matched kidneys. The risk of KPD for compatible pairs is the delay of surgery, benefits would be for those that need a better match.
It has been proposed to use a deceased donor kidney to help initiate a KPD chain similar to that of an NDD initiated KPD chain where the last live donor on the chain donates to the deceased donor waiting list, this will help in increasing the donor pool and will remove more patients from the deceased donor waiting list.
Desensitization:
The goal of this therapy is to reduce antibody levels so the FCXM is negative or lower than a pre-determined cutoff, in order to prevent hyperacute rejection.
Desensitization protocols involve plasmapheresis, IVIG, and Rituximab.
Plasmapheresis:
removes antibodies from the circulation
SE:
coagulopathy
hypocalcemia
thrombocytopenia
hypotension
pheresis catheter-related infection
sepsis
rebound increase in antibody levels.
IVIG:
Derived from gamma globulin fraction of plasma from thousands of donors. It modulates the alloimmune response via several mechanisms, it also inhibits B & T cells activation, cytokine production, maturation of dendritic cells, and induces B cells apoptosis.
It repleats normal human Ig and reduces the risk of infection caused by PP.
SE:
headache
hypersensitivity reaction
venous thrombosis
There are 2 approaches:
alternate day PP followed by low dose IVIG.
high dose IVIG with Rituximab.
Rituximab:
CD20 specific chimeric murine-human monoclonal ab.
Depletes CD20 expressing B cells. ( mature and immature cells)
Induce a modest decrease in anti-HLA antibodies particularly low-level antibodies.
SE: very small increased risk of JC virus infection.
Bortezomib:
Provide significant and sustained reduction in anti-HLA antibodies level when used in combination with other therapies such as PP7 IVIG.
Splenectomy:
Replaced by rituximab.
Another strategy in matching sensitized patients is to relax the restriction of unacceptable antigens as this will allow transplantation through low-level DSA whose role in allograft rejection is unclear.
KPD versus Desensitization:
The view of desensitization and KPD as competing strategies for matching suitable incompatible donors/recipient pairs is incorrect. Combining desensitization with KPD as a complementary modality will increase the chances of finding a compatible donor. Studies showed successful transplantation of highly sensitized patients following desensitization and participation in KPD program with 100% patient and graft survival after follow up of 22-23 weeks.
In my practice:
We don’t have KPD program, so we depend mainly on desensitization with PP+ IVIG+- Rituximab.
Ahmed Faisal
3 years ago
In 2015 in the United States, 100.000 ESRD patients in the waiting list for transplantation from deceased donors. Only 17.878 cases were transplanted. In the same year, there was only 6000 kidney transplantation from living donor.
This shows how disparity in what number of dialysis patients who need for transplantation either from living or deceased donors.
To match this needs, several strategies were developed to overcome this issue.
Transplantation has a better outcomes than dialysis. Living donor transplantation is better than the deceased donor transplantation in patient and graft survival. But the living donor transplantation is not available for most of the patient especially the highly sensitized patients who have high titer of antibodies in their blood.
Those patients have many obstacles to transplantation as they are at a great risk of ABMR and graft loss, so many of them being in the waiting list for long time unfortunately.
To make living donor transplantation is more accessible for those patients, combination of two important policies are evolved and they are kidney paired donation and desensitization.
This approach help in :
• decrease the waiting time in finding the compatible or suitable donor.
• decrease the need of intensive immunosuppression which is considered as economic burden in low economic countries and also leading to higher risk for serious infections and malignancies post transplantation
There are many factors affecting the success of this approach:
• size the donor pool.
• blood grouping of donor/recipient pairs
• status of sensitization of the candidates
• standarization of HLA laboratories.
This study describes Kidney Paired Exchange and desensitization modalities with their different proposals, advantages, and disadvantages.
In the Netherlands, the success was attributed to a national committee with a single central laboratory responsible for HLA. Australian and UK programs have included those with ABO incompatibility.
In the US, KPR introduction can be single-center (as with John Hopkins), regional (cPRA > 97%) or national (cPRA > 99.5%). The logistical advantages, cold ischemia time, and desensitization time make the single-center very effective, but dependent on the availability of the organ.
Currently, ABO and HLA incompatibility become the main causes of the need for transplant desensitization. The expansion of the KPD program to go beyond couples (including even deceased donors) scales with the algorithm involved. Sensitized patients with blood type O have greater difficulty finding a donor. The need to increase the distance is mandatory, but it increases logistical risks such as longer cold ischemia time.
Better immunological compatibility results in longer graft life and less need for immunosuppression.
Immunomodulation techniques for desensitization are not similar depending on the service, but it is usually plasma exchange plus immunoglobulins (low or high dose) and sometimes an anti-CD20 such as rituximab.
Plasma exchange depends on an intensive care structure, blood bank, and specialized multidisciplinary team, with the risk of hypocalcemia, thrombocytopenia, hypotension, and infections (associated or not with the catheter).
IVIg can inhibit B and T lymphocyte proliferation, cytokine production, dendritic cell maturation, and induction of apoptosis. It also replaces the immunoglobulin depleted by plasma exchange or by the consequent blockade of rituximab.
Rituximab alone has no impact, as it does not block circulating plasma cells and antibodies, but it has an important role in maintaining the response. There is a high risk of hepatitis B, Zoster, and PML infections in these cases.
Splenectomy has already been used in an attempt to reduce the humoral response, but the reticuloendothelial system prevents this compensation, and for this reason, it is no longer indicated.
The high cost of desensitization and the possibility of new antibodies after transplantation make more intensive follow-up and higher immunosuppression necessary.
Combining KPD and desensitization is the best way to optimize a better match. To define the need for desensitization will depend on CrossMatch and MFI, decreasing the circulation of antibodies from the donor to the recipient, and increasing graft survival. Acceptable antigen (AM) models are used in Europe and data are yet to be completed.
Unfortunately, we do not have KPD here in Brazil. When used, it is judicially, without following specific national desensitization protocols or not. The first took place now at the end of 2021, but we lack training and specialized staff.
Ben Lomatayo
3 years ago
Introduction ;
Living donation was introduced due to shortages of organ for deceased transplantation. How ever, living donation may not be possible due to a number of barrieres such as ABO-incompatability, HLA-incompatability, donor/recipient age & size discrepancies[1]
Highly sensitized patients(cPRA >95%) are dis-advantaged due to prolonged wait list time, removal from or dying on wait list time[2][11]
Two strategies to overcome these barriers are kidney paired donation(KPD) and desensitization
1.Kidney paired donation(KPD) ; The principle is to exchange donors between two incompatible donor/recipient pairs to enable their transplantability[4]
Introduced first time in South Korea at a single center in 1991 and the experience then spread to multiple centers in other places like India, Romania,Turkey, UK, Netherland,Canada, Australia, & USA[5]
In developing countries ,it may be attractive options because desensitization is expensive, the program more compatible match, less overall immune-suppression, and less infectious complications[6]
The first national registry was developed in Netherland ; the Ductch National Living Donor Kidney Exchange Program. They reported success rate of 49% in the first after it was established[7]
The US 2007 National Kidney Registry(NKR) is the largest KPD program worldwide.They performed > 1898 transplants and owned>300 active donors in its pool[8]
Single Center PKD program such as Methodist Hospital, John Hopkins has the advantages of single HLA laboratory & the simplification of logistics because of the presence of both donor and recipients at the same place.
PKD program involving 3 or more pairs needs sophisticated mathematical algorithms to accurately match patients for transplant.
Transplant must be done simultaneously to avoid declining and disruption of the chain.
ABO typing of donors/recipients is the major determinant for finding a match within a PKD program
The donor pool for PKD can be improve by non-directed donors(NDDs) ,also called non-simultaneous extended altruistic donor(NEAD) chain or ABO/HLA compatible pairs[15][1]
Risk of contributing in a KPD donor pool for compatible donor are ; 1. Delayed surgery as they wait for match 2. possibility of getting low quality allograft
There is recent proposal to involving deceased donor kidney to initiate a PKD program
The advantage of PKD program are better immunological match, improve long-term graft survival, less immune-suppression, & less economic hardships
2.Desensitization ; The goal is to decreased circulating antibodies and subsequently negative FCXM results allowing transplantation to proceed[19]
At the moments the numbers of highly sensitized patients are increasing due to second or third transplant. This resulted in development of several de-sensitization strategies ;
Plasmapheresis ; Remove circulating antibodies but does not affect the on going production by the plasma cells and therefore re-bound is common[2]
IVIG ; Inhibits T & B cells, cytokine release, complement, maturation of dendritic cells & anti-idiotypic against alloantibodies[2]. Two protocols ; low dose with alternate day PP( 100 mg/kg) & high dose (2g/kg)[2]
Rituximab ; Anti-CD 20, induce B cell depletion through complement-dependent cellular cyto-toxicity, & B cells apoptosis[20]. It causes modest reduction of antibodies in patients with low level antibodies. There is small risk of JC virus -associated PMLE[22]
Bortezomib ; This plasma cell inhibitor and therefore, reducing antibody production by these cells
Rituximab + Splenectomy + plasmapheresis ;
One study reported 100% one-year graft survival after desensitization protocol but acute ABMR was high[26,27]
Another reports showed 29% rates of ABMR but this didn’t translated into risk of short-term graft loss. Patient & graft survival was 95% and 94% respectively.
3.KPD versus desensitization ;
Highly sensitized patients have 15% possibility of match in PKD pools.Therefore, combining desensitization with PKD as complimentary modality will increase the chances of finding a compatible donor.
4.The updated National Kidney Allocation System(KAS) December 2014 ;
Established to improve transplant rates of the most highly sensitized patients(prolonged wait list, high mortality while on wait list) = cPRA > 98%[42]
Reduced deceased donor wait list & may provide a better HLA match than those of PKD pool with or without desensitization.
The role of desensitization in KAS is not clear
5.Relaxation of restrictions on unacceptable antigen ;
This is acceptance of low level DSA ; its role in allograft is not clear ?[39,44]
Conclusions ;
Highly sensitized patients represent a major barrier to transplantation
Options to overcome this problems are ; PKD, desensitization,and KAS which requires training & experiences in the centers
More studies are essential to evaluate the overall impact on PKD & desensitization
My practice ;
Living donor transplantation
The ideas of PKD, Desentization, KAS are brilliants without any doubts but it needs a lots of expertise’s, logistics,legislation’s,& resources
At them moment , non of them are part of our practice
We could probably initiate the discussions about the feasiblity of PKD because it may be economically suitable for our set up
Sherif Yusuf
3 years ago
Living kidney transplantation constitutes around 30% of transplantation in USA, and is associated with a relatively better outcome when compared to deceased donor transplantation
Highly sensitized transplant recipients are extremely difficult to find a suitable living donor and usually are maintained for a long time on the deceased donor waiting list
A highly sensitized transplant candidate who has ABO or HLA incompatible donor should be evaluated for desensitization, exchange the donor with other pairs (KPD) or both
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.
KPD is a complex technique that requires coordination between centers; computer-based matching system and shipping of organs.
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 donor may be directed to a specific recipient and this is called (Two-pair exchange) or maybe non-directed (willing to donate their kidney to any recipient)
The donor’s kidney is then matched for a recipient with an incompatible donor, and so the kidney of this recipient’s donor will be matched with the next incompatible pair and so on, this is called domino kidney paired donation.
Shipping of living donor kidneys provides a very good opportunity to expand the donor list for KPD (national KPD).
KPD may be the best option in countries where cost and infectious complications are impotent issues like India where desensitization is not an option and risk of infection is high due to poor socioeconomic status so KPD allows for transplantation of recipients with low overall immunosuppression that lower infection rate
On the other hand, 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
Desensitization
Desensitization offer a good transplant opportunity and survival advantage for the highly sensitized recipient with cPRA> 80% who has a very low likelihood for getting a transplant (living or deceased) due to positive crossmatch.
The goal of desensitization is to remove preformed DSA that cause a positive cross match with the donor and is associated with hyper acute rejection with immediate loss of the graft upon transplantation
3 main lines are available for desensitization including plasmapheresis, IVIG, Rituximab
The combination of low dose IVIG and plasmapheresis ± Rituximab 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 induced by a rebound increase in HLA antibodies after desensitization, 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 so cannot find the deceased offer and are expected to be waitlisted for a long time.
Combination of desensitization and PKD
This is may be the only way of living transplantation for a highly sensitized patient who has ABO and/or HLA incompatible donor and cannot find suitable pair, in this situation desensitization can be done and then re-matching can provide a suitable donor
In my practice
We are dealing with living-related transplant recipients
We have no kidney allocation system nor a system for KPD, also we do not do desensitization
Thus if the transplant recipient is not compatible with the done due to a positive crossmatch we do not proceed with transplantation
Summary of the article
Kidney paired exchange and desensitization: Strategies to transplant the difficult to match kidney patients with living donors
Kidney paired donation in conjunction with desensitization strategies considered to be a novel approach to transplantation in highly sensitized patients.
Kidney paired donation
· Involved the exchange of donors between two incompatible donor/recipient pairs. It was first performed in south Korea 1991.
· A more compatible match with less overall immunosuppression is the motive behind establishment and development of kidney exchange programs.
· KPD program can be single center or multi-center registry.
· The advantage of single center over multi-center registry is:
a. the simplification of logistics and the presence of the donor/recipient pair in the same region or center.
b. a single HLA laboratory with decisions made by a single program.
· Overall match rates are approximately 50–60% in a large KPD registry with more than 1000 pairs.
· The blood group of the pair(donor/recipient) has a significant impact on the match finding. Sensitized patients with blood group O, have a match rate as low as 15%.
· KPD can be extended to enlarge the donor population poll via non-directed donation and non-simultaneous extended altruistic donor-NEAD (domino linear chain of transplant). This is very helpful in increasing the match rate when there’s ABOi.
Desensitization
· The aim of goal of Desensitization therapy is to reduce the antibody level so the flow cytometry cross- match is negative or lower than a pre-determined cutoff, thereby preventing hyper acute rejection.
· Desensitization protocols generally use plasmapheresis along with infusions of IVIG and RTX to lower the titers of HLA antibodies in the candidate.
· Side effects of PP: coagulopathy, hypocalcemia, thrombocytopenia, hypotension, pheresis catheter related infection beside rebound increase in the level of antibody.
· IVIG modulates the allo-immune response in different ways:
a. Inhibition of T- and B-cell proliferation.
b. Inhibition of cytokine production.
c. Inhibition of dendritic cell maturation.
d. Induction of B cell apoptosis.
e. It provides the advantages of repleting normal immunoglobulins, therefore reducing the risk of infection associated with PP.
· IVIG potential adverse reactions: headache, HS-like reaction and venous thrombosis.
· IVIG approaches in desensitization: one of 2 approaches
a. alternate day plasmapheresis followed by low-dose IVIG (used in living donor transplant candidates).
b. high dose IVIG with rituximab.
· RTX is CD 20 monoclonal antibody that eliminate premature and mature B cell from the circulation:
a. results in a substantial elimination of B-cell populations.
b. induce a modest decrease in anti-HLA antibodies in a fraction of patients.
c. Side effects: very small but increased risk of JC virus infection and development of Progressive multifocal leukoencephalopathy.
· Bortezomib has been shown to provide significant and sustained reductions in anti-HLA antibody levels when used in combination with other therapies such as plasmapheresis and IVIG.
· The modified protocol of adding rituximab and splenectomy to plasmapheresis and IVIG did not decrease AMR rates in the past. Splenectomy was eventually replaced by anti-CD20 treatment, and post-transplant antibody removal via plasmapheresis was performed routinely in addition to pre-transplant treatments.
KPD and desensitization can be combined together as a novel strategy for transplanting highly sensitized patients with extreme difficulty in finding a suitable matching donor. KPD and desensitization are not a competing strategies.
Summary
non-blood type-O, sensitized patients with O-donors have a much greater chance of finding a match within the registry than sensitized O-recipients with blood-type A donors. Conversely, sensitized O-patients paired with an A-donor have less chance of finding a successful match and will need to rely on other means such as desensitization.
The donorpool canalsobeenriched by includingABO/HLA compatible pairs
Risks of participating in a KPD pool for the compatible pair include delay of surgery as they wait for a match and the possibility of receiving an inferior graft. Potential benefits would be for those that need or may benefit from a better HLA match.
The two most common methods used to deplete antiblood group antibodies are plasmapheresis and/or blood group-specific immunoadsorption. Some protocols institute routine post-transplant therapeutic plasma exchange (TPE) in an effort to keep titers b8 during the first weekpost-transplant .
The challenge remains in selection of the appropriate patients to optimize successful matching. Mathematical algorithms based on donor/recipient blood type, sensitization status, and pool size can determine the probability of successful matching in a KPD
Combining desensitization with KPD as a complimentary modalitywillincreasethechancesoffindingacompatibledonor
1. Introduction
Unfortunately many living donor recipient pair transplantations are not feasible because of ABO incompatibility, HLA mismatch/donor specific antibody, or donor/recipient age and size discrepancies.
The majority of patients awaiting kidney transplant are sensitized to human leukocyte antigens, for this reason, highly sensitized kidney transplant candidates experience longer wait times and have a higher chance of being removed from or dying on the transplant waiting list.
Two strategies to address these barriers to living donor kidney transplantation are Kidney Paired Donation (KPD) and desensitization which can be used individually and in combination.
2. Kidney paired donation
The exchange of donors between two incompatible donor/recipient pairs so that two compatible transplants could be performed. If multiple institutions within a country combine their registries, they can theoretically enable more matches.
Possible kidney paired donation chains.
(A) Traditional exchange between two incompatible pairs.
(B) Closed loop chain of 3+ pairs where the last donor donates to the first recipient.
(C) Non Directed Donor (NDD) initiated chain where a bridge donor may be used to start another chain or the last donor can terminate the chain by donating to a waitlist recipient.
3. Desensitization
The goal of therapy is to reduce the antibody level so the flow cytometry crossmatch is negative or lower than a pre-determined cutoff, thereby preventing hyper acute rejection.
Desensitization protocols generally use plasmapheresis along with infusions of intravenous immunoglobulin (IVIG) and rituximab to lower the titers of HLA antibodies in the candidate.
Plasmapheresis works by removing alloantibodies from the circulation. Aside from coagulopathy, side effects commonly seen with plasmapheresis include hypocalcemia, thrombocytopenia, hypotension, and pheresis catheter-related infection and sepsis. An obstacle to this method is rebound increases in antibody levels.
This occurs as a result of re-equilibration between the intravascular and interstitial compartments, as well as ongoing antibody synthesis by plasma cells.
IVIG has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, and to induce B-cell apoptosis.
IVIG provides the advantage of repleting normal immunoglobulins, thereby providing a theoretical advantage of reducing the infectious risk associated with
plasmapheresis. Potential adverse reactions that can be seen with IVIG administration include headache, hypersensitivity-like reactions, and venous thrombosis.
IVIG-based desensitization is currently conducted using one of two approaches: alternate day plasmapheresis followed by low-dose IVIG (used in living donor transplant candidates) and high dose IVIG with rituximab
Rituximab It is a CD20 specific chimeric murine-human monoclonal Ab.
It depletes CD20 expressing B cells via complement-mediated cytotoxicity and apoptosis. Rituximab has also been shown to induce a modest decrease in anti-HLA antibodies in a fraction of patients — particularly those with low-level antibodies. There is a very small but increased risk of JC virus-induced progressive multifocal leukoencephalopathy associated with Rituximab.
The newest agents added to the armamentarium for desensitization are therapies that target plasma cells. Bortezomib has been shown to provide significant and sustained reductions in anti-HLA antibody levels when used in combination with other therapies such as plasmapheresis and IVIG
4. KPD versus desensitization
The view of KPD and desensitization as competing strategies for matching suitable incompatible donors/recipient pairs is incorrect. The success of both strategies has been well established over the past decade and data supporting a combination strategy continue to emerge
The paucity of kidney transplant as compared to number of people needing a kidney is the result of limited amount of organs available. Unfortunately many potential recipient- donor pairs are either ABO or HLA incompatible. Presence of DSAs lead to hyperacute rejection, ABMR, and Graft loss.
2 main strategies to overcome this barrier–
1) Kidney paired donation programs.
-started off as exchange of donors in between 2 incompatible pairs so that 2 compatible transplants could be performed.
– now also includes even 3 or more pairs.
-ABOi , HLAi, Graft size or age incompatible pairs also included.
-single centre registries , national registries, and also international registries have been encouraged.
2) DESENSITIZATION
-Immunomodulating therapies that reduce or eliminate DSAs
-Therapies available- Plasmapheresis, IVIG, Rituximab, Bortezomib. And their combinations.
-Challenges faced are- the high cost, antibody rebound, and poor outcomes.
– Reliance over live donor transplantation is more, as patients will need to be at top of the deceased waiting list due to the high cost and Ab rebound.
3) COMBINATION OF KPD PROGRAM AND DESENSITIZATION
The idea is to find pairs that are less incompatible, or where the recipient has lower level of DSAs to the newly matched recipient, do that DESENSITIZATION strategy is more amenable .
Renal transplantation is considered the best option for ESRD patients , but there is shortage of deceased donors and living donor transplantation has several limitations including ABO incompatibility ,HLA mismatch/DSA and donor/ recipient age & size non matching.
Strategies used to overcome the obstacle to living donor transplantation: PKD, desensitization or combination of both.
PKD:
Started before >30 years ago for exchange donor between incompatible donor/recipient, so compatible transplant can be undertaken. .It is important where living donor is the only available option for transplantation. In UK, USA, Canada & Australia there are combined registries from different institutions in same country resulting in offering more compatible transplantation. Some programs match ABO incompatible donor/recipient to increase match rate. USA PKD is a unique program use multiple single & multiple registries that operate independent of each other.
It is better to use one HLA lab and decision made by single program and standard practice. The complexity of PKD increased to involve 3 or 4 pairs which require complicated mathematical algorithms.
Highly sensitized patients ; c PRA> 98% had better chance to have compatible donor by PKD.
Desensitization:
Different desensitization protocols which aim to remove or minimize Abs and convert positive crossmatch to negative , using PP,IVIG, and rituximab.
PP had many side effects including coagulopathy, hypotension, hypocalcemia, thrombocytopenia and CV line related infections with rebound Abs levels.
IVIG can modulate immune response through different mechanisms: It inhibit T cells & B cells proliferation, cytokine production, maturation of dendritic c cells, induce B cells apoptosis. IVIG can be used with PP on alternate day with low dose in living donor transplantation or high dose with rituximab. Rituximab can eliminate B cells population & induce moderate reduction in HLA Abs especially in case of low levels of DSA.
Bortezumib targets plasma cells.
There is clear survival advantage of desensitization in living donor transplantation when compared to patients remaining on dialysis especially in patients with positive FCXM ;also in Negative FCXM but positive CDC.
Considering desensitization cost & rebound phenomenon of Abs it is preferred to implement desensitization for patients who are on the top of waiting list.
Highly sensitized patients has 15% chance to get matched donor in PKD program .Combination of desensitization with PKD can lead to better chance of finding compatible donor with better graft and patients outcomes.
☆Kidney paired exchange &desensitization: Strategies to transplant the difficult to match kidney patients with living donors
¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤
☆Introduction:
▪︎ Many living donor recipient pair transplantations are not feasible because of ABO incompatibility, HLA mismatch/donor specific antibody, or donor/recipient age, size discrepancies and sensitization to HLA.
▪︎ Two strategies to address these barriers to living donor kidney transplantation are:
1) Kidney Paired Donation (KPD)
2) Desensitization (alone or in combination
Kidney paired donation (KPD)).
KPD:
_____
▪︎lnvolve the exchange of donors between two incompatible donor/recipient pairs.
▪︎ Is essential in developing countries where living donation is the primary means
▪︎ Used in ABO incompatible pairs.
▪︎ Despite the success of larger multi-center registries, single center KPD programs still exist.
☆The advantage of single center registry over a multi-center registry:
_________________________
1) Simplification of logistics
2) The use of a single HLA laboratory with decisions made by a single program
▪︎KPD can involve three or more pairs. This requires sophisticated mathematical algorithms to best match patients for transplant.
▪︎ KPD now commonly involves highly sensitized recipients age and graft size mismatch pairs, and those pairs that are borderline compatible but will benefit from a better HLA match.
▪︎The highly sensitized patient has been defined as patients with a calculated panel reactive antibody (cPRA) greater than 95% but some KPD registries show that those with cPRA between 50 and 96% had equivalent match rates as those less than 50%.
▪︎Patients greater than or equal to 97% were less likely to find a match overall.
▪︎Sensitized pts and/or blood type O have match rates as low as 15%.
▪︎ The donor pool can be enriched by including ABO/HLA compatible pairs.
☆Risk of KPD pool for the compatible pair :
1) Delay of surgery as they wait for a match 2) Possibility of receiving an inferior graft.
3. Desensitization stratigies:
_________________________________
▪︎ Adopted to increase transplant rates in highly sensitized pts with low match rates.
▪︎ Immunomodulation therapies are administered to eliminate or reduce
HLA antibody levels.
▪︎The goal of therapy is to reduce the antibody level so the flow cytometry crossmatch is negative or lower than a pre-determined cutoff.
▪︎ Desensitization protocols generally use plasmapheresis along with infusions of intravenous immunoglobulin (IVIG) and rituximab.
▪︎ Due to the plasmapheresis cost and other reasons, IVIG is used.
▪︎IVIG has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, and to induce B-cell apoptosis.
▪︎IVIG provides the advantage of repleting normal immunoglobulins,so reduce the infection risk.
☆ IVIG-based desensitization approaches:
_______________________________
1) Alternate day plasmapheresis followed
by low-dose IVIG (used in living donor
transplant candidates).
2) High dose IVIG with rituximab.
▪︎ Rituximab depletes CD20 expressing B cells and decrease anti-HLA antibodies in patients with low-level antibodies.
▪︎ Bortezomib is used in combination with other therapies such as plasmapheresis and IVIG.
▪︎Desensitization followed by living donor kidney transplantation give a clear benifit (compared to staying on dialysis).
4. KPD versus desensitization:
________________________________
▪︎ Both strategies are successed.
▪︎Data supporting a combination strategy continue to emerge
▪︎ The challenge remains in selection of the appropriate patients to optimize successful matching.
▪︎Mathematical algorithms based on donor/recipient blood type, sensitization status, and pool size can determine the probability of successful matching in a KPD
▪︎Cross matching and solid phase assays against the determine the degree of desensitization needed.
▪︎The highly sensitized patient has a match rate as low as 15% in KPD
pools.
▪︎Combining desensitization with KPD as a complimentary modality will increase the chances of finding a compatible donor.
▪︎ The updated national kidney allocation system (KAS) initiated by the Organ Procurement and Transplant Network (OPTN) on December 4th 2014 is designed to improve transplant rates of the most highly sensitized patients with cPRA ≥98%.
▪︎The role of desensitization in the setting of the new KAS remains unclear. Highly sensitized patients may have their cPRA decreased thus giving them less priority on the deceased donor waitlist. Conversely, those with antibodies against common HLA antigens will have difficulty being matched regardless of the cPRA.
▪︎Desensitization still play a critical role in highly sensitized patients but these patients will have to be carefully chosen according their HLA antibody profile.
▪︎Another strategy in matching sensitized patients is to relax restrictions on unacceptable antigens. This will allow for low level DSAs whose role in allograft rejection remains unclear.
5. Conclusions:
________________
▪︎ The best option for highly sensitized patients is to be transplanted at a center
with access and expertise in KPD, desensitization and deceased donor priority. The center should then be able to analyze each patient’s immunological profile and determine the best strategy for transplant.
▪︎Future studies are needed to assess its overall impact on KPD and desensitization
A highly sensitized transplant candidate who has ABO or HLA incompatible donor should be evaluated for desensitization, exchange the donor with other pairs or both.
*KPD is the process of exchange of kidneys between living donor-recipient pairs due to ABO or HLA incompatibility. It’s worth to say that only 15% of highly sensitized transplant recipient with cPRA ≥ 98% has a chance to find a compatible donor.
*The goal of desensitization is to remove preformed DSA that cause a positive cross match with the donor and is associated with hyper acute rejection with immediate loss of the graft upon transplantation. The 3 main lines available for desensitization include plasmapheresis, IVIG, Rituximab
*The Combination of desensitization and PKD may be the only way of living transplantation for a highly sensitized patient who can’t find suitable pair.
Regarding my own practice; no cadaveric experience, no kidney allocation system but we implement desensitization accordingly.
To overcome against HLAi and ABOi living TX, KPD and desensitization protocols are emerged.
Highly sensitized recipients experience prolonged waiting times.
1- KPD:
Exchange of donors with other pairs to do a compatible TX.
This program is done by joining multiple institution registries in a country.
The first one was in the Netherlands called Dutch KPD. NKP is the largest
KPD program in the world with more than 300 active donors.
But there are single center registries too.
For example, in Johns Hopkins hospital KPD program in combination with desensitization is performed for highly sensitized patients.
Frequency of blood groups may impacts the chance of finding a match using KPD programs.
To solve this problem NDDS (non-directed donors) is used.
Australian KPD program used ABOi TX to reach a better HLA matching but the outcome of this program have to be determined.
Some centers deceased donors to increase KPD program.
2- Desensitization:
By using plasmapheresis in combination with IVIG and rituximab, the titer of DSA is lowered to reach a negative flow cytometry or reaching a pre-determined out off.
Plasmapheresis removes antibodies but could have rebound increase again IVIG inhibits B and T cell proliferation and cytokine production but may be associated with hypersensitivity reaction.
Rituximab eliminates B cell and bortezomib targets plasma cell with sustained reduction in DSA levels.
Higher pre-transplant DSA titers could result in AMR.
In some centers ABOi TX using anti-CD20 and post-TX plasmapheresis in addition to pre-TX ones was performed with deleting splenectomy.
But only patients low titer anti-ABO Abs can have successful ABOi TX and keeping titer < 8 during the first post–TX week is important.
3- KPD vs desensitization:
A combination strategy is emerging
In this strategy exchanging of donors lowers the need to desensitization.
New KAS program in 2014 was invented to increase chance of TX for the highly sensitized ones with CPRA ≥ 98%
Another strategy is to lower restriction on unacceptable antigens.
Living kidney donation has become a standard of practice. The outcomes of living donor kidney transplants are significantly better than those of deceased donor grafts. Unfortunately many living donor recipient pair transplantations are not feasible because of ABO incompatibility, HLA mismatch/donor specific antibody, or donor/recipient age and size discrepancies.
The presence of DSAs in highly sensitized recipients is associated with hyper acute rejection, antibody-mediated rejection (ABMR), and graft loss so, they experience longer waiting times and have a higher chance of being removed from or dying on the transplant waiting list. Therefore, Kidney Paired Donation (KPD) and desensitization can be used individually and in combination as good solutions.
The idea is based on the exchange of donors between two incompatible donor/recipient pairs so that two compatible transplants could be performed with the advantage of avoiding the cost of desensitization while offering a more compatible match with less overall immunosuppression and serious infectious complications. Better immunological match will also result in improved long term graft survival.
Immunomodulation therapies aimed to reduce the antibody level so the flow cytometry cross match is negative or lower than a pre-determined cutoff, thereby preventing hyper acute rejection.
Desensitization protocols generally are plasmapheresis along with infusions of intravenous immunoglobulin (IVIG) and rituximab.
Plasmapheresis side effects commonly include coagulopathy, hypocalcemia, thrombocytopenia, hypotension, pheresis catheter-related infection and sepsis.
IVIG has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, and to induce B-cell apoptosis.
Rituximab is a CD20 specific human monoclonal Ab. It depletes CD20 expressing B cells via complement-mediated cytotoxicity and apoptosis. Side effects include risk of JC virus-induced progressive multifocal leukoencephalopathy.
Most studies showed that a clear survival benefit for desensitization followed by living donor kidney transplantation (compared to staying on dialysis).
However, acute antibody-mediated rejection rates were higher. A modified protocol adding rituximab and splenectomy to plasmapheresis and IVIG did not decrease AMR rates.
Baseline anti-blood group antibody titers seem to be the strongest predictor of early antibody-mediated rejection in ABO incompatible transplants.
Highly sensitized patients are considered to be a challenge for transplant centers. Several options have become available mainly KPD and desensitization.
Future studies are needed to assess its overall impact on KPD and desensitization.
In our center practice, we perform desensitization for highly sensitized recipients .Our main protocol consists of plasmapheresis and rituximab guided by the CDC, flowcytometry, calculated PRA
Transplantation of the difficult to match kidney patients with living donors.
The combination of both kidney paired donation (KPD) and desensitisation increase the successful rate of living donor transplantation in highly sensitised recipients. However, calculated panel reactive antibody (cPRA) of more than 95% remain technically challenge for transplantation with match rates as low as 15% in KPD pools. On the other hand, ABO incompatibility of donor / recipient pair significantly affect the probability to get match transplant even in KPD registry. For instance, sensitised non-blood type-O, recipients with O blood-donors have greater chance of finding a match than sensitised O-recipients with blood-type A donors. On the other hand, sensitised O-patients paired with an A-donor have less chance of finding successful match.
Following are the strategies for successful living donor transplantation for highly sensitised recipients. Non-directed donors (NDD) should be recruited to start linear domino chains of transplants to increase the proportion of blood group O donor. Besides, ABO HLA compatible pairs should be enriched in the donor pool in KPD. Matching ABO incompatible yet HLA compatible pairs allowing more successful transplants which include highly sensitise kidney transplant recipients. Furthermore, lowering the threshold for unacceptable antigens at transplant centres has boost up the transplant rate in the highly sensitised recipients.
Desensitising protocol is crucial to eliminate HLA antibody levels for successful transplantation especially among highly sensitised recipients. Most of the desensitising protocol include plasmapheresis along with infusions of intravenous immunoglobulin (IVIG) and rituximab. Bortezomib is a newer agent target at plasma cell in transplant medicine for desensitisation to induce effective reduction of HLA antibody level. Routine therapeutic plasma exchange in the first week following transplantation may ensure good graft survival among highly sensitise recipients. However, it still remain controversial for the optimum antibody titre is acceptable before and after ABO incompatible renal transplantation.
Combining KPD and desensitisation increase the probability of finding compatible donor especially among highly sensitised recipients. The updated national kidney allocation system (KAS) has improve transplant rates among highly sensitised recipients with cPRA more than 98% .
Revision of unacceptable antigen listing among transplant centres allow more highly sensitised recipients for transplantation. This will permit for lower level of donor specific antibodies ( DSA ) whose role in allograft rejection remains unclear. The transplant centres are responsible for the determination of acceptable antibody level.
In my opinion, the novel approach by combining the KPD and effective desensitisation protocol is the key for the better outcome among highly sensitise recipients in living donor transplantation. However, we need to personalise the management of difficult to match recipients with living donors by studying the immunological profile and determine the best strategy based on our patient circumstances and the transplant centre facilities.
Paired kidney donation is cheap safe and good option for highly sensitized patient ,suitable and cost effective for developing country
Summarise this article and reflect on your practice ?
Unfortunately many living donor recipient pair transplantations are not feasible because of ABO incompatibility, HLA mismatch/donor specific antibody, or donor/recipient age and size discrepancy , majority of patients awaiting kidney transplant are sensitized to human leukocyte antigens (HLA) ,two strategies to address these barriers are Kidney Paired Donation (KPD) and desensitization.
Paired Donation (KPD), performed in 1991 at a single center in South Korea where kidney transplantation relies heavily on living donation because of the lack of an established deceased donor program.
The highly sensitized patient remains particularly challenging. Generally, this has been defined as patients with a calculated panel reactive antibody (cPRA) greater than 95% but more recent data from the Australian and Canada KPD registries show that those with cPRA between 50 and 96% had equivalent match rates as those less than 50%. Those patients greater than or equal to 97% were less likely to find a match overall.
Desensitization immunomodulation therapies are administered to transplant candidates as a means to eliminate or reduce HLA antibody levels in order to enable transplantation the goal of therapy is to reduce the antibody level so the flow cytometry crossmatch is negative or lower than a pre-determined cutoff, thereby preventing hyper acute rejection.
Most studies on desensitization outcomes are small, non-randomized, not adequately powered, and have a relatively short follow-up time. Montgomery et al. reported one of the first long-term experiences with alternate day plasmapheresis and low dose IVIG. They demonstrated a clear survival benefit for desensitization followed by living donor kidney transplantation (compared to staying on dialysis).
While initial experience with ABO incompatible renal transplants resulted in hyperacute rejection, the 1970s were notable for extended survival of some of the A2 kidneys transplanted into blood group O patients who were receiving conventional immunosuppression
Splenectomy was eventually replaced by anti-CD20 treatment, and post-transplant antibody removal via plasmapheresis was performed routinely in addition to pre-transplant treatments. Subsequent studies reported comparable results with conventional immunosuppression and antibody removal, with omission of splenectomy and rituximab.
The highly sensitized patient has a match rate as low as 15% in KPD pools , Combining desensitization with KPD as a complimentary modality will increase the chances of finding a compatible donor.
reflect on my practice ?
we need more RCT or more study and consensus on desensitization protocol.
SUMMARY
The paucity of kidney transplant as compared to number of people needing a kidney is the result of limited amount of organs available. Unfortunately many potential recipient- donor pairs are either ABO or HLA incompatible. Presence of DSAs lead to hyperacute rejection, ABMR, and Graft loss.2 main strategies to overcome this barrier–>
1) Kidney paired donation programs.
-started off as exchange of donors in between 2 incompatible pairs so that 2 compatible transplants could be performed.
– now also includes even 3 or more pairs.
-ABo incompatible, HLA incompatible, Graft size or age incompatible pairs also included.
-single centre registries , national registries, and also international registries have been encouraged.
2) DESENSITIZATION
-Immunomodulating therapies that reduce or eliminate DSAs
-Therapies available- Plasmapheresis, IVIG, Rituximab, Bortezomib. And their combinations
– Each centre has its own desensitization protocol
-Challenges faced are- the high cost, antibody rebound, and poor outcomes.
– Reliance over live donor transplantation is more, as patients will need to be at top of the deceased waiting list due to the high cost and Ab rebound.
3) COMBINATION OF KPD PROGRAM AND DESENSITIZATION
The idea is to find pairs that are less incompatible, or where the recipient has lower level of DSAs to the newly matched recipient, do that DESENSITIZATION strategy is more amenable and hence give better Graft survival.
REFLECT ON PRACTICE-
We do not have well established national registries for KPD program, but it may be considered at the state level atleast.
Desensitization protocols are in practice in few centres, but it is considered only as the very last step .
-Approximately 100,000 people are waiting for a deceased donor kidney transplant but only 17,878 solitary kidney transplants were performed in 2015 in the United States. . To offset this disparity, living kidney donation has become a standard of practice at most transplant centers in the United States.
-The outcomes following living donor kidney transplants are significantly better than those of deceased donor grafts .
– Many living donor recipient pair transplantations are not feasible because of ABO incompatibility, HLA mismatch/donor specific antibody, or donor/recipient age and size discrepancies.
-Two strategies to address these barriers to living donor kidney transplantation
are Kidney Paired Donation (KPD) and desensitization which can be used individually and in combination.
Kidney paired donation
-It is involved the exchange of donors between two incompatible donor/recipient
pairs so that two compatible transplants could be performed.
-A more compatible match with less overall immunosuppression is ideal because the most common cause of death in their posttransplant population is infectious complications.
-If multiple institutions within a country combine their registries,
they can theoretically enable more matches. This has been accomplished
in countries such as the United Kingdom (U. K), Canada,
Netherland, Australia and the United States (U.S.).
– Dutch KPD success has been well published and attributed to its use of a national oversight committee and a single central HLA laboratory.
-The Dutch KPD has served as the model for other national multicenter KPD registries that followed in the UK, Canada and Australia.
-The first U.S. KPD exchange took place in the year 2000, three years prior to the
initial KPD exchange in the Netherlands. Since then it has grown to
over 500 transplants a year .
-National Kidney Registry (NKR) in 2007, has facilitated more than 1898 transplants since its inception and has over 300 active donors in its pool, making it the largest paired exchange donor pool in the world .
– Likely more important is the use of a single HLA laboratory with decisions made by a single program as opposed to multiple programs with their own individual HLA laboratory and standards of practice.
-This advantage is clearly seen in the Johns Hopkins Hospital KPD program where they have combined desensitization with KPD for a number of years in order facilitate transplant of highly sensitized individuals.
-Traditionally, pairs were entered into the registry because of ABO incompatibility but the use of KPD now commonly involves highly sensitized
recipients age and graft size mismatch pairs, and those pairs that are borderline compatible but will benefit from a better HLA match.
-The highly sensitized patient has been defined as patients with a calculated panel reactive antibody (cPRA) greater than 95% but more recent data from the
Australian and Canada KPD registries show that those with cPRA between 50 and 96% had equivalent match rates as those less than 50%. Those patients greater than or equal to 97% were less likely to find a match overall .
-Overall match rates are approximately 50–60% in a large KPD registry with more than 1000 pairs.
-Highly sensitized patients are less likely to find a compatible match they will have longer waiting times and will accrue in the KPD pool.
-Non-blood type-O, sensitized patients with O-donors have a much greater chance of finding a match within the registry than sensitized O-recipients with
blood-type A donors.
-Sensitized O-patients paired with an A-donor have less chance of finding a successful match and will need to rely on other means such as desensitization.
-A potential strategy to match these patients through KPD is to increase the proportion of O-donors. This can be accomplished by using non-directed donors (NDDs) to start linear domino chains of transplants otherwise known as non-simultaneous extended altruistic donor (NEAD) chain . NDDs presumably have a similar blood type distribution to the general public with approximately 45–57% having blood type-O depending on ethnicity .
– The donor pool can also be enriched by including ABO/HLA compatible pairs
-Risks of participating in a KPD pool for the compatible pair include delay of surgery as they wait for a match and the possibility of receiving an inferior graft.
-Potential benefits would be for those that need or may benefit from a better HLA match.
-KPD benefits reach beyond living paired donation as NDD’s can contribute to chains and the deceased donor list simultaneously.
-Highly sensitized patients will still suffer from low match rates even with an increase in the donor/recipient pool.
Desensitization
– Immunomodulation therapies are administered to transplant candidates as a means to eliminate or reduce HLA antibody levels to enable transplantation.
-The goal of therapy is to reduce the antibody level so the flow cytometry crossmatch is negative or lower than a pre-determined cutoff, thereby
preventing hyper acute rejection .
-Desensitization protocols generally use plasmapheresis along with infusions of intravenous immunoglobulin (IVIG) and rituximab to lower the titers of HLA antibodies in the candidate.
-Side effects commonly seen with plasmapheresis include hypocalcemia, thrombocytopenia, hypotension, and pheresis catheter-related infection and sepsis.
– An obstacle to this method is rebound increases in antibody levels as a result
of re-equilibration between the intravascular and interstitial compartments,
as well as ongoing antibody synthesis by plasma cells.
– IVIG has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, and to induce B-cell apoptosis. Potential adverse reactions that can be seen with IVIG administration include headache, hypersensitivity-like reactions, and venous thrombosis.
-IVIG-based desensitization is currently conducted using one of two approaches: alternate day plasmapheresis followed by low-dose IVIG (used in living donor transplant candidates) and high dose IVIG with rituximab.
-Rituximab is a CD20 specific chimeric murine-human monoclonal Ab.
It depletes CD20 expressing B cells via complement-mediated cytotoxicity
and apoptosis . CD20 is expressed early in B lymphocyte ontogeny
in immature bone marrow-resident pre-B cells up to the point of
initiation of plasma cell differentiation in secondary lymphoid tissues.
-This broad expression of CD20 in multiple immature and mature B cell
populations results in a substantial elimination of B-cell populations
by rituximab .
– Rituximab has also been shown to induce a modest decrease in anti-HLA antibodies in a fraction of patients — particularly those with low-level antibodies . -There is a very small but increased risk of JC virus-induced progressive multifocal leukoencephalopathy associated with Rituximab .
-Bortezomib has been shown to provide significant and sustained reductions in anti-HLA antibody levels when used in combination with other therapies such as plasmapheresis and IVIG .
-There is a clear survival benefit for desensitization followed by living donor kidney transplantation (compared to staying on dialysis) in recipients who were flow cytometric cross-match negative, flow cytometric cross-match positive but cytotoxic crossmatch negative, and cytotoxic crossmatch positive .
-Despite high transplant rates and 100% one-year graft survival, acute antibody-mediated rejection rates were high .
– A modified protocol adding rituximab and splenectomy to plasmapheresis
and IVIG did not decrease AMR rates .
-The high cost of desensitization and the tendency for antibody rebound after treatment require that the candidates be near the top of the waiting list, so that it is realistic for them to receive organ offers soon after treatment .
– The optimal desensitization protocol before transplant and the best maintenance immunosuppression program post-transplant remain to be determined.
-Improved ABO incompatible outcomes with splenectomy at the time of transplant led to splenectomy being a required component of pioneering Japanese ABO incompatible programs that began in the late 1980s but it was considered to be high risk for antibody mediated rejection, viral infections,
and decreased graft survival.
-Splenectomy was e replaced by anti-CD20 treatment, and post-transplant antibody removal via plasmapheresis was performed routinely in addition to pre-transplant treatments.
-The two most common methods used to deplete anti blood group antibodies are plasmapheresis and/or blood group-specific immunoadsorption.
KPD versus desensitization
– The success of both strategies has been well established over the past decade
and data supporting a combination strategy continue to emerge.
-The challenge remains in selection of the appropriate patients to optimize successful matching.
– The highly sensitized patient has a match rate as low as 15% in KPD
pools .
Combining desensitization with KPD as a complimentary modality will increase the chances of finding a compatible donor.
-The updated national kidney allocation system (KAS) initiated by the Organ Procurement and Transplant Network (OPTN) on December 4th 2014 is designed to improve transplant rates of themost highly sensitized patientswith cPRA ≥98% .
-Highly sensitized patients may have their cPRA decreased thus giving them less priority on the deceased donor waitlist.
-Another strategy in matching sensitized patients is to relax restrictions on unacceptable antigens. This will allow for low level donor specific antibodies whose role in allograft rejection remains unclear .
-In sudan ,we mainly focus on KPD and in limited cases.
Summary of the article
Kidney transplantation is the best treatment for ESRD patients, living kidney donation has become a standard of practice at most transplant centers in the United States.
The outcomes of living donor kidney transplants are significantly better than those of deceased donor grafts .
But there are many obstacles to living doner transplantation as ABO incompatibility, HLA mismatch/donor specific antibody, or donor/recipient age and size discrepancies .
Most of awaiting kidney transplant are sensitized to HLA DSAs which is associated with poor out come they usually have longer wait time to find compataibile doner.
Kidney Paired Donation (KPD) and desensitization are used to over come this obstacles.
■Kidney paired donation
It allows finding more compatible donor and decrease the load of heavy immunosuppression and its complications mainly infections.
It includes exchange of donors between two incompatible donor/recipient pairs so that two compatible transplants could be performed .
multiple single center KDP registries have been developed worldwide in countries such as India, Romania and Turkey.
It is essential in developing countries as desensitization are not easily accessible because of poor socioeconomic conditions.
The first established national registry originated from the Netherlands where all seven transplant centers combined to form The Dutch National Living Donor.
Which was a model for other national multicenter KPD registries that followed in other countries .
In the years following the first KPD exchange, multiple multi-center registries were born .
-The advantage of single center registry over a multi-center registry is the simplifications as donor and recipient are at the same institution. And the use of a single HLA laboratory with decisions made by a single program as seen in the Johns Hopkins Hospital KPD program they have combined desensitization with KPD .
KPD involves ABO incompatibile pair, highly sensitized recipients, age and graft size mismatch pairs, and those pairs that are borderline compatible but will benefit from a better HLA match.
The highly sensitized defined as patients with a calculated panel reactive antibody (cPRA) greater than 95% .
Recipients with cPRA between 50 and 96% had equivalent match rates as those less than 50%.
■Desensitization
The goal of therapy is to reduce the antibody level so the flow cytometry cross-match is negative or lower than a pre-determined cutoff to prevent hyper acute rejection.
Desensitization protocols usually involve combinatiòn of plasmapheresis along +IVIG and rituximab to lower the titers of HLA antibodies.
*Plasmapheresis works by removing alloantibodies from the circulation.
An obstacle to this method is rebound increases in antibody levels.
*IVIG modulates the alloimmune response via several mechanisms ,it inhibits T-and B-cell proliferation, cytokine production, maturation of dendritic cells, and induce B-cell apoptosis.
one of two approaches are currently in practice: alternate day plasmapheresis followed by low-dose IVIG (used in living donor transplant candidates) and high dose IVIG with rituximab .
*Rituximab :It depletes CD20 expressing B cells via complement-mediated cytotox-icity and apoptosis .
CD20 is expressed in immature and mature B-cell so rituximab results in elimination of B-cell populations.
Rituximab also dcrease in anti-HLA antibodies in some patients .
*Bortezomib: target plasma cells provides significant and sustained reductions in anti-HLA antibody levels when used in combination with other therapies such as plasmapheresis and IVIG.
Protocols of desensitization are not standard and studies on desensitization outcomes are small, non-randomized, not adequately powered, and have a relatively short follow-up time.
■KPD versus desensitization
Combination of both strategies proved to be successful .
The highly sensitized patient has a match rate as low as 15% in KPD pools Combining desensitization with KPD as a complimentary modality will increase the chances of finding a compatible donor.
■Conclusions
several options have become available for Highly sensitized patients including KPD, desensitization and most recently deceased donor priority listing.
these patients is better to be transplanted at experienced centres with strategies providing a multi-modality approach to transplant.
Future studies are needed to assess its overall impact on KPD and desensitization.
Renal transplantation is the best treatment option for patients with ESRD, but the shortage of available deceased donor was a big obstacle. So living transplantation can overcome this shortage. Living donor transplantation das several limitation:
There are 2 strategies used to overcome over the barrier to living donor transplantation: PKD, desensitization or combination of both.
PKD:
This program start before >30 years ago for exchange donor between incompatible donor/recipient, so compatible transplant can be done.It is essential in countries where living donor is the only available option for transplantation. In UK, USA, Canada & Australia there are combined registries from different institutions in same country leading to offering more compatible transplantation. Some programs match ABO incompatible donor/recipient to increase match rate. USA PKD is a unique program use multiple single & multiple registries that operate independent of each other.
It is better to use single HLA lab & decision made by single program & standard practice. Over years the complexity of PKD increased to involve 3 or 4 pairs which require complicated mathematical algorithms.
Now, highly sensitized patients ( cPRA> 98%) had better chance to had compatible donor by PKD. PKD benefit can reach beyond :
Desensitization:
Large number of highly sensitized patients including patients with retransplantation leading to development of different desensitization protocols which aim to eliminate or reduce Abs & convert positive crossmatch to negative one, through PP+IVIG+ rituximab.
PP had many side effects as coagulopathy, hypotension, hypocalcemia, thrombocytopenia & CV line associated infections in addition to rebound in Abs level.
IVIG can modulate immune response through different mechanisms. It inhibit T cells & B cells proliferation, cytokine production, maturation of dendritic c cells, induce B cells apoptosis. IVIG can be used with PP on alternate day with low dose ( living donor transplantation) or high dose with rituximab. Rituximab can eliminate B cells population & induce moderate reduction in HLA Abs especially in patients with low level of DSA.
Bortezumib is a new agent used in sensitization protocols, It target plasma cells.
There is clear advantage( survival) of desensitization strategies in living donor transplantation when compared to patients staying on dialysis especially in patients with positive FCXM & Negative FCXM but positive CDC.
Due to cost of desensitization & rebound phenomenon of Abs it is better to use desensitization for patients who are on the top of waiting list.
Highly sensitized patients has 15% chance to get matched donor in PKD pool, so combining desensitization with PKD can increase the chance of finding compatible donor with good graft & patients outcome.
VI. Kidney paired exchange and desensitization: Strategies to transplant the difficult to match kidney patients with living donors
INTRODUTION
The majority of patients awaiting kidney transplant are sensitized to human leukocyte antigens (HLA). The presence of DSAs has been associated with hyper acute rejection, antibody-mediated rejection (ABMR), and graft loss. For this reason, highly sensitized kidney transplant candidates experience longer wait times and have a higher chance of being removed from or dying on the transplant waiting list.
KIDNEY PAIRED DONATION
It has proven to be essential in developing countries such as India where living donation is the primary means of kidney transplantation and options such as desensitization are not easily accessible because of poor socioeconomic conditions. In fact, a more compatible match with less overall immunosuppression is ideal because the most common cause of death in their post-transplant population is infectious complications.
If multiple institutions within a country combine their registries, they can theoretically enable more matches. The advantage of single center registry over a multi-center registry is the simplification of logistics when both the donor and recipient are at the same institution. Likely more important is the use of a single HLA laboratory with decisions made by a single program as opposed to multiple programs with their own individual HLA laboratory and standards of practice.
However, highly sensitized patients will still suffer from low match rates even with an increase in the donor/recipient pool. Other strategies such as desensitization and/or owering the threshold for unacceptable antigens will have to be adopted to increase transplant rates in this subset of patients.
DESENSITIZATION
An increasing population of highly sensitized patients including those seeking repeat kidney transplants has led to the development of several desensitization strategies. Immunomodulation therapies are administered to transplant candidates as a means to eliminate or reduce HLA antibody levels in order to enable transplantation. The goal of therapy is to reduce the antibody level so the flow cytometry crossmatch is negative or lower than a pre-determined cutoff, thereby preventing hyper acute rejection. Desensitization protocols generally use plasmapheresis along with infusions of intravenous immunoglobulin (IVIG) and rituximab to lower the titers of HLA antibodies in the candidate.
Plasmapheresis works by removing alloantibodies from the circulation. IVIG is a blood product derived from the gamma globulin fraction of plasma from thousands of donos and has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, and to induce B-cell apoptosis. Rituximab is a CD20 specific chimeric murine-human monoclonal, responsible for a substantial elimination of B-cell populations and has also been shown to induce a modest decrease in anti-HLA antibodies in a fraction of patients — particularly those with low-level antibodies.
The high cost of desensitization and the tendency for antibody rebound after treatment require that the candidates be near the top of the waiting list, so that it is realistic for them to receive organ offers soon after treatment. The optimal desensitization protocol before transplant and the best maintenance immunosuppression program post-transplant remain to be determined.
KPD VERSUS DESENSITIZATION
The view of KPD and desensitization as competing strategies for matching suitable incompatible donors/recipient pairs is incorrect. The success of both strategies has been well established over the past decade and data supporting a combination strategy continue to emerge. The highly sensitized patient has a match rate as low as 15% in KPD pools, combining desensitization with KPD as a complimentary modality will increase the chances of finding a compatible donor. An example is to match a sensitized recipient to a donor that is more compatible than the patient’s original donor. This new match will have fewer antibodies against the KPD donor and thus a better chance at successful desensitization. This strategy has been utilized at several centers with emerging success.
CONCLUSION
Highly sensitized patients continue to be a challenge for transplant centers. Over the years, several options have become available including KPD, desensitization and most recently deceased donor priority listing. The best option for these patients is to be transplanted at a center with access and expertise in all of the aforementioned strategies provid[1]ing a multi-modality approach to transplant. The center should then be able to analyze each patient’s immunological profile and determine the best strategy for transplant. It is clear that the new deceased donor allocation system giving priority to those patients ≥98% cPRA is increasing the rate of transplantation in this group. Future studies are needed to assess its overall impact on KPD and desensitization
Kidney paired exchange and desensitization: Strategies to transplant the difficult to match kidney patients with living donors.
Introduction:
Kidney transplantation is the best modality for those with end stage renal disease, living kidney transplant has better outcome than deceased kidney transplant but there are many causes of incompatibility
Such as ABO incompatibility, HLA mismatch/donor specific antibody, or donor/recipient age and size discrepancies which keep the highly sensitized kidney transplant candidates experience longer wait times and have a higher chance of being removed from or dying on the transplant waiting list for that PKD /desensitization or both together considered to override these difficulties.
A-Kidney paired donation:
It depends on the exchange of donors between two incompatible donor/recipient pairs so that two compatible transplants could be performed and this allow better matched transplantation with good survival and less immunosuppression.
The national Dutch KPD reported a transplant success rate of 49% within the first two years of its adoption which increase the donor pool.
Despite the success of larger multi-center registries, single center KPD programs still exist specially when combined with desensitization.
KPD in its simplest form is an exchange of donors between two incompatible pairs such that now they are compatible . The complexity has grown over time, regularly involving three or more pairs.
Those that are sensitized and/or are blood type O have match rates as low as 15% and so the become on waiting list or long time.
KPD allowing better matching for better outcome but still highly sensitized patients suffer to find compatible donor so we can use another strategy like desensitization or lowering the threshold for unacceptable antigens.
B- Desensitization:
Its target to reduce the antibody level so the flow cytometry cross-match is negative or lower than a pre-determined cutoff to prevent hyper-acute rejection.
Desensitization protocols are center dependent but generally PEX,IVIG + or – Rituximab are used.
Plasmapheresis works by removing alloantibodies from the circulation, but the obstacle to this method is rebound increases in antibody levels The side effects commonly seen with plasmapheresis include hypocalcemia, thrombocytopenia, hypotension, and apheresis catheter-related infection and sepsis.
IVIG has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, and to induce B-cell apoptosis. IVIG provides the advantage of repleting normal immunoglobulins so not led to infection.
Two approaches: alternate day plasmapheresis followed by low-dose IVIG and high dose IVIG with rituximab.
Rituximab is anti CD20 monoclonal antibody used to deplete B-cell but associated with increased risk of JC virus-induced progressive multifocal leukoencephalopathy .
Bortezomib has been shown to provide significant and sustained reductions in anti-HLA antibody levels when used in combination with other therapies such as plasmapheresis and IVIG.
Standard protocol of desensitization shown good result and survival benefit from it.
A modified protocol adding rituximab and splenectomy to plasmapheresis and IVIG did not decrease AMR rates specially with high HLA antibody titer.
The two most common methods used to deplete anti-blood group antibodies are plasmapheresis and/or blood group-specific immunoadsorption.
C-KPD versus desensitization:
They are not competing strategy but complementary for highly sensitized patients to select good matching by KPD and desensitization for lower titer of HLA DSA antibodies.
By using KPD with desensitization together increase the chance of good donor matching with recipients with high c PRA and by relaxing the restrictions on unacceptable antigen.
Many studies shown mean follow up at 23 months showed 100% graft and patient survival.
Conclusion:
Still transplantation of highly sensitized patients is an obstacle and need more facility and collaboration between KPD and new protocols of desensitization.
Reflect on your practice:
–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.
Highly sensitized patients whose with cPRA ≥95% remain a challenge in kidney transplantation so strategies as Kidney paired exchange and desensitization are considered .Kidney paired exchange is the exchange of donors between at least two incompatible donor-recipient pairs such that they are now compatible. Desensitization is the removal of circulating DSA to prevent graft rejection.
Combination of both KPD and desensitization is a promising strategy in this population of patients. One factor which affect finding a match within a KPD registry is the blood group of the pair especially if they have different blood groups. To improve this, more donors with o group are recruited, non-directed donors to start linear domino chains of transplants( non-simultaneous extended altruistic donor chain) and the use of ABO/HLA compatible pairs. The latter was associated with more risks of delaying of surgery and the possibility of receiving an inferior graft. Using deceased donor kidney to initiate a KPD chain will help to initiate living donor transplants that would not have happened otherwise and would remove more patients from the deceased donor waiting list which will increase the availability of deceased donor kidneys. Desensitization use plasmapheresis , intravenous immunoglobulin and rituximab. Side effects of plasmapheresis include hypocalcemia, thrombocytopenia, hypotension, and pheresis catheter-related infection and sepsis. A rebound increases in antibody levels are noted in this method due to ongoing antibody synthesis and re-equilibration between the intravascular and interstitial compartments.
IVIG inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, to induce B-cell apoptosis with less risk of infection due to repletion of normal immunoglobulins. Side effects include headache, hypersensitivity-like reactions, and venous thrombosis.
There are two approaches:
1. Alternate day plasmapheresis followed by low-dose IVIG (used in living donor transplant candidates)
2. High dose IVIG with rituximab.
Bortezomib provide significant and sustained reductions in anti-HLA antibody levels when used in combination with other therapies such as plasmapheresis and IVIG.
The two most common methods used to deplete anti-blood group antibodies are plasmapheresis and/or blood group-specific immunoadsorption.
The challenge remains in selection of the appropriate patients to optimize successful matching. Mathematical algorithms were suggested to determine the probability of successful matching in a KPD to predict who will likely benefit from desensitization. Combining desensitization with KPD as a complimentary modality will increase the chances of finding a compatible donor.
In Sudan both modalities are used but we focus mainly on PKD at it is less expensive than desensitization. combining both modalities is faced with many challenges including the lack of pool of donors to initiate PKD and the sole dependence on direct donation in PKD.
Summary of the article:
It is so difficult to find a suitable living donor therefore, these patients are usually remaining on the waiting list for a long time. Highly sensitized patients are those who have c PRA >95%. It is challenging to transplant them. Kidney paired Donor exchange(KPD) and desensitization are strategies used to facilitate transplantation in those sensitized patients.
Paired kidney donation:
1- exchange of donors between two incompatible donor/recipient pairs so that two compatible transplants could be performed. (direct-paired exchange)
2- Exchange of donors between 3 or more pairs (closed-loop KPD) in which the last donor donate to the first recipient.
3- Non-Directed Donor (NDD) initiated chain where a bridge donor may be used to start another chain or the last donor can terminate the chain by donating to a waitlist recipient. Domino exchange
4- ABO-type affect the KPD, O-sensitized patients paired with an A-donor have less chance to get a suitable match. Including ABO/HLA compatible pairs can increase the donor pool in the KPD although ABO incompatibility is the main reason to enter the KPD.
5- KPD recently extends beyond living donors. NDD, s can contribute to the chain and the deceased donor list simultaneously.
6- KPD not only proved donor but also better immunologic match that affects the longe term graft survival.
7- KPD is suitable in counters with high infectious complication due to low socioeconomic status and the cost also represent an important issue there.
8- Even with KPD the highly sensitized patients remain very difficult to provide suitable donor, only 15% have a chance to find a suitable donor. As well; O-blood type recipients have low chance to find a good donor
Desensitization:
It temporally removes DSA from the circulation and allows for transplantation against negative cross match.
Although rebound increase of these antibodies can occur post-transplantation leading to acute ABMR.
It depends on the use of plasmapheresis to remove these antibodies from the circulation in combination with other agents that affect antibody-producing cells like IVIG, Rituximab, and bortezomib. Historically splenectomy had been used.
Combination of KPD and desensitization: this will increase the possibility of the sensitized recipient being transplanted.
In my centre:
Desensitization has been used with success, although occasionally due to decreased resources. I faced one case. Paired kidney donors for two couples are in our strategy and discussed with the patients and their families, but I do not apply due to the patient’s fairness.
We have no allocation program and we do not use deceased donors yet.
Kidney transplantation is the standard of care for those with end stage renal disease .
Deceased kidney donor transplantation has some limitation in regard to organ supply , its acceptance in some cultures and having inferior outcomes , so living kidney donation has become a standard of practice at many transplant centers worldwide .
Unfortunately many living donor recipient pair transplantations are not feasible because of :
*ABO incompatibility
* HLA mismatch/donor specific antibody
* donor/recipient age and size discrepancies
sensitized patients have higher incidence of hyperacute rejection , ABMR & graft loss , therefore have lower chances to get transplanted . Two strategies to address these barriers to living donor kidney transplantation are Kidney Paired Donation (KPD) and desensitization which can be used individually and in combination
Kidney paired donation
The KPD strategy, as originally proposed & applied over 30 years ago in South korea, itinvolved the exchange of donors between two incompatible donor/recipient pairs so that two compatible transplants could be performed .
It has proven to be essential in developing countries such as India where living donation is the primary means of kidney transplantation and options such as desensitization
are not easily accessible because of poor socioeconomic conditions In fact, a more compatible match with less overall immunosuppression is ideal because the most common cause of death in their posttransplant population is infectious complications
the program can be extended to be national like the Dutch KPD that served as the model for other national multicenter KPD registries
KDP possible scenarios currently include :
A) Traditional exchange between two incompatible pairs.
(B) Closed loop chain of 3+ pairs where the last donor donates to the
first recipient.
(C) Non Directed Donor (NDD) initiated chain where a bridge donor may be used to start another chain or the last donor can terminate the chain by donating to a waitlist recipient.
Traditionally, pairs were entered into the registry because of ABO incompatibility but the use of KPD now commonly involves highly sensitized recipients age and graft size mismatch pairs, and those pairs that are borderline compatible but will benefit from a better HLA match. The highly sensitized patient remains particularly challenging (those that are sensitized and/or are blood type O have match rates as lowas 15% ) and as the number of sensitized patients accumulates in a pool themore difficult it will be to initiate chains . KDP programs tend to have disproportionately large numbers of O recipients
and A-donors and disproportionately low numbers of A recipients and O-donors , also
sensitized O-patients paired with an A-donor have less chance of finding a successful match and will need to rely on other means such as desensitization and also by using the NDDs ( Non Directed Donors ) to increase group O donors to the group O recipients .
It has recently been proposed to use deceased donor kidney to help initiate a KPD chain; similar to that of an NDD initiated KPD chainwhere the last live donor on the chain donates to the deceased donor waiting list . This has the potential to initiate living donor transplants that would not have happened otherwise. In addition, it will remove more patients from the deceased donor waiting list which will
increase the availability of deceased donor kidneys
Desensitization
sensitization occurs mainly in pregnancy , blood transfusion & previous organ transplantation . Or such cases desensitization aims to reduce the antibody level so the flow cytometry crossmatch is negative or lower than a pre-determined cutoff, thereby
preventing hyper acute rejection . Desensitization protocols generally use plasmapheresis along with infusions of intravenous immunoglobulin (IVIG) and rituximab to lower the titers of HLA antibodies in the candidate.
Plasmapheresis works by removing alloantibodies from the circulation. An obstacle to this method is rebound increases in antibody levels ,as well as ongoing antibody synthesis by plasma cells .
IVIG has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of
dendritic cells, and to induce B-cell apoptosis. IVIG provides the chance of repleting normal immunoglobulins, thereby providing a theoretical advantage of reducing the infectious risk associated with plasmapheresis.IVIG-based desensitization is currently conducted using one of two approaches:
1- alternate day plasmapheresis followed by low-dose IVIG (used in living donor transplant candidates)
2- high dose IVIG with rituximab
Rituximab depletes Bells population by targeting CD20
Bortezomib targerts plasma cells
Most studies on desensitization outcomes are small, non-randomized, not adequately powered, and have a relatively short follow-up time.
Montgomery et al. reported one of the first long-term experiences with alternate day plasmapheresis and low dose IVIG. They demonstrated a clear survival benefit for desensitization followed by living donor kidney transplantation (compared to staying on dialysis) .
The high cost of desensitization and the tendency for antibody rebound after treatment require that the candidates be near the top of the waiting list, so that it is realistic for them to receive organ offers soon after treatment .
Baseline anti-blood group antibody titers seem to be the strongest predictor of early antibody-mediated rejection in ABO incompatible transplants. Masterson and colleagues demonstrated that selected patients with low anti-blood group antibody titers can successfully undergo ABO incompatible transplants using conventional immunosuppression alone . The two most common methods used to deplete antiblood
group antibodies are plasmapheresis and/or blood group-specific iimunoadsorption . however , kidney transplants of blood group A2 into group O recipents had extended survival with conventional immunosuppression as the A2 antigen is less expressed in tissues .
KPD + Desensitization is increasingly being recognized to be successful . The challenge remains in selection of the appropriate patients to optimize successful matching. Mathematical algorithms based on donor/recipient blood type, sensitization status, and pool size can determine the probability of successful matching in a KPD .
Predicting who will likely benefit from desensitization is more difficult.
Cross matching and solid phase assays against the donor will assess the donor specific antibody specificity and quantity. This will determine the degree of desensitization needed. The highly sensitized patient has a match rate as low as 15% in KPD pools . Combining desensitization with KPD as a complimentary modality will increase the chances of finding a compatible donor. An example is to match a sensitized recipient to a donor that is more compatible than the patient’s original donor. This new match will have fewer antibodies against the KPD donor and thus a better chance at successful
desensitization.
Although cPRA is used as a surrogate to sensitization level , those with antibodies against common HLA antigens will have difficulty being matched regardless of the
cPRA.
Conclusions
Highly sensitized patients continue to be a challenge for transplant centers.Over the years, several options have become available including KPD, desensitization and most recently deceased donor priority listing or a combination
The center should then be able to analyze each patient’s immunological profile and determine the best strategy for transplant. It is clear that the new deceased donor allocation system giving priority to those patients ≥98% cPRA is increasing
the rate of transplantation in this group.
Future studies are needed to assess its overall impact on KPD and desensitization.
reflection on practice :
there are no KPD , deceased kidney donation nor ABO incompatible transplantation in our country
Summarise this article and reflect on your practice.
Definition of highly sensitized patient;
Patients with a calculated panel reactive antibody (cPRA) greater than 95% are defined as highly sensitized patients .Those patients greater than or equal to 97% were less likely to find a match. The new deceased donor allocation system giving priority to those patients ≥98% cPRA is increasing the rate of transplantation in this group.
Strategies to transplant the difficult to match kidney patients with living donors
Two strategies to address these barriers to living donor kidney transplantation are Kidney Paired Donation (KPD) and desensitization which can be used individually and in combination.
Kidney paired exchange donation ;
KPD in its simplest form is an exchange of donors between two incompatible pairs such that now they are compatible . The complexity has grown over time, regularly involving three or more pairs .
The blood type of the donor/recipient pair significantly impacts the likelihood of finding a match within a KPD registry. The non-blood type-O, sensitized patients with O-donors have a much greater chance of finding a match within the registry than sensitized O-recipients with blood-type A donors. Conversely, sensitized O-patients paired with an A-donor have less chance of finding a successful match and will need to rely on other means such as desensitization .
Non-directed donors NDDs;
A potential strategy to match these patients through KPD is to increase the proportion of O-donors. This can be accomplished by using non-directed donors (NDDs) to start linear domino chains of transplants otherwise known as non-simultaneous extended altruistic donor (NEAD) chain .Presumably have a similar blood type distribution to the general public with approximately 45–57% having blood type-O depending on ethnicity.
The donor pool can also be enriched by including ABO/HLA compatible pairs. While part of their motivation to participate in KPD maybe altruistic, compatible pairs may benefit by obtaining a better quality or better matched kidney.
Risks of participating in a KPD pool for the compatible pair include delay of surgery as they wait for a match and the possibility of receiving an inferior graft.
The benefits of KPD have shown to be substantial and its potential has yet to be maximized as algorithms evolve. Its benefits reach beyond living paired donation as NDD’s can contribute to chains and the deceased donor list simultaneously. A better immunological match will result in improved long term graft survival and less economical strain with the use of less immunosuppression.
Desensitization:
The goal of therapy is to reduce the antibody level so the flow cytometry cross match is negative or lower than a pre-determined cutoff, thereby preventing hyper acute rejection.
The high cost of desensitization and the tendency for antibody rebound after treatment require that the candidates be near the top of the waiting list, so that it is realistic for them to receive organ offers soon after treatment . The optimal desensitization protocol before transplant and the best maintenance immunosuppression program post-transplant remain to be determined.
Desensitization protocols generally use plasmapheresis along with infusions of intravenous immunoglobulin (IVIG) and rituximab to lower the titers of HLA antibodies in the candidate.
1-Plasmapheresis;
Works by removing alloantibodies from the circulation.
Side effects commonly seen with plasmapheresis include hypocalcemia, thrombocytopenia, hypotension,and pheresis catheter-related infection and sepsis.
2-IVIG ;
is a blood product derived from the gamma globulin fraction of plasma from thousands of donors.
IVIG has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, and to induce B-cell apoptosis.
IVIG provides the advantage of repleting normal immunoglobulins, thereby providing a theoretical advantage of reducing the infectious risk associated with plasmapheresis.
Potential adverse reactions that can be seen with IVIG administration include headache, hypersensitivity-like reactions, and venous thrombosis.
IVIG-based desensitization is currently conducted using one of two approaches: alternate day plasmapheresis followed by low-dose IVIG (used in living donor transplant candidates) and high dose IVIG with rituximab .
3-Rituximab;
It is a CD20 specific chimeric murine-human monoclonal Ab. It depletes CD20 expressing B cells via complement-mediated cytotoxicity and apoptosis .
Rituximab has also been shown to induce a modest decrease in anti-HLA antibodies in a fraction of patients particularly those with low-level antibodies .
There is a very small but increased risk of JC virus-induced progressive multifocal leukoencephalopathy associated with Rituximab .
4-Bortezomib ;
It targets plasma cells. Bortezomib has been shown to provide significant and sustained reductions in anti-HLA antibody levels when used in combination with other therapies such as plasmapheresis and IVIG.
5-Splenectomy ;
was eventually replaced by anti-CD20 treatment .
KPD versus desensitization;
The highly sensitized patient has a match rate as low as 15% in KPD
pools . Combining desensitization with KPD as a complimentary
modality will increase the chances of finding a compatible donor.
Reflect on your practice:
KPD and Desensitization for ABO incompatibility programs are not available in our center .
With the increased number of patients waiting for transplantation considering alternatives to finding matched donors should be considered. the alternatives are:
**Kidney paired donation
**Desensitization
kidney paired donation can be done among more than two couples to find the best match. despite that, still, it is difficult to match most of patients so still we need desensitization
For desensitization: plasmapheresis, Rituximab, and IVIG is utilized
Plasmapheresis works by removing alloantibodies from the circulation. It has side effects like coagulopathy, hypocalcemia, adverse reaction like hypotension and catheter-related issues like infection etc.
IVIG was shown to inhibit both T and B cells proliferation, modulate the immune system, inhibit the maturation of dendritic cells and induce T and B cell apoptosis. It also inhibits cytokine production
Rituximab depletes B cells which express CD20 by this was decreasing antibody production. It replaced splenectomy.
ABO-incompatible transplantation is risky costly and difficult. most common used methods are plasmapheresis and immune-adsorption.
In Turkey, there is wide use of deceased donors. many centers have paired kidney exchange. some centers do as many as 4 pairs. since more than 15 years no ABO incompatible transplant is done (because of cost). the government insurance covers transplantation from A to Z but not ABO incompatible transplants. ABO-incompatible transplants are replaced with kidney paired donation. desensitization is reserved for those with high PRA in some centres
kidney pair donation program: (KPD)started since1991 in developing countries like Korea and India limited to local centers then gradually expanded to multicenter , national base registry and innovation of Kidney exchange program in many countries worldwide , such program improved the matching and allow for better compatible and HLA matched donation its ideal for living transplant program in developing countries especially when there is no access to desensitization or DD programs also the low socio-economic status with high rate of infection so such program allowed for less intense immunosuppression use such program should be encouraged in our setting as we are dealing mainly with LD transplant program, this will improved the access for better matched donors and limit access to commercial transplantation .
Available protocol for PKD, including:
1- Two Paired donation that allow exchange between HLA incompatible donor to recipient
2- Closed loop chain KPD, 3 pairs with one NDD
3-NDD initiated KPD chain with bridge donor can initiated the chain or last donor can donate for waitlisted recipient. NDD can increase the access to blood group O donors with better ABO /HLA compatible pairs Risk with KPD program that still sensitized patients will be difficult to get match donor and delay in the surgery time, in addition risk of receiving an inferior graft.
Recently extended the registry of KPD to the DD list similar to NDD-KPD chain when the last living donor in the chain NDD can donate to the waiting DD
This will further expand the pool of better match donors with less cost, less immunosuppression, better use of resources and better graft survival and outcome
KPD still of limited benefit for highly sensitized patients with CPRA >95%, access to matched donor reported in < 10%
Alternative will be desensitization alone or the combination of both for better match and less DSA exposures in order to increase rate of transplantation in such specific group.
Desensitization protocol:
Limited use for highly sensitized recipients with target to remove HLA specific DSAs and convert the FXCM to negative in order to get access for transplantation , used alone or in combination with KPD ,different protocols , based on local center resources and experiences , available resources and expertise , risk of infection coagulopathy with PP and depleting agents
By principles by desensitization we are targeting the DSA removal by plasmapheresis and further reduction of DSA production by using immunomodulating agent like IVIG with pleotropic effect as inhibit T and B cells proliferation, reduce cytokines expression, induce B cells apoptosis followed by B cells depleting agents to prevent further production of DSA like rituximab or plasma cells depleting agent bortezomib
Based on available limited evidence from underpowered studies, standardized desensitization protocol no yet performed with doubtful benefits as its associated with higher rate of AMR due to the DSA rebound post-transplant in addition its use limited by cost, over suppression and risk of infections, malignancy.
Combination of both KPD and desensitization will further expand the access for better HLA matched donor in highly sensitized groups.
Our kidney donor pool from living related donors no access to DD, no KPD program started yet but we are planning to start KPD this will allow for better match with less cost and less access to commercial transplantation, desensitization I will individualize its use.
Donation of kidneys in pairs
This refers to the exchange of donors between two incompatible donor/recipient pairings in order to execute two compatible transplants.
Over time, the level of difficulty has increased, with three or more pairs of players frequently involved.
The use of complex mathematical algorithms is required in order to optimally match patients for transplantation. Transplant facilities that participate in national registries must conduct transplants at the same time in order to avoid donor reneging and causing a break in the chain.
Pairs were traditionally entered into the registry because of ABO incompatibility, but the use of KPD is increasingly common among highly sensitized recipients, those with age and graft size mismatches, and those who are borderline compatible but will benefit from a better HLA match, according to the National Kidney Foundation.
Desensitization
During immunomodulation therapy, transplant candidates’ HLA antibodies are eliminated or reduced in order to allow for the transplantation of a healthy organ.
To prevent excessive acute rejection, the objective of treatment is to decrease antibody levels to the point where the flow cytometry cross-match is negative or lower than a pre-determined threshold.
Plasmapheresis, in combination with intravenous immunoglobulin (IVIG) and rituximab infusions, is commonly used in desensitization programs to reduce the titers of HLA antibodies in candidates.
Plasmapheresis
Alloantibodies are removed from the circulation as a result of this treatment.
an adverse effect of the medication:
Coagulopathy
hypocalcemia
thrombocytopenia
hypotension
as well as infection and sepsis caused by apheresis catheter.
Because of the high expense of desensitization and the likelihood of antibody rebound following treatment, applicants must be at the head of the waiting list in order to get organ offers as soon as possible after therapy.
In response to subsequent findings of improved ABO-incompatible outcomes associated with splenectomy at the time of transplant, splenectomy became a mandatory component of the pioneering Japanese ABO-incompatible programs that began in the late 1980s and were implemented throughout the country.
Because ABO-incompatible transplantation was considered to be associated with a significant risk of antibody-mediated rejection, viral infections, and poor graft survival, it was not routinely performed in the past.
As anti-CD20 therapy became more widely available, splenectomy became less common, and post-transplant antibody elimination by plasmapheresis became commonplace in addition to pre-transplant therapies. Several follow-up studies found that standard immunosuppression and antibody elimination, with the exclusion of splenectomy and rituximab, produced results that were equivalent.
Anti-blood group antibody titers at the time of the transplant appear to be the most reliable predictor of early antibody-mediated rejection in ABO-incompatible transplants.
KPD and desensitization should not be seen as competing techniques for matching acceptable incompatible donor/recipient couples, as this is wrong. Over the past decade, the effectiveness of both tactics has been well established, and new evidence supporting a combined strategy is continually emerging.
In KPD Pools, the match rate for the highly sensitive patient might be as low as 15 per cent in some cases. The use of desensitization in conjunction with KPD as a complementary therapy will boost the likelihood of finding a donor who is compatible. The matching of a sensitized recipient to an organ donor who is more compatible with the patient than the patient’s initial donor is an example. There will be fewer antibodies against the KPD donor in this new match, which will increase the likelihood of effective desensitization.
Reflect on practice:
we have paired exchanges in our centre(the limited number we have done). I found it is an excellent option for highly sensitised and ABO-incompatible.
VI. Kidney paired exchange and desensitization: Strategies to transplant the difficult to match kidney patients with living donors
Summarise this article and reflect on your practice.
Introduction
There is a big gap between the need for & the actual number of kidney transplants; and it is clear that this is due to limited amount of organs available.
Although living kidney donation has become a common practice at many centers, however many such transplants fail to proceed due to:
– ABO incompatibility
– HLA mismatch
– DSA or
– Donor/recipient age & size discrepancies
Highly sensitized transplant candidates spend longer times on waitlists & are more likely to die or being removed from the list before finding a suitable donor.
KPD & desensitization are strategies to surmount the immunological barriers; & can be used either individually or in combination.
Kidney paired donation
It is a good option in developing countries where living donation is the primary means of transplantation & where access to desensitization is not easy regarding poor socioeconomic conditions.
More matches can be enabled by combining multiple registries within a country , which is the case in countries like UK, Canada, Australia & USA.
Some programs also match ABO-i pairs to increase their match rate.
Single center KPD programs still exist despite the success of larger multi-center registries.
The highly sensitized patient, defined as cPRA >95%, remains particularly challenging.
Those with cPRA=>97% are less likely to find a match overall.
Overall match rates are roughly 50–60% in a large KPD registry with > 1000 pairs.
Those that are sensitized &/or are ABO type O have match rates as low as 15%.
Non-ABO type-O, sensitized patients with O-donors have a greater chance of finding a match within the registry than sensitized O-recipients with ABO-type A donors.
In contrast, sensitized O-patients paired with an
A-donor have less chance of a successful match & will need to look for other means such as desensitization.
The proportion of O-donors can be increased in such programs by the use of non-directed donors (NDDs) to expand the chains of transplants; also known as non-simultaneous extended altruistic donor (NEAD) chain.
The donor pool can also be increased by including ABO/HLA compatible pairs.
Disadvantages of KPD include:
– delay of surgery while waiting for a match
– possibility of receiving an inferior graft.
The use of deceased donor kidney to help initiate a KPD chain has recently been proposed; it is similar to that of an NDD initiated KPD chain where the last live donor on the chain donates to the deceased donor waiting list.
This will likely initiate living donor transplants that would not have happened otherwise. It will also remove
more patients from the deceased donor waiting list & thus will increase the availability of deceased donor kidneys.
Even with an increase in the donor/recipient pool a subgroup of highly sensitized patients will still suffer from low match. They can benefit from other strategies such as desensitization and/or lowering the threshold for unacceptable antigens.
Desensitization
It aims to reduce the antibody level so the FCM-XM is negative or lower than a pre-determined cutoff, thus
preventing hyper acute rejection.
Protocols use PP plus IVIG & rituximab to lower the titers of HLA antibodies.
PP removes alloantibodies from the circulation.
S/E commonly seen include:
– coagulopathy
– hypocalcemia
– thrombocytopenia
– hypotension and
– catheter-related infection & sepsis.
– rebound increases in antibody levels occurs
IVIG modulates the alloimmune response via several
mechanisms:
– inhibit T- & B-cell proliferation, cytokine production, maturation of DCs, & induce B-cell apoptosis.
IVIG replete normal immunoglobulins, thus theoretically reduces the infectious risk associated with PP.
Potential S/E of IVIG:
– headache
– hypersensitivity-like reactions, and
– venous thrombosis.
Rituximab depletes CD20 expressing B cells via CDC & apoptosis.
It results in a substantial elimination of B-cell populations
Rituximab can increase the risk of JC virus-induced progressive multifocal leukoencephalopathy.
Bortezomib, when combined with PP & IVIG, provide significant & sustained reductions in anti-HLA antibody levels.
The high cost of desensitization & the tendency for antibody rebound after treatment require that the candidates be near the top of the waiting list so as to receive organ offers soon after treatment.
The optimal pre-transplant desensitization protocol & the best maintenance IS remain to be determined.
Masterson et al showed that selected patients with low anti-ABO antibody titers can successfully undergo ABO-i transplants using conventional IS alone.
The methods used to deplete anti-ABO antibodies are PP &/or blood group-specific IA.
It is unclear what minimum titer is acceptable before & after ABO-i transplantation.
KPD versus desensitization
It is not correct to view these strategies as competing for matching suitable incompatible donors/recipient pairs.
There are data supporting a combination strategy.
Mathematical algorithms determine the probability of successful matching in a KPD.
Predicting who will likely benefit from desensitization is more difficult.
The highly sensitized patient has a match rate as low as 15% in KPD pools.
Combining desensitization with KPD will increase the chances of finding a compatible donor. An example
is to match a sensitized recipient to a donor that is more compatible than the patient’s original donor. This new match will have fewer antibodies against the KPD donor & thus a better chance at successful desensitization.
The updated national KAS initiated by the OPTN in 2014 is meant to improve transplant rates of the most highly sensitized patients with cPRA ≥98%.
Desensitization will likely play a critical role in highly sensitized patients, however these patients will have to be carefully chosen according their HLA antibody profile.
Relaxing restrictions on unacceptable antigens is also another strategy in matching sensitized patients. This will allow for low level DSAs.
The individual center would then determine the level of antibody reactivity they are comfortable with. Raising this threshold will increase the number compatible donors; not only in the KPD pool but also from available deceased donors.
Desensitization goals will also be easier to reach.
Conclusions
Highly sensitized patients continue to be a challenge for transplant centers.
Several options have become available including KPD, desensitization & most recently deceased donor priority listing.
The best option for these patients is to be transplanted at a center with access & expertise in all of the strategies providing a multi-modality approach to transplant.
The new deceased donor allocation system, which gives priority to patients with ≥98% cPRA, is increasing the rate of transplantation in this group.
Future studies are needed to assess its overall impact on KPD & desensitization.
Reflection on my practice:
Desensitization is rarely done in our center; the local program is generally not supporting transplantation of highly sensitized patients due logistic issues.
KPD is in its early infancy in our country. There is a modest experience in only one center. No published data.
No deceased donation transplant program in our country.
No ABO-i transplantation in our country.
Surely the inormations gained from this article will help us in planning for our future in this setting.
ERRATUM:(the line before last)
inormation
CORRECT:
information
summary of Kidney paired exchange and desensitization: Introduction:
Living donor kidney transplant outcome are significantly better than those of deceased donor graft but it is difficult to have living donor recipient pair transplant because of ABO incompatibility HLA mismatch donor specific Ab or donor /recipient age ,size discrepancies .
DSA formation is result in :
1) Hyperacute rejection
2) ABMR and graft loss
To overcome barriers for living donor kidney transplant are:
1) Kidney pared donation
2) Desensitization
3) Combination PKD +desensitization.
KPD
More compatible match with less over all immunosuppression which is deal as post transplant cause of death is infection.
Multiple institutions within a country combine their registry and enable more match.
Despite the success of large multi-centre registries ,single centre PKD program still exist.
In order to facilitate transplant of highly sensitized patients combined KPD programme and desensitized patients.
KPD it is an exchange of donor between two incompatible pairs such that now they are compatible .
Patient pairs were entered into the registry because:
1) ABO incompatible
2) Highly sensitized recipient age and graft size mismatch pairs
3) Border line compatible but will benefit from better HLA match
Highly sensitized patients defined as patients with (cPRA) greater than 95%.
Over all match rate are approximately 50—60% in a large KPD registry .
The blood type of donor/recipient pair impact the like hood of finding a match within a KPD registry specially group O recipient and A donor .
Non blood group type sensitized patients with O donor have a much greater chance of finding match with registry than sensitized O recipient and blood group A donor .
Sensitized O patients paired planed with a donor have less chance of finding successful match.
So strategy-to match O recipient through PKD increase the O donor so can be through non-direct donors(NIDS) to start linear dominos chains of transplant .
To help in initial a KPD chain has really proposed use deceased donor kidney .
NIDD has potential to initiate living donor transplant that would not have happened other wise ,so will remove more patients from the deceased donor waiting list which will increase the available of deceased donor kidney.
Abetter immunological match will result in improved long term graft survival and less economic status with use of less immunosuppression .
Desensitization use to lowering the threshold to unacceptable antigens will have adapted to high transplant rate in slim patients.
Desensitization:
In order to enable transplant for highly sensitized patients administrated immunomodulation therapy is necessary .
Goal of therapy is to reduce HLA Ab level in order so flow cytometry crossmatch is -ve prevent hyperacute rejection .
Desensitization protocol generally use plasmapheresis with IVIG and rituximab to lower titre of HLA Abs
S/E of plasmapheresis:
1) Decrease ca
2) Decrease ph
3) Hypotension
4) Catheter related infection and sepsis
5) Rebound increase in antibody level
IVIG modality alloimmune response via several mechanism:
1) -ve Tand B cell proliferation
2) -ve cytokins production
3) -ve maturation of dendritic cells
4) B-cell apoptosis
IVIG replating normal immunological so decrease risk of infection with plasmapheresis.
S/E of IVIG:
1) Headache
2) Hypersensitivity like reaction
3) Venous thrombosis
IVIG based sensitization :is currently conduct using one of two approaches:
1) Alternative day plasmapheresis followed by low dose IVIG
2) High dose IVIG with rituximab
Rituximab depleted CD20 expression B cells via complement-mediated cytotoxicity and apoptosis
Rituximab induce modest decease in anti HLA level Abs
S/E of rituximab:
Risk of JC virus leading to progressive multilucoencephalopathy .
New desensitization agents:
Bortezomib is reduce anti-HLA Abs level when used in combination with plasmapheresis or IVIG.
Although most of studies on desensitization use small but clear survival benefit of desensitization followed by living donor kidney transplant.
Despite high rate of transplantation 100% one year graft survival, acute Ab-mediated rejection rate were high .
Adding rituximab to IVIG and plasmapheresis and splenectomy did not decrease AMR.
There is suggestion that increase level of DSA associated with AMR
In pioneering Japanese ABO incompatible program begin 1980 report that improved ABO incompatible outcome with splenectomy but splenectomy replace by antiCD20.
It remain unclear what minim titre is acceptable before and after ABO incompatible kidney transplant.
Kidney paired donation versus desensitization
Combined approach of KPD and desensitization selection of appropriate patient to optimize successful matching mathematical algorisms based on
Donor /recipient blood type ,sensitization, statistical pool size can determine the probability of successful matching in KPD.
Combined class with KPD as complementary modality will increase the chance of function a compatible donor.
New match have few antibodies against the KPD donor and thus has better chance at successful desensitization .
With the new allocation system deceased system donor match wait time will be short and may provide abetter HLA match than in KPD pool with or without desensitization.
The role of desensitization in the setting of new KAS remain unclear.
Desensitization play crucial role in highly sensitized patients but these patients still have to be carefully.
Chosen according their HLA antibody profile.
Matching sensitized patients is to relax restriction on acceptable antigens.
Conclusion
Transplantation of highly sensitized patients still running challenge.
There are options available for highly sensitized patients include :KPD ,desensitization and deceased donor priority listing.
Highly sensitized patients should be transplant at centre with access and expertise in approach in transplant.
The centre should be able to analyse each patient immunological profile and determine the best strategies for transplantation.
New deceased donor allocation system gives priority to those patients equal or >98 cPRA is high rate of transplant in this group.
For the studies need to access its overall impact on KPD and desensitizing.
Reflect in my practize
KPD program and ABO incompatible transplant is not availble in our center.
for desensitation they use Rituxmab in our center,graft survival out come is variable .
This paper has again raised concerns about another important question of devising strategies how to transplant highly sensitized patients who other wise carry a very little chance to find an appropriate well matched donor.
Two strategies to address these barriers to living donor kidney transplantation are Kidney Paired Donation (KPD) and desensitization which can be used individually and in combination.
KPD was first performed in 1991 at a single center in South Korea where kidney transplantation relies heavily on living donation because of the lack of an established deceased donor program .
The best way would be if If multiple institutions within a country combine their registries, they can theoretically enable more matches. This has been accomplished in countries such as the United Kingdom (U. K), Canada, Netherland, Australia and the United States .
KPD in its simplest form is an exchange of donors between two in- compatible pairs such that now they are compatible however it gets complex if majority of sensitized pools carry’s blood group O and most of donors belong to another blood group.
Inspite of all this highly sensitized patients will still suffer from low match rates even with an increase in the donor/recipient pool. Other strategies such as desensitization and/or lowering the threshold for unacceptable antigens will have to be adopted to increase transplant rates in this subset of patients.
Different desensitization protocols have been adopted by different centers and different modalities used are as follows
Plasmapheresis works by removing alloantibodies from the circulation Aside from coagulopathy, side effects commonly seen with plasmapheresis include hypocalcemia, thrombocytopenia, hypotension, and pheresis catheter-related infection and sepsis.
IVIG is a blood product derived from the gamma globulin fraction of plasma from thousands of donors.
IVIG modulates the alloimmune response via several mechanisms but it is not known which mechanisms are important in mediating anti-humoral effects in humans . IVIG has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, and to induce B-cell apoptosis. IVIG provides the advantage of repleting normal immunoglobulins, thereby providing a theoretical advantage of reducing the infectious risk associated with plasmapheresis.
Rituximab was originally approved for the treatment of B-cell lymphomas. It is a CD20 specific chimeric murine-human monoclonal Ab. It depletes CD20 expressing B cells via complement-mediated cytotoxicity and apoptosis . Rituximab has also been shown to induce a modest de- crease in anti-HLA antibodies in a fraction of patients particularly those with low-level antibodies .
The newest agents added to the armamentarium for desensitization are therapies that target plasma cells. Bortezomib has been shown to provide significant and sustained reductions in anti-HLA antibody levels when used in combination with other therapies such as plasmapheresis and IVIG .
The highly sensitized patient has a match rate as low as 15% in KPD pools. Combining desensitization with KPD as a complimentary modality will increase the chances of finding a compatible donor.
The best option for these patients is to be transplanted at a center with access and expertise in all of the aforementioned strategies providing a multi-modality approach to transplant.
The outcome of living kidney transplantation is better than deceased kidney transplantation however many pairs are not compatible due to ABO Incompatibility, presence of DSA or high HLA mismatch, and inappropriate size of the donor’s kidney
So this lead to overcoming these problems through two strategies: kidney paired donation and desensitization
Kidney paired donation:
Exchange of donors of two pairs or more noncompatible donor /recipient pairs with a result of matching donor-recipient pairs so early transplantation, less use of desensitization, decrease the need for immunosuppression.
combining KPD with desensitization protocols facilitates transplantation of highly sensitized patients
Highly sensitized patients represent the main problems of the waiting list in KPD with 68 % of waiting list were having c-PRA > 80 % since 2012
KPD has many problems first due to many recipients with blood group O and paucity of donors with blood group O
many donors with group A with less number of recipients with group A
So we can overcome these problems by including ABO-incompatible transplantation
Deceased donors now can be involved in KPD to extend the donors pool and start the chain of KPD
Importance of KPD: transplantations of patients with ABO-incompatible pairs, good immunological match, less economic needs for desensitization, early transplantation for highly sensitized patients on the waiting list.
Desensitization
Decrease or elimination of antibodies levels to enable highly sensitized patients for earlier transplantation and prevent hyperacute rejection
many strategies used for desensitization
first plasmapheresis by removing antibodies from the circulation
secondly, IVIG blocks antibodies as it inhibits both B cell and T cells decrease cytokine production and induce B cell apoptosis with less risk of immunosuppression of plasmapheresis
Third Rituximab is a chimeric monoclonal antibody against CD20 of B cells lymphocytes with a modest decrease of antibodies
fourthly new agents like Bortezomib target plasma cells with a significant decrease in antibodies.
With many protocols with plasma pheresis with low dose IVIG on alternate days
another protocol of High dose IVIG in addition 2 doses of rituximab
and modified protocol with plasmapheresis , Rituximab, IVIG and splenectomy, however, didn’t show a better decrease of alloantibodies reduction with more risk of infection
KPD and desensitization :
Combining two strategies improve significantly transplantation of highly sensitized patients with increased chance of finding a suitable donor
reflect on your practice:
unfortunately, KPD programs are not available in our center however desensitization protocols improve significantly transplantation of highly sensitized patients
ABO-incompatible transplantation is not allowed in our country
Sensitization and ABO incompatibility, age and size discrepancies of donors are the
main barriers to transplant, strategies such as KPD and desensitization have been
developed to overcome this.
KPD:
Start long time, good for areas where deceased donor program is not established.
And when desensitization are not easily accessible because of poor socioeconomic
conditions.
It is the exchange of donors between at least two incompatible donor-recipient pairs
such that they are now compatible. Complexity has grown over time, regularly involving
three or more pairs.
This requires sophisticated mathematical algorithms to best match patients for
transplant. Transplant centers involved in national registries must perform transplants
simultaneously to prevent donor reneging and disruption of the chain.
Traditionally, pairs were entered into the registry because of ABO incompatibility but the
use of KPD now commonly involves:
Highly sensitized recipients.
Age and graft size mismatch pairs.
Pairs that are borderline compatible but will benefit from a better HLA match.
If multiple institutions within a country combine their registries, they can theoretically
enable more matches.
Programs such as the UK and Australia match ABO incompatible pairs to increase their
match rate.
Match rates are approximately 50–60% in a large KPD registry with more than 1000
pairs.
Those that are sensitized and/or are blood type O have match rates as low as 15%.
The number of sensitized patients accumulates in a pool the more difficult it will be to
initiate chains. The blood type of the donor/recipient pair significantly impacts the
likelihood of finding a match within a KPD registry.
Non-blood type-O, sensitized patients with O-donors have a much greater chance of
finding a match within the registry than sensitized O-recipients with blood-type a donors.
Conversely, sensitized O-patients paired with an A-donor have less chance of finding a
successful match and will need to rely on other means such as desensitization.
A potential strategy to match these patients through KPD is to increase the proportion of
O-donors.
By using non-directed donors (NDDs) to start linear domino chains of transplants
otherwise known as non-simultaneous extended altruistic donor (NEAD) chain.
Australian KPD program has matching ABO incompatible yet HLA compatible pairs. This
overall does not increase the donor/recipient pool but allows for more possible matches
to be made allowing for more transplants to occur and possibly the inclusion of more
highly sensitized recipients.
Use deceased donor kidney to help initiate a KPD chain; similar to that of an NDD
initiated KPD chain where the last live donor on the chain donates to the deceased
donor waiting.
Desensitization:
The goal of therapy is to reduce the antibody level so the flow cytometry crossmatch is
negative or lower than a pre-determined cutoff.
Desensitization protocols generally use:
Plasmapheresis.
Intravenous immunoglobulin (IVIG).
Rituximab.
Side effects of PE:
Coagulopathy, hypocalcemia, thrombocytopenia, hypotension, and apheresis catheter-
related infection and sepsis.
Potential adverse reaction OF IVIGs:
Include headache, hypersensitivity-like reactions, and venous thrombosis.
Rituximab SIDE EFFECT:
There is a very small but increased risk of JC virus-induced progressive multifocal
leukoencephalopathy associated with Rituximab.
KPD versus desensitization:
A novel approach is the combination of both KPD and desensitization.
Conclusions:
Highly sensitized patients continue to be a challenge for transplant centers.
Several options have become available including KPD, desensitization and most
recently deceased donor priority listing.
The best option for these patients is to be transplanted at a center with access and
expertise in all of the aforementioned strategies providing a multi-modality approach to
transplant.
Reflect on your practice:
Expansion of KPD, we are still using single center program.
Use of new agent for sensitization medication i.e. bortezomib
Highly sensitised patients remain a large problem to get suitable donor for successfully transplant.
Highly sensitised defined as cPRA >97%. they are difficult to find matching.
Recently with start the program of kidney paired donation provide a better matching kidney also used for patients who are ABO incompatible to exchange with compatible donor to maintain kidney transplant with negative cross match.
This program not used for compatible matching because there’s risk of surgery delays and risk of inferior graft.
Non blood group type O sensitised patients with O donor have greater chance of transplant.
In contrast sensitised patients who are O type paired with A donor have less chance to find successful match.
For sensitised patients with cPRA >20 or more but less than 95% are get benefits from kidney allocation system with desensitisation protocol and they get successful transplant and reduce list of waiting.
But still highly sensitised patients not get benefits from kidney allocation system and kidney paired donation because there’s less chance to get suitable donor and many of them dying on dialysis while they still on waiting list.
The program of national kidney registry help sensitised patients to get suitable donor and decrease waiting list.
Desensitisation protocol using for highly sensitised patients despite it’s costy but helps to reduce immunity response and decrease risk of rejection.
Using IV Ig whether low dose or high dose help to reduce all risk ABMR.
Immunoglobulin derived from human plasma immune globulin and it’s action reduce B cell and T cell activation reduce maturation of dentric cells and reduce cytokines production and Increase B cell apoptosis.
it is side effects are hypersensitive and viral infection and venous thrombosis
High dose Iv Ig used with plasma exchange as alternative days
plasma exchange help to remove allantibodies but there’s risk of rebounding of antibodies after equilibrium between intravascular and interstitial cell.
it’s side effects hypotension and hypocalcemia and bleeding tendency and infection related catheter.
or low dose with rituximab
Rituximab are CD30 inhibitors lead to depletion of B cell activation
In the past patients with highly sensitised patients do splenectomy at the time of transplant.
Now rituximab used in state Splenectomy.
Bortezomib another regimen using in highly sensitised patients for removal anti HLA antibodies and can using in combination with plasmapheresis and rituximab.
Combination of kidney paired donation with desensitisation protocol help to improve survival of transplant and decrease percentage of waiting list.
In our centre they do only ABO compatible
there’s no KPD or kidney allocation system
DESENTIZATION STRATIGES,
2.IV IGG,
3. Rituximab ,
CONCLUSION,
· Summarise this article and reflect on your practice
Kidney transplantation is the best form of treatment for ESRD patients. Living donor transplants have better results than deceased donor transplants. The transplant wait-list has high number of sensitized patients who can be transplanted either using kidney paired donation (KPD) or desensitization.
KPD was initially performed in South Korea amongst 2 pairs of incompatible pairs for getting 2 compatible transplants. It is an important tool especially in countries with poor access to desensitization. The Dutch KPD program led to 49% transplant rate among the highly sensitized, following which, other countries like UK, Australia and US also started KPD program. KPD program in US, be in single center or multi-center registry, has also shown increased transplant rates. Programs have used ABO incompatible pairs to increase their match rates.
KPD is offered to patients with ABO incompatibility, highly sensitized pairs with age and graft size mismatch or borderline compatible pairs who can benefit with a better HLA match. A KPD can be either between 2 pairs, closed loop chain with 3 or more pairs, or a non-directed donor-initiated chain. Analysis of data revealed that 50-60% of patients receive a match in large KPD program but the patients with cPRA≥97% had lower chances to find a match, especially with blood group O showing only 15% match rate.
Those with O group donor had higher chances to get a match while O group recipients had low chances to get a donor in KPD. So, to increase their chances, the proportion of O donors need to be increased, either by living non-directed donors or adding ABO/ HLA compatible pairs in the KPD program, or even using a deceased donor to start a KPD chain. This way, KPD helps in getting a better immunological match, lower costs and less immunosuppression leading to lower infection risk and better graft outcomes.
Desensitization is a tool to reduce the antibody levels so that a transplant can be performed. Various protocols have been used for desensitization. These include:
1) Plasmapheresis: It involves antibody removal, but is associated with unintended side-effects like coagulopathy, hypocalcemia, thrombocytopenia, hypotension, infections etc. Rebound in antibody levels happens after plasmapheresis which led to search of other methods of desensitization.
2) IVIG: It modulates alloimmune response by multiple mechanisms and in addition reduces risks of infections associated with plasmapheresis. Side-effects include headache, hypersensitivity reactions and venous thrombosis. IVIG use can be either low dose IVIG with plasmapheresis or high dose IVIG with rituximab.
3) Rituximab: It decreases CD20 expressing B cells as well as anti-HLA antibodies.
4) Bortezomib: It acts on plasma cells, reducing anti-HLA antibody levels when used with IVIG and plasmapheresis.
Living donor transplant after desensitization using plasmapheresis and IVIG has been shown to have survival advantage over remaining on waitlist. These patients have high rates of antibody mediated rejections (AMR), which did not decrease with adding rituximab or splenectomy. Among the patients with baseline titres <1:4 20% had subclinical AMR, with no clinical AMR. Another study using rituximab and IVIG showed 50% acute rejection with 30% AMR. By desensitization, the waiting period for transplant drastically comes down with good short-term graft results. In ABO incompatible transplants, splenectomy was used for desensitization and later on was replaced by rituximab. Newer data shows that antibody removal using plasmapheresis and routine immunosuppression without rituximab or splenectomy has similar results. ABO incompatible transplants with low baseline antibody titres can be performed even without plasmapheresis, although there is no consensus on minimum acceptable titre for transplant.
Rather than comparing KPD with desensitization, combination of the 2 strategies can be a better strategy. So, a donor who is more compatible to the recipient as compared to the original donor, having better chance of successful desensitization, can lead to better graft results. The updated KAS (Kidney Allocation System) decreased the wait-time and increased the percentage of deceased donor transplant among patients with cPRA of 100% by 10 times. By desensitization, the cPRA of the patients can go down, leading to lowering their priority in the wait-list. The restriction on the unacceptable antigens can be relaxed for highly sensitized patients to increase their chances to get a match.
To conclude, it is important to assess each recipient individually and treatment modalities (be it KPD, desensitization, or a combination) be planned to get best results.
In our practice, we usually enroll the patients in KPD program. Most of the ABO incompatible transplants are able to get a donor in KPD except blood group O recipients. They require desensitization. We do not have much experience with respect to highly sensitized patients.
Highly sensitized patients with cPRA of more than 95% due to preformed DSAs, secondary to blood transfusion, pregnancy or prior sold organ transplant, is a hindering status ,as it would be extremely difficult to find a living or cadaveric donor without the unacceptable HLA antigens.
Those highly sensitized patients would be having prolonged waiting list time in order to have a donor with acceptable HLA antigens.
In order to overcome this immunologic barrier , two strategies were invented :
1) kidney Paired donation KPD: in which a patient with a living donor who is having an unacceptable HLA antigen,would be switched with other pairs whose donor is without the unacceptable antigens.
This strategy improved the rate of transplantation and shortened the waiting time .However highly sensitized patients remain difficult to transplant. PKD improved matching rate to less than 15%.
Therefore some patients would continue on HD for years before finding a suitable match,if ever.
2) The other modality implemented in this situation is the desenzitization protocol:
As there’s no potential acceptable HLA antigens.
Desenzitization includes Plasma pheresis to remove the circulating DSAs.
IVIG to Induce apoptosis of T and B lymphocytes, neutralization of DSAs and other less well identified effect. Rituximab is another agent used routinly in desensitization protocol to deplete B-lymphocytes clone sensitized to HLA antigen .However post transplant higher rate of AMR and inferior long term graft outcome hinder the growing enthusiasm in desensitization.
3) A third modality was to combine both PKD and Desensitization .
Therefore, PKD will get better immunologic profile donor,which will be translated into lesser immunologic risk and AMR ,ensuring better tolerance after desensitization which would be implemented simultaneously.
I never worked in a transplant center performing desenzitization protocol.
PKD is not implemented yet in our practice.
Kidney paired exchange and desensitization: Strategies to transplant the difficult to match kidney patients with living donors
Living donor kidney transplants have better outcomes than those of deceased donor grafts. Majority of patients awaiting kidney transplant are sensitized to human leukocyte antigens (HLA).Highly sensitized kidney transplant cases had worse outcomes .KPD program and or desensitization are the strategies to facilitate such cases.
Kidney paired donation: involves the exchange of donors between two incompatible donor/recipient pairs so that two compatible transplants could be performed leading to long term graft survival and less financial burden. ABO typing of donors/recipients is essential consideration for matching. The donor pool for PKD can be improved by non-directed donors (NDDs),also called non-simultaneous extended altruistic donor (NEAD) chain or ABO/HLA compatible pairs. Risk of contributing in a KPD donor pool for compatible donor is; 1. Delayed surgery as they wait for match 2. possibility of getting low quality allograft. KPD is considered to be the best option in underdeveloped countries where desensitization can’t be the option due to the cost and infectious complication.
Desensitization: The goal is to reduce or remove preformed DSA so the flow cytometry crossmatch is negative or lower than a pre-determined cutoff, preventing hyper acute rejection . Desensitization should be limited to transplant recipients with no other living donor, who are highly sensitized and also cannot find the deceased offer and are expected to be waitlisted for a long time. Desensitization include:
Plasmapheresis: Remove circulating antibodies but does not affect the on going production by the plasma cells.
IVIG : Inhibits T & B cells, cytokine release, complement, maturation of dendritic cells & anti-idiotypic against alloantibodies. : Two approaches:alternate day plasmapheresis followed by low-dose IVIG (used in living donor transplant candidates) and high dose IVIG with rituximab.
Rituximab : Anti-CD 20, induce B cell depletion through complement-dependent cellular cytotoxicity, & B cells apoptosis.
Bortezomib : Plasma cell inhibitor
Rituximab + Splenectomy + plasmapheresis
According to one study,29% of kidney transplant recipients after desensitization experienced AMR. Patient and overall graft survival at 24 months was 95% and 84%, respectively.
KPD versus desensitization
The highly sensitized patient has a match rate as low as 15% in KPD pools .Combining desensitization with KPD as a complimentary modality will increase the chances of finding a compatible donor But more studies are needed to evaluate the overall impact on PKD & desensitization.
In my center ,Only living-related transplant recipients are being done.No kidney allocation system nor a system for KPD available.Desensitization is being done very rarely at our Centre due to cost issues.
Living donor kidney transplants are associated with significantly better outcome than deceased donor transplant but it is limited by the ABO incompatibility, HLA mismatch, DSA, age and size discrepancies.
Highly sensitized patients stay on dialysis or waiting list for long time till find a compatible donor.
KPD and desensitization aim to facilitate living donor kidney transplantation.
Kidney paired donation (KPD):
It includes exchange of donors between incompatible donor/recipient pairs to perform 2 compatible transplant and may involve 3 or more pairs.
It is essential in developing countries that depend on living donor kidney transplantation and desensitization is difficult due to socioeconomic conditions and associated increased risk of infection (a common cause of death post transplant).
It requires mathematical algorithms to best match patients for transplant.
Transplantation is performed simultaneously to prevent donor reneging.
It involves pairs with ABO incompatibility, highly sensitized recipients, pairs with age or size mismatch and pairs with borderline compatibility who will benefit from having a better HLA match.
Highly sensitized patients with cPRA>/= 97% are less likely to find a match and may accumulate in the KPD pool.
Blood type of donor/recipient pair has a significant impact on finding a match due to disproportionate numbers of O recipients, A donors, A recipients and O donors this may be overcome by increasing number of nondirected donors.
Inclusion of ABO/HLA compatible pairs enriches the donor pool with having the benefit of receiving better matched kidneys but with the risk of delaying the surgery till find a better match.
KPD provides better immunological match with better long-term graft survival and less economic cost.
Desensitization:
Aims to decrease the antibody level so FCXM is negative or lower than predetermined cutoff.
Plasmapheresis:
Removes alloantibodies from the circulation.
Side effects include coagulopathy, hypocalcemia, thrombocytopenia and catheter related infections.
Associated with rebound increase in antibody levels.
It is difficult to maintain recipients on plasmapheresis due to cost and logistical reasons.
IVIG:
Modulate allo-immune response with advantage of repleting normal immunoglobulins.
Side effects include hypersensitivity like reaction and venous thrombosis.
It is either used as alternate day plasmapheresis followed by low dose of IVIG or as high dose IVIG and rituximab.
Rituximab:
Anti-CD20 monoclonal antibody, depletes CD20 expressing B cells.
Decreases anti-HLA antibodies in some patients with low level antibodies.
Bortezomib:
New agent in desensitization, leads to significant and sustained reduction in anti-HLA antibody levels when used with other therapies.
Studies on outcome of desensitization are small, non-randomized, not adequately powered and have short follow up time.
Studies showed that survival benefit for desensitization followed by living donor transplant compared to remaining on dialysis but with high AMR rates.
Optimal desensitization protocol and best maintenance immunosuppression are not determined yet.
ABO incompatible transplants show comparable results with conventional immunosuppression, antibody removal and rituximab, baseline anti-blood group antibody titer is strong predictor of AMR, It is depleted using plasmapheresis and/or blood group specific immunoadsorption.
KPD versus desensitization:
Combining KPD and desensitization increases probability of finding a compatible donor for highly sensitized patients
Patients undergoing desensitization should be carefully chosen according to their HLA antibody profile as patients with antibodies against common HLA antigens are difficult to match regardless the cPRA.
Decreasing restrictions of unacceptable antigens will increase probability of having transplant and role of desensitization will be easily achieved.
In our practice, we have no KPD programs, only do desensitization.
Kidney paired donation
Mean the exchange of donors between two incompatible donor/recipient pairs so that two compatible transplants could be performed.
The complexity has grown over time, regularly involving three or more pairs .This requires sophisticated mathematical algorithms to best match patients for transplant. Transplant centers involved in national registries must perform transplants simultaneously to prevent donor reneging and disruption of the chain.
Traditionally, pairs were entered into the registry because of ABO incompatibility but the use of KPD now commonly involves highly sensitized recipients age and graft size mismatch pairs, and those pairs that are borderline compatible but will benefit from a better HLA match.
Those that are sensitized and/or are blood type O have match rates as low as 15%.
Since these patients are less likely to find a compatible match they will have longer waiting times and will accrue in the KPD pool.
As the number of sensitized patients accumulates in a pool the more difficult it will be to initiate chains.
The blood type of the donor/recipient pair significantly impacts the likelihood of finding a match within a KPD registry.
such as the NKR tend to have disproportionately large numbers of O- recipients and A-donors and disproportionately low numbers of A- recipients and O-donors (Table 1) .Therefore, non-blood type-O, sensitized patients with O-donors have a much greater chance of finding a match within the registry than sensitized O-recipients with blood-type A donors. Conversely, sensitized O-patients paired with an A-donor have less chance of finding a successful match and will need to rely on other means such as desensitization.
A potential strategy to match these patients through KPD is to increase the proportion of O-donors. This can be accomplished by using non-directed donors (NDDs) to start linear domino chains of transplants otherwise known as non-simultaneous extended altruistic donor (NEAD) chain .
In theory, this will increase the number of blood type O donors to be used for dis- advantaged blood type O recipients in the KPD pool .
Possible kidney paired donation chains:
(A) Traditional exchange between two incompatible pairs.
(B) Closed loop chain of 3+ pairs where the last donor donates to the first recipient.
(C) Non Directed Donor (NDD) initiated chain where a bridge donor may be used to start another chain or the last donor can terminate the chain by donating to a waitlist recipient.
The donor pool can also be enriched by including ABO/HLA compatible pairs.
Risks of participating in a KPD pool for the compatible pair include delay of surgery as they wait for a match and the possibility of receiving an inferior graft.
Potential benefits would be for those that need or may benefit from a better HLA match.
ABO incompatible kidney transplantation outside of the KPD has been performed for several years with success in selected patients
It has recently been proposed to use deceased donor kidney to help initiate a KPD chain; similar to that of an NDD initiated KPD chain where the last live donor on the chain donates to the deceased donor waiting list .
A better immunological match will result in improved long term graft survival and less economical strain with the use of less immunosuppression.
Highly sensitized patients will still suffer from low match rates even with an increase in the donor/recipient pool.
Other strategies such as desensitization and/or lowering the threshold for unacceptable antigens will have to be adopted to increase transplant rates in this subset of patients.
Desensitization
Immunomodulation therapies are administered to transplant candidates as a means to eliminate or reduce HLA antibody levels in order to enable transplantation.
The goal of therapy is to reduce the antibody level so the flow cytometry cross- match is negative or lower than a pre-determined cutoff, thereby preventing hyper acute rejection .
Desensitization protocols generally use plasmapheresis along with infusions of intravenous immunoglobulin (IVIG) and rituximab to lower the titers of HLA antibodies in the candidate.
Plasmapheresis
works by removing alloantibodies from the circulation.
side effects :
Coagulopathy
hypocalcemia
thrombocytopenia
hypotension
and pheresis catheter-related infection and sepsis.
rebound increases in antibody levels after plasmapheresis is an obstacle . This occurs as a result of re-equilibration between the intravascular and interstitial compartments, as well as ongoing antibody synthesis by plasma cells.
IVIG :
IVIG is a blood product derived from the gamma globulin fraction of plasma from thousands of donors.
mechanism of action:
inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, and to induce B-cell apoptosis.
IVIG provides the advantage of repleting normal immunoglobulins, so reducing the infectious risk associated with plasmapheresis.
adverse reactions :
headache, hypersensitivity-like reactions, and venous thrombosis.
IVIG-based desensitization is currently conducted using one of two approaches:
alternate day plasmapheresis followed by low-dose IVIG (used in living donor transplant candidates) and high dose IVIG with Rituximab.
Rituximab:
It is a CD20 specific chimeric murine-human monoclonal Ab. It depletes CD20 expressing B cells via complement-mediated cytotoxicity and apoptosis
Rituximab has also been shown to induce a modest de- crease in anti-HLA antibodies in a fraction of patients — particularly those with low-level antibodies .
There is a very small but increased risk of JC virus-induced progressive multifocal leukoencephalopathy associated with Rituximab .
Bortezomib:
provide significant and sustained reductions in anti-HLA antibody levels when used in combination with other therapies such as plasmapheresis and IVIG.
Outcome:
Montgomery et al. reported experiences with alternate day plasmapheresis and low dose IVIG. They demonstrated a clear survival benefit for desensitization followed by living donor kidney transplantation .
However, despite high transplant rates and 100% one-year graft survival, acute antibody-mediated rejection rates were high.
A modified protocol adding rituximab and splenectomy to plasmapheresis and IVIG did not decrease AMR rates .
-higher pre-treatment DSA levels are associated with AMR.
Jordan et al. evaluated adding Rituximab to a high dose IVIG based regimen . Patient survival and allograft survival at one year were 100% and 94%, respectively. Half of the patients had acute rejection episodes of these; 30% had AMR. Most acute rejection episodes occurred within the first month post-transplant and were reversed with treatment.
The high cost of desensitization and the tendency for antibody rebound after treatment require that the candidates be near the top of the waiting list, so receive organ offers soon after treatment .
Subsequent reports of improved ABO incompatible outcomes with splenectomy at the time of transplant led to splenectomy being a required component of pioneering Japanese ABO incompatible programs that began in the late 1980s.
Because this type of transplantation was con- sidered to be high risk for antibody mediated rejection, viral infections, and decreased graft survival, ABO incompatible transplants were not commonly performed.
Splenectomy was eventually replaced by anti-CD20 treatment, and post-transplant antibody removal via plasmapheresis was performed routinely in addition to pre-transplant treatments. Subsequent studies reported comparable results with conventional immunosuppression and antibody removal, with omission of splenectomy and rituximab.
Baseline anti-blood group antibody titers seem to be the strongest predictor of early antibody-mediated rejection in ABO incompatible transplants.
It remains unclear what minimum titer is acceptable before and after ABO incompatible kidney transplantation.
Another strategy in matching sensitized patients is to relax restrictions on unacceptable antigens. This will allow for low level donor specific antibodies whose role in allograft rejection remains unclear .The transplant center then would determine the level of antibody reac- tivity they are comfortable with. By raising this threshold the likelihood of identifying an immunologically compatible donor increases not only in the KPD pool but also from available deceased donors. Desensitization goals will also be easier to reach.
Conclusions:
Highly sensitized patients continue to be a challenge for transplant centers. Over the years, several options have become available including KPD, desensitization and most recently deceased donor priority listing. The best option for these patients is to be transplanted at a center with access and expertise in all of the aforementioned strategies providing a multi-modality approach to transplant. The center should then be able to analyze each patient’s immunological profile and determine the best strategy for transplant. It is clear that the new deceased donor allocation system giving priority to those patients ≥98% cPRA is increasing the rate of transplantation in this group. Future studies are needed to assess its overall impact on KPD and desensitization.
In my country there is no KPD program
Article IV
Kidney paired exchange and desensitization: Strategies to transplant the difficult to match kidney patients with living donors
Two strategies to address barriers to living donor kidney transplantation are Kidney Paired Donation (KPD) and desensitization which can be used individually and in combination.
The KPD strategy, as originally proposed over 30 years ago, involved the exchange of donors between two incompatible donor/recipient pairs so that two compatible transplants could be performed. Traditionally, pairs were entered into the registry because of ABO incompatibility
but the use of KPD now commonly involves highly sensitized recipients age and graft size mismatch pairs, and those pairs that are borderline compatible but will benefit from a better HLA match.
The highly sensitized patient remains particularly challenging. Generally, this has been defined as patients with a calculated panel reactive antibody (cPRA) greater than 95% but more recent data from the Australian and Canada KPD registries show that those with cPRA between 50 and 96% had equivalent match rates as those less than 50%.
Those patients greater than or equal to 97% were less likely to find a match overall. The blood type of the donor/recipient pair significantly impacts the likelihood of finding a match within a KPD registry. KPD registries such as the NKR tend to have disproportionately large numbers of O- recipients and A-donors and disproportionately low numbers of A-recipients and O-donors (Table 1) [13]. Therefore, non-blood type-O, sensitized patients with O-donors have a much greater chance of finding a match within the registry than sensitized O-recipients with blood-type A donors. Conversely, sensitized O-patients paired with an A-donor have less chance of finding a successful match and will need to rely on other means such as desensitization
A potential strategy to match these patients through KPD is to increase the proportion of O-donors. This can be accomplished by using non-directed donors (NDDs) to start linear domino chains of transplants otherwise known as non-simultaneous extended altruistic donor (NEAD) chain
Risks of participating in a KPD pool for the compatible pair include delay of surgery as they wait for a match and the possibility of receiving an inferior graft. Potential benefits would be for those that need or may benefit from a better HLA match. The benefits of KPD have shown to be substantial and its potential has yet to be maximized as algorithms evolve. Its benefits reach beyond living paired donation as NDD’s can contribute to chains and the deceased donor list simultaneously. A better immunological match will result in improved long term graft survival and less economical strain with the use of less immunosuppression. Highly sensitized patients will still suffer from low match rates even with an increase in the donor/recipient pool.
Desensitization protocols generally use plasmapheresis along with infusions of intravenous immunoglobulin (IVIG) and rituximab to lower the titers of HLA antibodies in the candidate. Most studies on desensitization outcomes are small, non-randomized, not adequately powered, and have a relatively short follow-up time.
Montgomery et al. reported one of the first long-term experiences with alternate day plasmapheresis and low dose IVIG. They demonstrated a clear survival benefit for desensitization followed by living donor kidney transplantation (compared to staying on dialysis) in recipients who were flow cytometric cross-match negative, flow cytometric cross-match positive but cytotoxic crossmatch negative, and cytotoxic crossmatch positive. This larger experience was preceded by similar but smaller reports, which also had favorable outcomes. However, despite high transplant rates and 100% one-year graft survival, acute antibody-mediated rejection rates were high.
The view of KPD and desensitization as competing strategies for matching suitable incompatible donors/recipient pairs is incorrect. The success of both strategies has been well established over the past decade and data supporting a combination strategy continue to emerge
The highly sensitized patient has a match rate as low as 15% in KPD Pools Combining desensitization with KPD as a complimentary modality will increase the chances of finding a compatible donor. An example is to match a sensitized recipient to a donor that is more compatible than the patient’s original donor. This new match will have fewer antibodies against the KPD donor and thus a better chance at successful desensitization.
Highly sensitized patients continue to be a challenge for transplant centers. Over the years, several options have become available including KPD, desensitization and most recently deceased donor priority listing. The best option for these patients is to be transplanted at a center with access and expertise in all of the aforementioned strategies providing a multi-modality approach to transplant. The center should then be able to analyze each patient’s immunological profile and determine the best strategy for transplant. It is clear that the new deceased donor allocation system giving priority to those patients ≥98% cPRA is increasing the rate of transplantation in this group. Future studies are needed to assess its overall impact on KPD and desensitization.
In our hospital, we only transplant from a matched first-degree relative living donor (Palestine).
Kidney transplantation is the main standard of care for patients with end stage renal disease and patients who received kidney transplant have better outcome as compared to those who remain on haemodialysis. Patients who receive live related donor have better outcome as compared to those who receive donation from deceased donors. Unfortunately many related kidney transplantations or not possible due to multiple factors which include HLA incompatibility, ABO incompatibility ,extremes of age etc. the presence
The preserve presence of DSA can lead to hyper acute rejection or antibody mediated rejection. For patients who are highly sensitised the waiting time for transplantation is very long . Such patients can be considered for KPD or desensitization.
Paired kidney donation
This s basically an exchange of donation between two or more couples to achieve better matching and outcomes. Better matching can lead to less cost and less side effects from aggressive immunosuppression. It is more suitable for developing countries due to financial impacts. One strategy to have more transplants through PKD can be to increase the number of Blood group O donors which can be achieved by NDDs- non directed donors to start a linear domino chain also known as NEAD ( Non simultaneous extended altruistic donor. Disadvantage can be delay in finding suitable matches.
Desensitization
This can be achieved by –
· Plasmaphresis
· IVIG
· Rituximab
· Bortuximab
· Ides
Combined desensitization and PKD
It can increase the chance of finding a suitable donor although its role is still not established.
Conclusion
Highly sensitized patients are a challenge in transplant centres. Their options include desensitization, PKD and deceased donors priority listing. PKD can achieve a better matches transplant with less risk of desensitisation. Such highly sensitized patients should be transplanted at centres with significant expertise in handling such cases
Effect on my current Practice
At our centre we only do live related kidney transplants . PKD and KSA is not available in my country however the development of PKD approach is an area which higher attention for policy makers
The majority of patients on the waiting list of kidney transplant are sensitized to HLA
Several strategies are used to address these barriers to living donor kidney transplantation:
1-Kidney Paired Donation
2- Desensitization which can be used individually and in combination with KPD.
Kidney Paired Donation
The KPD strategy involves the exchange of donors between two incompatible donor/recipient pairs so that two compatible transplants could be performed. Programs target to match ABO incompatible and HLA incompatible pairs to increase their match rate. A better immunological match will result in improved long term graft survival and less economical strain with the use of less immunosuppression.
A more compatible match with less overall immunosuppression is ideal because the most common cause of death in their posttransplant population is infectious complications.
KPD in its simplest form is an exchange of donors between two incompatible pairs such that now they are compatible. The complexity has grown over time, regularly involving three or more pairs. 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.
Low numbers of A- recipients and O-donors.Therefore, non-blood type-O, sensitized patients with O-donors have a much greater chance of finding a match within the registry than sensitized O-recipients with blood-type A donors. A potential strategy to match these patients through KPD is to increase the proportion of O-donors.
Desensitization
Several desensitization strategies developed to overcome the need of transplantation for highly sensitized recipients. 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.
Although KPD and desensitization are distinct strategies to improve the access to transplantation, both competing strategies are complementary for matching suitable incompatible donors/recipient pairs. The success of both strategies has been well established over the past decade and data support the combination strategy.
Highly sensitized patients has a match rate as low as 15% in KPD pools, but when combined with desensitization treatment, the chances of finding a compatible donor is increased.
In conclusion, KPD program and desensitization are two different strategies to increase the access of sensitized recipients to transplantation. Combination of both strategies is worth in some patients for better graft and patient survival.
Our practice
I think that KPD is feasible and economic method that can be developed and used in our
Islamic world, especially with exclusively living donor transplantation. Better matching for ABO incompatible and HLA incompatible dono/recipient pair would be solved with national and international KPD programs.
Highly sensitized kidney transplant cases suffer worse outcomes either due to being removed from or dying on the transplant waiting list.
Therefore KPD program and or desensitisation increased their chance of finding an acceptable donor.
KPD is the donor exchange between two incompatible donor/recipient pairs so that two compatible transplants could be done depending on living donors rendering more compatible matches .
A model for national multicentre KPD registries was first established by Netherland increased the chance of successful transplantation.
Then other countries followed, USA is special in having multiple single and multicenter registries independent of each others working beside governmental registries.
The advantage of single center registry over a multi-center registry is the simpler logistics and the use of a single HLA laboratory.
Highly sensitised cases having c PRA >95% remain a difficult group of patients to find a suitable donor .
Some countries registry mentioned that cases with c PRA from 50 -96% had equal match rates as those < 50%.
The accumulation of sensitized patients in a pool renders it difficult to initiate chains.
Sensitised blood group O patients have low chance of finding a match so Non direct donor (NDD)and Non simultaneous extended altruistic donor (NEAD) chain can solve this case
The Australian KPD program matches ABO incompatible but HLA compatible pairs.
It was recommended to use deceased donor kidney to start a KPD chain; similar to NDD initiated KPD chain.
KPD has many advantages as providing the NDD who can participate in chains and the deceased donor list as well improving the immunological match.
Desensitisation protocols applied to highly sensitised cases to decrease HLA antibody levels rendering FCX negative to a level preventing hyperacute rejection to occur.
The protocol includes
plasmapheresis removing alloantibodies from the recipient’s blood but can lead to coagulopathy, hypotension , hypocalcemia and rebound increase of Ab levels.
IVIG inhibiting T- and B-cell proliferation and cytokine release, it can cause hypersensitivity like reaction and venous thrombosis ,it is used in alternate days with plasmapheresis and with Rituximab.
Rituximab depletes CD20 expressing B cells by CDC ,it’s side effect is that it can increase the risk of JC virus-induced progressive multifocal leukoencephalopathy.
Bortezomib gave acceptable results when used with plasmapheresis and IVIG .
Cases with higher DSA levels prior to desensitisation are associated with higher possibility of AMR.
The expenses of desensitization and the antibody rebound possibility after treatment needs to consider cases near the top of the waiting list, so that they can have organ offers after treatment. The best desensitization protocol and the best maintenance immunosuppression program post-transplant are not established yet.
In Japan at the late 1980 ,ABO incompatible transplants were not commonly performed even with splenectomy due to the high risk for antibody mediated rejection, viral infections, and lower graft survival.
Later some studies demonstrated that low anti-blood group antibody titers can have ABO incompatible transplantation using plasmapheresis and immunoadsorption methods.
Recently it was published that combing KPD and desensitisation is better than applying each one separately, in fact choosing the cases whom will benefit the most is challenging as highly sensitised patients been offered donors with more acceptable antigens ie less immunogenic than their own donors improving the overall outcome .
Another issue is to decrease the restrictions for unacceptable antigens enabling more deceased donors to be available increasing the KPD pool.
The majority of patients awaiting kidney transplant are sensitized to human leukocyte antigens (HLA). The presence of DSAs has been associated with hyper acute rejection, antibody-mediated rejection (ABMR), and graft loss. The highly sensitized patient remains particularly challenging. Generally, this has been defined as patients with a calculated panel reactive antibody (cPRA) greater than 95%. Those patients greater than or equal to 97% were less likely to find a match overall.
Two strategies to address these barriers to living donor kidney transplantation are Kidney Paired Donation (KPD) and desensitization which can be used individually and in combination.
Kidney paired donation (KPD)
KPD in its simplest form is an exchange of donors between two incompatible pairs such that now they are compatible. The complexity has grown over time, regularly involving three or more pairs. A potential strategy to match these patients through KPD is to increase the proportion of O-donors. This can be accomplished by using non-directed donors (NDDs) to start linear domino chains of transplants otherwise known as non-simultaneous extended altruistic donor (NEAD) chains. It has recently been proposed to use a deceased donor kidney to help initiate a KPD chain; similar to that of an NDD initiated KPD chain where the last live donor on the chain donates to the deceased donor waiting list.
Highly sensitized patients will still suffer from low match rates even with an increase in the donor/recipient pool.
Desensitization
The goal of therapy is to reduce the antibody level so the flow cytometry crossmatch is negative or lower than a pre-determined cut-off, thereby preventing hyperacute rejection. Desensitization protocols generally use plasmapheresis along with infusions of intravenous immunoglobulin (IVIG) and rituximab to lower the titers of HLA antibodies in the candidate. An obstacle to this method is rebound increases in antibody levels.
Bortezomib as the newest agent has been shown to provide significant and sustained reductions in anti-HLA antibody levels when used in combination with other therapies such as plasmapheresis and IVIG.
A modified protocol adding rituximab and splenectomy to plasmapheresis and IVIG did not decrease AMR rates. Splenectomy was eventually replaced by anti-CD20 treatment, and post-transplant antibody removal via plasmapheresis was performed routinely in addition to pre-transplant treatments.
KPD versus desensitization
A combination strategy of both techniques (KPD & desensitization) continues to emerge with a high success rate. Cross-matching and solid phase assays against the donor will assess the donor-specific antibody specificity and quantity. This will determine the degree of desensitization needed. Combining desensitization with KPD as a complementary modality will increase the chances of finding a compatible donor.
Conversely, those with antibodies against common HLA antigens will have difficulty being matched regardless of the cPRA. It is likely that desensitization will still play a critical role in highly sensitized patients but these patients will have to be carefully chosen according to their HLA antibody profile
Conclusion: A highly sensitized patient can be paired with a better immunological match in the KPD pool and subsequently desensitized to a lesser degree. Other strategies such as lowering the threshold for unacceptable antigens will have to be adopted to increase transplant rates in this subset of patients.
PKD:
o Exchange donors between 2 or mor couples to find the most suitable matching.
o Preferred in developing countries to avoid cost of desensitization and decrease cost of immune-suppression, and infections.
o Transplant must be done simultaneously to avoid declining and disruption of the chain.
o ABO typing of donors/recipients is essential consideration for matching.
o The donor pool for PKD can be improve by non-directed donors (NDDs) ,also called non-simultaneous extended altruistic donor (NEAD) chain or ABO/HLA compatible pairs.
o Disadvantages are delayed surgery as they wait for matched donor and possibility of getting low quality allograft
KSA: with prioritization of highly sensitized recipients.
Desensitization available options:
1. Plasmapheresis ; Remove circulating DSA but re-bound is common.
2. IVIG: bind DSA.
3. Rituximab ; Anti-CD 20, deplete B cells.
4. Bortezomib: anti CD22, plasma cell inhibitor and therefore, reducing antibody production by these cells
5. Ides (IgG degrading enzyme of strept pyogens)
· Combined desensitization with PKD (hybrid approach) will increase the chances of finding a compatible donor.
· However, the role of desensitization in KAS is not clear
· Decrease restrictions on unacceptable antigen as not every DSA are clinically significant or reflected on graft outcome.
Our practice:
Summarise this article and reflect on your practice :
1- it was 1st performed in 1991 in south Korea. later it was successfully done in many world-wide centers.
2- the probability of successful matching can be determined by mathematical matching based on donor/recipient blood type, sensitization status and pool size
3-despite so, the highly sensitized patient has a match rate of only 15 % in KPD pools.
1- it is difficult in those with high antibody titre.
2- predicting who will benefit from it is difficult.
3- combination with KPD increase the rate of successful cases.
Kidney Paired Donation:
Proposed 30 years ago, based on the exchange of donors between 2 incompatible donor/recipient pairs so that 2 compatible transplants could be done. It was first performed in Korea, since then, multiple single-center KPD registries have been developed worldwide.
If multiple institutions within a country combine their registries, they can enable multiple matches. In the years following the first KPD exchange, multiple multi-center registries were born such as the Alliance for paired donation in 2001, the national kidney registry in 2007 which made the largest paired exchange donor pool in the world, the new England kidney exchange in 2005, and the UNOS KPD in 2010.
The complexity of KPD has grown over time involving three or more pairs. transplant centres involved in the national registries should perform transplants simultaneously to prevent donor reneging and disruption of the chain.
Traditionally, pairs were entered into the registry because of ABO incompatibility but the program now involves highly sensitized recipients’ age and graft size mismatch pairs.
The highly sensitized patient remains a challenge, this had been defined as patients with cPRA> 95%, and those with cPRA>97% were less likely to find a match overall.
The blood group of the donor/recipient pair significantly impacts the likelihood of finding a match within a KPD registry, and those who are sensitized and/ or blood group O have a match rate as low as 15%. In general, there is a disproportionately large number of O recipients and A donors, and disproportionately low numbers of A recipients and O donors. A potential strategy to match these patients is to increase O donors through the use of non-directed donors to start linear domino chains of transplants otherwise known as non-simultaneous extended altruistic donor chains.
The donor pool can be enriched by the use of HLA/ABO compatible pairs as this will offer better quality or better-matched kidneys. The risk of KPD for compatible pairs is the delay of surgery, benefits would be for those that need a better match.
It has been proposed to use a deceased donor kidney to help initiate a KPD chain similar to that of an NDD initiated KPD chain where the last live donor on the chain donates to the deceased donor waiting list, this will help in increasing the donor pool and will remove more patients from the deceased donor waiting list.
Desensitization:
The goal of this therapy is to reduce antibody levels so the FCXM is negative or lower than a pre-determined cutoff, in order to prevent hyperacute rejection.
Desensitization protocols involve plasmapheresis, IVIG, and Rituximab.
Plasmapheresis:
removes antibodies from the circulation
SE:
IVIG:
Derived from gamma globulin fraction of plasma from thousands of donors. It modulates the alloimmune response via several mechanisms, it also inhibits B & T cells activation, cytokine production, maturation of dendritic cells, and induces B cells apoptosis.
It repleats normal human Ig and reduces the risk of infection caused by PP.
SE:
There are 2 approaches:
Rituximab:
CD20 specific chimeric murine-human monoclonal ab.
Depletes CD20 expressing B cells. ( mature and immature cells)
Induce a modest decrease in anti-HLA antibodies particularly low-level antibodies.
SE: very small increased risk of JC virus infection.
Bortezomib:
Provide significant and sustained reduction in anti-HLA antibodies level when used in combination with other therapies such as PP7 IVIG.
Splenectomy:
Replaced by rituximab.
Another strategy in matching sensitized patients is to relax the restriction of unacceptable antigens as this will allow transplantation through low-level DSA whose role in allograft rejection is unclear.
KPD versus Desensitization:
The view of desensitization and KPD as competing strategies for matching suitable incompatible donors/recipient pairs is incorrect. Combining desensitization with KPD as a complementary modality will increase the chances of finding a compatible donor. Studies showed successful transplantation of highly sensitized patients following desensitization and participation in KPD program with 100% patient and graft survival after follow up of 22-23 weeks.
In my practice:
We don’t have KPD program, so we depend mainly on desensitization with PP+ IVIG+- Rituximab.
In 2015 in the United States, 100.000 ESRD patients in the waiting list for transplantation from deceased donors. Only 17.878 cases were transplanted. In the same year, there was only 6000 kidney transplantation from living donor.
This shows how disparity in what number of dialysis patients who need for transplantation either from living or deceased donors.
To match this needs, several strategies were developed to overcome this issue.
Transplantation has a better outcomes than dialysis. Living donor transplantation is better than the deceased donor transplantation in patient and graft survival. But the living donor transplantation is not available for most of the patient especially the highly sensitized patients who have high titer of antibodies in their blood.
Those patients have many obstacles to transplantation as they are at a great risk of ABMR and graft loss, so many of them being in the waiting list for long time unfortunately.
To make living donor transplantation is more accessible for those patients, combination of two important policies are evolved and they are kidney paired donation and desensitization.
This approach help in :
• decrease the waiting time in finding the compatible or suitable donor.
• decrease the need of intensive immunosuppression which is considered as economic burden in low economic countries and also leading to higher risk for serious infections and malignancies post transplantation
There are many factors affecting the success of this approach:
• size the donor pool.
• blood grouping of donor/recipient pairs
• status of sensitization of the candidates
• standarization of HLA laboratories.
In Egypt, there is no kidney paired donation.
This study describes Kidney Paired Exchange and desensitization modalities with their different proposals, advantages, and disadvantages.
In the Netherlands, the success was attributed to a national committee with a single central laboratory responsible for HLA. Australian and UK programs have included those with ABO incompatibility.
In the US, KPR introduction can be single-center (as with John Hopkins), regional (cPRA > 97%) or national (cPRA > 99.5%). The logistical advantages, cold ischemia time, and desensitization time make the single-center very effective, but dependent on the availability of the organ.
Currently, ABO and HLA incompatibility become the main causes of the need for transplant desensitization. The expansion of the KPD program to go beyond couples (including even deceased donors) scales with the algorithm involved. Sensitized patients with blood type O have greater difficulty finding a donor. The need to increase the distance is mandatory, but it increases logistical risks such as longer cold ischemia time.
Better immunological compatibility results in longer graft life and less need for immunosuppression.
Immunomodulation techniques for desensitization are not similar depending on the service, but it is usually plasma exchange plus immunoglobulins (low or high dose) and sometimes an anti-CD20 such as rituximab.
Plasma exchange depends on an intensive care structure, blood bank, and specialized multidisciplinary team, with the risk of hypocalcemia, thrombocytopenia, hypotension, and infections (associated or not with the catheter).
IVIg can inhibit B and T lymphocyte proliferation, cytokine production, dendritic cell maturation, and induction of apoptosis. It also replaces the immunoglobulin depleted by plasma exchange or by the consequent blockade of rituximab.
Rituximab alone has no impact, as it does not block circulating plasma cells and antibodies, but it has an important role in maintaining the response. There is a high risk of hepatitis B, Zoster, and PML infections in these cases.
Splenectomy has already been used in an attempt to reduce the humoral response, but the reticuloendothelial system prevents this compensation, and for this reason, it is no longer indicated.
The high cost of desensitization and the possibility of new antibodies after transplantation make more intensive follow-up and higher immunosuppression necessary.
Combining KPD and desensitization is the best way to optimize a better match. To define the need for desensitization will depend on CrossMatch and MFI, decreasing the circulation of antibodies from the donor to the recipient, and increasing graft survival. Acceptable antigen (AM) models are used in Europe and data are yet to be completed.
Unfortunately, we do not have KPD here in Brazil. When used, it is judicially, without following specific national desensitization protocols or not. The first took place now at the end of 2021, but we lack training and specialized staff.
Introduction ;
1.Kidney paired donation(KPD) ; The principle is to exchange donors between
two incompatible donor/recipient pairs to enable their transplantability[4]
2.Desensitization ; The goal is to decreased circulating antibodies and
subsequently negative FCXM results allowing transplantation to proceed[19]
3.KPD versus desensitization ;
4.The updated National Kidney Allocation System(KAS) December 2014 ;
5.Relaxation of restrictions on unacceptable antigen ;
Conclusions ;
My practice ;
Living kidney transplantation constitutes around 30% of transplantation in USA, and is associated with a relatively better outcome when compared to deceased donor transplantation
Highly sensitized transplant recipients are extremely difficult to find a suitable living donor and usually are maintained for a long time on the deceased donor waiting list
A highly sensitized transplant candidate who has ABO or HLA incompatible donor should be evaluated for desensitization, exchange the donor with other pairs (KPD) or both
Kidney Paired Donation (KPD)
Desensitization
Combination of desensitization and PKD
In my practice
Thanks
How this article will change your practice?