Desensitization involves removal of pre existing donor specific antibodies from the plasma combined with agents that inhibit their further production or alter their binding capacity..
Desensitization is essential to prevent hyperacute rejections in case of pre existing DSA which can interfere with graft function…Anti HLA antibodies are formed after blood transfusions, pregnancy and after repeat transplantations…These patients are classified as highly sensitized….
Plasmapheresis: removes pre existing antibodies from the circulation. It is not specific as it removes other plasma proteins, immunoglobulins. It is not effective as a sole therapy as antibody levels rebound after apheresis…There are 2 types which can be done – membrane based and centrifugal based apheresis techniques…
Intravenous Immunoglobulin (IVig) – inhibit T and B cell proliferation, binds to the Fc portion of anti HLA antibody altering its binding capacity, inhibits cytokine production and inhibits complement activation..There are 2 protocols using IVIg – Low dose (0.5-1g/kg) whch i sused after every PP and the high dose IvIG protocol 2gm/day..Mayo clinic have published their results of comparison of the low dose and the high dose IvIG and found that High dose IVIG alone is not useful and the best results of desensitization is seen with Low dose IVIG +PP, Inj Rituximab and triple immunosuppression. The use of ATG as induction agents was also described as a part of the protocol with Low dose IVIG, else there was high rate of AMR which was described…
Other novel agents used in desensitization are Bortezomib, Eculizumab, Toclizumab, Ides (Ig derived streptococcus enzyme), daratumumab….
Benefits of desensitization:
Various trials across USA, show that renal transplant carried out after desensitization in HLAi renal transplants had better 1 year, 2 year and 5 year graft survival as compared to waiting on hemodialysis which has a higher mortality. On the other hand trials from UK showed no difference in the overall survival between HLAi renal transplants as compared to those who are on the waiting list…Unfortunately these 2 studies cannot be compared as they are across different continents with different population groups..
Long term consequences of desensitization:
While most studies of desensitization are short lived, theoretical concerns about over immunosuppression is always there. Patients need to be on Cotrimoxazle prophylaxsis and Valganciclovir prophylaxsis. Further long term studies are needed to ascertain their safety
Desensitization is not cost effective..the overall cumulative cost is more on desensitization as compared to staying on dialysis..
Alyaa Ali
2 years ago
Different techniques of desensitization
The goal of desensitization is to reduce/eliminate DSA, thereby preventing hyperacute rejection and allowing a successful transplantation
Desensitization protocols have typically combined an approach of removing circulating DSA with plasmapheresis (PP) , combined with agents that decrease antibody production, or ones that block their actions.
Plasmapheresis removes antibodies from the circulation, not specific as it removes all plasma proteins , this removal is short lived with rebound, also do not affect the ongoing production of antibodies by plasma cells. It is a poor choice as a sole therapy
Intravenous immunoglobulin (IVIg) inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation.
IVIg-based desensitization can be divided into two general approaches: combined with alternate day PP at a low dose ; or used at a high dose
Low-dose IVIg and PP protocols have been used for ESRD patients with living donors and high levels of DSA.The low-dose IVIg with PP, protocol was modified to include anti-thymocyte globulin for induction along with the addition of rituximab and splenectomy to decrease rate of acute rejection
High dose IVIG showed higher rate of AMR, so Rituximab was added
3.Other agents used in desensitization include :
Bortezomib – a proteasome inhibitor which induces ER stress, cause inhibitition and apoptosis in normal and transformed plasma cells
Eculizumab – humanized monoclonal antibody that blocks cleavage of human complement component C5 and prevents terminal complement activation. It prevents AMR.
Tocilizumab – humanized monoclonal antibody directed at IL-6 receptor
IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS) that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization
Daratumumab is an IgG1j human mAb that binds to CD and inhibits the development of CD expressing cells including plasma cells and plasmablasts.
Benefits of desensitization
Multi-centre study in the US on the survival benefit of kidney transplant from HLA-incompatible live donors showed that recipient of kidney transplant from in-computable live donor had a higher survival rate than waiting list or transplant from deceased donor at 1 year, 3 years, 5 years and 8 years. Study in UK adult transplant centre showed no difference in survival between patients who underwent a HLA-incompatible transplant compared with the listed only group, or listed or transplant group Comparing these two studies is difficult as two studies have different definitions of sensitization have different matching methods for patients awaiting a transplant. Study different population different so go economic factors and different study period in two populations
Long-term risks of desensitization
It is difficult to determine the impact desensitization therapies have on the long-term health since most published studies are short-termed.
Desensitization therapies add to overall immunosuppression raising the obvious concerns of infection and other immunosuppression related complications including malignancies. Some of studies showed high prevalence of infection and other no so it is important to recognize that infection-related mortality is a risk factor to desensitization More studies are necessary to arrive at stronger conclusion.
Cost-effectiveness of desensitization
Desensitization therapies significantly increase the cost of the transplant procedure.
While desensitization treatments increase the cost of transplant, the overall economic impact needs to be considered in light of longer survival and a reduced need for haemodialysis.
The cost-effectiveness of incompatible living donor transplant was assessed using a discrete event simulation model . Over 10 years, incompatible living donor kidney transplant was associated with a greater mean cost of care ($440 234 vs. $292 117) and longer mean survival (5.47 years vs. 4.03). Thus, the incremental cost-effectiveness of desensitization was estimated to be $80 486 per quality-adjusted life year. In comparison, compatible living donor transplant was estimated to cost $39 939 per quality-adjusted life year.
Wee Leng Gan
2 years ago
The different techniques of desensitisation. Plasmapheresis involve the removal of antibodies in the body. Plasmapharesis is only short-lived. The antibodies rebounding to pretreatment levels following re-equilibration between intravascular and interstitial compartments. It does not affect ongoing antibody production. Thus, it is a poor treatment choice for desensitization as sole therapy. The side effects include coagulopathy, hypocalcemia, thrombocytopenia, hypotension and CRBSI and infection. Intravenous immunoglobulin (IVIg) inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation . IVIg-based desensitization can be divided into two general approaches: combined with alternate day PP at a low dose (100 mg/kg); or used at a high dose (1–2 g/kg) . Low-dose IVIg and PP protocols have been used for ESRD patients with living donors and high levels of DSA. Depending on the titres of antibodies patients undergo varying numbers of PP sessions (higher titres, more sessions of PP) followed with the infusion of IVIg. Using low-dose IVIg with PP, AMR has been reported to be as high as 36% with 100% 1-year graft survival. The low-dose IVIg with PP, protocol was modified to include anti-thymocyte globulin for induction along with the addition of rituximab and splenectomy in an attempt to reduce the rejection rate. High-dose IVIg-based protocols for desensitization have been reported in many single centre experiences with variable results. Other agents used in desensitization list as following:
1. Bortezomib (BTZ) is a proteasome inhibitor.
2. Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation.
3. Interleukin (IL)-6 is a pleiotropic cytokine that has powerful stimulatory effects on B cells and plasma cells.
4. Tocilizumab (TCZ) a humanized monoclonal antibody directed at the IL-6 receptor.
5. IgG-degrading enzyme derived from Streptococcus pyogenes .
6. Daratumumab is an IgG1j human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts.
Benefits of desensitization
The benefits of desensitization in term of survival rate were controversial due to the different definitions of sensitisation and matching methods for patients awaiting a transplant. Long-term risks of desensitization Infection. Malignancy.
Cost-effectiveness of desensitization
The arbitrary incremental cost-effectiveness of desensitization was estimated to be $80 486 per quality-adjusted life year. In comparison, compatible living donor transplant was estimated to cost $39 939 per quality-adjusted life year. Generally, the incompatible living donor kidney transplant was associated with a greater mean cost of care and longer mean survival.
Nandita Sugumar
2 years ago
Summary
Introduction
Sensitization can occur through blood transfusions, pregnancy or a previous transplantation. This can be a barrier to a good outcome. The extent of sensitization is calculated using cPRA, wherein 0% indicates no anti-HLA antibody, while 100% indicates incompatibility with the donor pool. This is crucial, since sensitization can lead to AMR, early loss of graft, and a higher chance of death while on waiting list.
Different techniques of desensitization
The goal of sensitization is to reduce DSA and thereby prevent hyper acute rejection, increasing the chances of a good outcome.
Desensitization protocols combine removing circulating DSA with plasmapheresis with agents that decrease antibody production or block their actions.
IVIG inhibits T and B cell proliferation, cytokine production, maturation of dendritic cells and induce B cell apoptosis and inhibit complement activation.
Low dose IVIG is used for ESRD patients with living donors and high DSA levels.
High dose IVIG is used for highly sensitized patients and those with deceased donors.
Other drugs used in desensitization include :
Bortezomib – a proteasome inhibitor which induces ER stress.
Eculizumab – humanized monoclonal antibody that blocks cleavage of human complement component C5 and prevents terminal complement activation. It prevents AMR.
IL-6 – pleiotropic cytokine
Tocilizumab – humanized monoclonal antibody directed at IL-6 receptor
Benefits of desensitization
Improved life expectancy of the patient
Less expensive compared to long term dialysis
Long term risks of desensitization
infection
Malignancy
Long term risks of desensitized and non-desensitized patients in terms of infection risk appears to be equal.
No neurological symptoms suggestive of progressive multifocal leukoencephalopathy.
Cost effectiveness of desensitization
Desensitization increases the total cost of the transplant.
incompatible living donor kidney transplant is associated with a greater mean cost and longer mean survival.
Cost per quality adjust life year is almost double the cost for desensitization in comparison with a compatible living donor transplant.
Conclusion
Patients with DSA and high levels of HLA antibodies can go for desensitization in order to have good outcome post transplant. The cost is higher for patients requiring desensitization. IVIG and plasma exchange form the cornerstone of desensitization with other agents available as well. An alternative to desensitization is kidney paired donation programmes. KPD is associated with better outcomes and lower costs while providing access to organs where immunological barrier can be avoided. If KPD is not possible then desensitization should be considered.
Newer medications to modify antibody mediated graft injury post transplant are being researched for better outcome for more patients.
ahmed saleeh
2 years ago
🍁Transplant candidates with a cPRA 98% are in a dire situation, as mortality rates on dialysis exceed those of most forms of cancer
🍁Four transplant possibilities are currently available for this high cPRA more than 98% group of dialysis patients :
*wait for poper donor (takes very long time)
*Cross immuno barrier
*kidney paired donation program
*Desensitization
🍁The authors concluded that PP/low-dose IVIG and rituximab demonstrated more success in abrogating positive crossmatch and lower acute rejection rates, but no regimen was completely effective in preventing AMR.
🍁the PI BTZ might deplete antibody-secreting long-lived plasma cells and have an impact on DSA production
🍁Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation
🍁Interleukin (IL)-6 is a pleiotropic cytokine that has powerful stimulatory effects on B cells and plasma cells and is responsible, in conjunction with other cytokines, for normal antibody production. It has also been recognized as an important mediator of allograft rejection
🍁IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS) that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization
Since the Fc region of IgG is critical for interaction with Fc receptors and complement binding, proteolytic activity on IgG molecules at this site prevents the occurrence of IgG-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity,
🍁Daratumumab is an IgG1j human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts.
🍁There is no desensitization strategy that can universally allow transplantation in the presence of significant levels of anti-HLA antibody to the donor or a positive crossmatch.
🍁Desensitization therapies add to overall immunosuppression raising the obvious concerns of infection and other immunosuppression related complications including malignancies.
🍁desensitization therapies significantly increase the cost of the transplant procedure.
🍁Alternatives to desensitization: kidney paired donation
Manal Malik
2 years ago
-Desensitiztion in kidney transplant=A risky (but necessary) What is the take-home message advised by this article?
Highly sensitized patients without living donors where pared exchange is not possible and expected wait time is considered unacceptable so proceeding with desensitization may be reasonable consideration
So those patients at the highest risk of posttransplant immunologic injury following desensitization and emphasizes the importance of careful antibody maintaining throughout the post renal transplant period
Desensitization strategies: is it worth it?
Discuss the following:
· The difference techniques of desensitization
· Benefits of desensitization
· Long-term of desensitization
· Cost effectiveness of desensitization Difference techniques of desensitization: 1. Plasmapheresis:
Non-specific removal of antibodies including clotting factors
Disadvantages: short-lived with antibodies rebounding and PP does not affect ongoing antibody production by plasma cells.
Side effects include: coagulopathy, hypocalcaemia, thrombocytopenia, hypotension and catheter-related infection and sepsis. 2. Intravenous immunoglobulin (IVIG)
· Inhibit B and T-cell proliferation
· Cytokines production
· Maturation of dendritic cells
· B-cell apoptosis
· Inhibit complement activation
IVIG based desensitization can be divided in two:
1) Alternative day PP at a low dose 100mg/kg
2) High dose 1-2 gm/kg
· Combination of IVIG and PP used for ESRD patients with living donors and high levels of DSA
· Combination of PP, low dose IVIG, and Rituximab is lower the pastime crossmatch and outcome rejection rate compare to high dose IVIG 3. Bortezomib (BTZ):
Is a proteasome inhibitor and cause inhibition and apoptosis of normal and transformed plasma cells.
Had more study and trials to be evaluated 4. Eculizumab:
Humanized monoclonal antibody that blocks cleavage of human complement C5 and prevent terminal complement activation
Expensive medication
Pre dose vaccination for encapsulated organisms
It is effective in prevention AMR in renal transplant recipient who had positive crossmatch against their living donor 5. Interleukin (IL-6):
Is a pleiotropic cytokine that has powerful stimulating effects on B cells and plasma cells and is responsible in conjunction with other cytokines for normal antibody production? 6. Tocilizumab (TCZ):
A humanized monoclonal antibody direct at the IL-6 receptor
Phase 1,2 pilot study was performed with TCZ and IVIG to eliminate anti-HLA antibodies as well as test its safety and efficacy in desensitization agent.
Larger controlled studies are essential to better study its efficacy 7. Ides:
IgG-degrading enzyme derived from streptococcus pyrogens
Fc region of IgG. Is critical for interaction with Fc receptors and complement binding activity of IgG molecules at this site prevent the occurrence of IgG mediated antibody-depend cellular cytotoxicity and complement mediated cytotoxicity
2 processes are critical for AMR:
Need more studies and trials for efficiency and potential long-term complication 8. Daratumumab:
Is an IgG1k human mAb that binds to CD 38 and inhibit the development of CD 38 expressing cells and plasmablast
However, the reduction of DSA treated animals was not maintained and rapid rebound of antibodies develop with profound rejection
There is no desensitization study that can universally allow transplantation in the presence of significant level of anti-HLA antibody to the donor or appositive crossmatch
Challenge question of whether sensitized patients are better of waiting on dialysis or undergoing desensitization
2 large multi-centre studies have attempted to answer this different dilemma Benefit of desensitization:
Multi-centre analysis on the survival benefit of kidney transplant from HLA-incompatible live donors examined .the result across 22 centre in the US with 1025 recipient
The result that recipient of kidney transplant from incomputable live donor had a higher survival rate than waiting list or transplant from deceased donor
Study in UK adult transplant centre
Result of study in this centre no difference in survival was noted between patients who underwent a HLA-incompatible transplant compared with the listed early group
Comparing these two studies is difficult as two studies have different definitions of sensitization have different matching methods for patients awaiting a transplant. Study different population different so go economic factors and different study period in two populations Long-term risk of desensitization:
It is difficult to determine the impact desensitization therapies have on the long-term health since most published studies are short-termed
Desensitization therapy add to are all immunosuppression raising 2 risks for recipient transplant patient:
1) Infection
2) Malignancies
Some of studies showed high prevalence of infection and other no so it is important to recognize that infection-related mortality is a risk factor to desensitization
More studies are necessary to arrive at stronger conclusion Economic assessment of desensitization:
Desensitization therapies significantly increase the cost of the transplant
Desensitization treatment increase the cost of transplant the overall economic impact need to considered in hight of longer survival and reduced need for haemodialysis
The cost-effectiveness of incompatible living donor was assessed using a discrete event stimulation model over 10 years incompatible living donor kidney transplant was associated with a greater mean cost of care
$440.234
$292.117
Mean survival==years vs 4-0-3
In comparison, compatible living donor transplant was estimated to cost $39.9 regularly adjust life year to $ 80.48 regularly adjust life year Conclusion:
The choice of desensitization or not remaining difficult and should be approach individually rather than group.
For patients with DSAs and high level of HLA antibodies paired donor exchange programme and transplant chains can provide access to organs where immunological barrier can be avoided.
Abdullah Raoof
3 years ago
Introduction
Renal transplantation is the preferred treatment of choice as
ü it improves their survival,
ü quality of life
ü costs lower after the first year compared to dialysis
sensitization to (HLA) from
o blood transfusions,
o pregnancy or
o aprevious transplantation
is an additional barrier to successful outcomes.
extent of sensitization is reflected in the calculated panel reactive antibody
(cPRA) score that can range from 0% indicating no anti-HLA antibody, to 100% that predicts incompatibility with 100% of the donor pool.
The presence of a cPRA <80% creates difficulty in finding matched kidneys
highly sensitized patients have
ü higher rates of (ABMR),
ü early graft loss
ü a higher chance of being removed from or dying on the waiting list.
Transplant candidates with a cPRA 98% are in a bad situation, as mortality rates on dialysis exceed those of most forms of cancer.
Four transplant possibilities are currently available for dialysis patients.
1.to wait for deceased donor transplant,
2.a living donor
3.a kidney paired donation (KPD) programme
4.desensitization procedure.
Desensitization can increase access to both living and deceased donor transplants and can be used individually or in combination with KPD.
The different techniques of desensitisation
Desensitization treatments
The goal of desensitization is to reduce/eliminate DSA, thereby preventing hyperacute rejection and allowing a successful transplantation. Desensitization protocols have typically combined an approach of removing circulating DSA with plasmapheresis (PP) ,combined with agents that decrease antibody production, or ones that block their actions. Plasmapheresis removes antibodies from the circulation.
It is not specific for the removal of alloantibodies and all plasma proteins are reduced including clotting factors.
But the removal is only short-lived with antibodies rebounding occur .
PP does not affect ongoing antibody production by plasma cells therefore it is a poor treatment choice for desensitization as sole therapy.
Its side effects include
1. coagulopathy,
2. hypocalcemia,
3. thrombocytopenia,
4. hypotension
5. catheter-relatedinfection and sepsis.
Intravenous immunoglobulin (IVIg) derived from the gamma globulin fraction of plasma from pooled donors Action :-
inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells,induce B-cell apoptosis and inhibit complement activation
IVIg-based desensitization can be divided into two general approaches: combined with alternate day PP at a low dose (100 mg/kg); or
used at a high dose (1–2 g/kg) .
conclusion: IVIg ( both low and high dose )as a sole treatment is not adequate for treatment of high sensitized patients.
If combined with PP may produce better transplant outcome , although the ABMR is still higher ( around 30%) with lower patient and graft survival than in patient without sensitization .
In another study the conclusion was, that PP/low-dose IVIG and rituximab
demonstrated more success in abrogating positive crossmatch and lower acute rejection rates, but no regi men was completely effective in preventing AMR.
The addition of rituximab or splenectomy did not appear to decrease the acute AMR rate.
Another study to assess the role of IVIg to reduce DSA shows , IVIg was associated with a modest decrease in reactivity to both class I and II HLA antigens but did not significantly alter mean cPRA. Bortezomib (BTZ) is a proteasome inhibitor (PI) that induces apoptosis in normal and transformed plasma cells. PI BTZ might deplete antibody-secreting long-lived plasma cells and have an impact on DSA production.
One study shows – no patient developed a negative crossmatch against their original intended donor, and the calculated panel reactive was unchanged in all patients . Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation.
It has been shown to be efficacious in the prevention AMR in renal transplant recipients who had a positive crossmatch against their living donor.
Side effects : infection with encapsulated microorganisim, costs ( it is very costy ) Interleukin (IL)-6 is a pleiotropic cytokine that has powerful stimulatory effects on B cells and plasma cells and is responsible, in conjunction with other cytokines, for normal antibody production.
It has also been recognized as an important mediator of allograft rejection.
The conclusion of one study — TCZ with IVIg appears to be an additional agent with potential in desensitization. IgG-degrading enzyme derived from Streptococcus pyogenes(IdeS)
that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization.
It prevents the occurrence of IgG-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity .
Result :
IdeS reduced or eliminated DSAs and permitted HLA incompatible transplantation in 24 of 25 patients. AMR occurred in 10 patients at 2 weeks to 5 months after transplantation; all these patients had a response to treatment. Daratumumab is an IgG1j human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts.
Evidence weak only animal studies .
Despite the availability of the above-described agents for desensitization, the quality of evidence comparing one to another is poor.
Benefits of desensitization
Benefits of desensitization
whether sensitized patients are better of waiting on dialysis or undergoing desensitization ?
two study try to answer this question .
first study showed the beneficial effect of transplantation of highly sensitized patient with desensitization , regarding patient and graft survival second study shows no benefit over remaining on dialysis .
Long-term risks of desensitization
Long-term risks of desensitization
Desensitization thera pies add to overall immunosuppression raising the obvious concerns of infection and other immunosup pression
related complications including malignancies.
Cost-effectiveness of desensitization
Economic assessment of desensitization
desensitization therapies significantl increase the cost (42%) of the transplant procedure Alternatives to desensitization: kidney paired donation
Inits simplest form, KPD is an exchange of donors between two incompatible pairs such that they are now compatible.
Traditionally pairs were entered into the registry due to ABO incompatibility but the use of KPD has extended and now commonly involves highly sensitized recipients.
Different techniques of desensitization The aim of desensitization is to reduce DSA and prevent rejection. Desensitization protocols: –Plasmapheresis: It removes antibodies also clotting factors Disadvantages: Transient effect and antibodies rebounding as it doesn’t affect antibody production by plasma cells. Coagulopathy , electrolyte disturbance -Intravenous immunoglobulin (IVIG) it Inhibits B and T-cell proliferation, cytokines release, maturation of dendritic cells and complement activatio Other drugs used in desensitization include : *Bortezomib *Eculizumab *Tocilizumab Benefits of desensitization: –Allowing highly sensitized patient to doing renal transplant -less expensive if compared with continuing on dialysis Long term risks of desensitization: –infection -Malignancy Cost effectiveness of desensitization -Desensitization increases the total cost of the transplant but provide better quality of life also longer survival .
AMAL Anan
3 years ago
Cost-effectiveness of desensitization:
– While desensitization treatments increase the cost of transplant, the overall economic impact needs to be considered in light of longer survival and a reduced need for dialysis.
– Desensitisation cost of care 42% , CDC positive 58 % and Flowcytometry crossmatch positive 38 % in comparison to mean cost of care than remaining on dialysis.
AMAL Anan
3 years ago
Long-term risks of desensitization
– raising the obvious concerns of infection and other immunosuppression related complications including malignancies.
– The most common cause of death was
infection-related. Multivariable risk factor analysis
revealed that desensitization attempts rather than ABO or HLA incompatibility were more significant risk factors for infection-related mortality.
AMAL Anan
3 years ago
Benefits of desensitization :
Helps highly desensitised patients who not getting cadaveric or living donor and expected for long waiting list which leads best quality of life reflecting on patient and graft survival.
AMAL Anan
3 years ago
The different techniques of desensitisation:
– The goal of desensitization is to reduce/eliminate DSA, thereby preventing hyperacute rejection and allowing a successful transplantation.
– different methods for desensitisation:
1- PLASMAPHERESIS ALONE :
removes antibodies from the circulation. This technique is not specific for the removal of
alloantibodies and therefore all plasma proteins are reduced including clotting factors. However, this removal is only short-lived with antibodies rebounding to pretreatment levels following re-equilibration between intravascular and interstitial compartments. More importantly, PP does not affect ongoing antibody production by plasma cells and, hence, is a poor treatment choice for desensitization as sole therapy. Its side effects include coagulopathy, hypocalcemia,
thrombocytopenia, hypotension and catheter-related infection and sepsis.
2- IVIG:
– derived from the gamma globulin fraction of plasma from pooled donors has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells,
induce B-cell apoptosis and inhibit complement activation.
* either :
a – low dose ( 100 mg/ kg ) with plasmapheresis.
( it shows AMR 36 % with 100 % graft survival)
b – low dose IVIG with plasmapheresis, ATG ,rituximab and splenectomy.
( acute AMR rate was 43% with
a 78% graft survival at 15 months. A similar high incidence of acute AMR of 39% and graft survival of 89%was noted with a median follow-up of 22 months )
c- High dose of IVIG ( 2g/kg) :
used in cadaveric transplant with slight decrease in PRA level .
e- high dose of IVIG Alone with rituximab .
3- Bortezomib (BTZ)
is a proteasome inhibitor (PI) that induces endoplasmic reticulum stress, NFjB inhibition and apoptosis in normal and transformed plasma cells. This led to the hypothesis that treatment with the PI BTZ might deplete antibody-secreting long-lived plasma cells and have an impact on DSA production.
– no patient developed a negative crossmatch against their original intended donor, and the calculated panel reactive was unchanged in all
patients.
4- Eculizumab
– is a humanized monoclonal antibody that
blocks cleavage of the human complement component C5 and prevents terminal complement activation. It has been shown to be efficacious in the prevention AMR in renal transplant recipients who had a positive crossmatch against their living donor.
– It is unfortunately quite expensive with an average wholesale price of $21 000 per
dose . Another consideration is the risk of development of invasive infections with encapsulated organisms during eculizumab therapy due to which certain vaccinations are pre requisite .
5- Tocilizumab (TCZ)
IL 6 antagonist, a humanized monoclonal
antibody directed at the IL-6 receptor has also been studied as a potential desensitization agent. A phase I/II pilot study was performed with TCZ and IVIg to reduce and eliminate anti-HLA antibodies as well as test its safety and efficacy in desensitization.
6- IgG-degrading enzyme :
derived from Streptococcus pyogenes (IdeS) that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization .Since the Fc region of IgG is critical for interaction with Fc receptors and complement binding, proteolytic activity on IgG molecules at this site prevents the occurrence of IgG-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity, two processes that are critical for AMR.
– All crossmatches became negative post- IdeS and the patients underwent successful transplantation. Three patients had DSA rebound and AMR, which responded to SOC therapies. At a median follow-up of 235 days, all patients had a functioning renal allograft.
7- Daratumumab
– is an IgG1j human mAb that binds to
CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts. In this context, its potential to control the production of antiHLA antibodies in a nonhuman primate was tested.
Asmaa Khudhur
3 years ago
The different techniques of desensitisation :
Four transplant options are currently available for this disadvantaged group of dialysis patients. The first is to wait for a compatible deceased donor transplant, which may take years without a suitable donor ever being identified .Fortunate ones who have a living donor can undergo transplantation if the immunological barrier can be successfully crossed (option 2). Patients for whom a living donor transplantation is not possible due to unacceptable antibodies, have the option of enrolling in a kidney paired donation (KPD) programme (option 3) or undergoing a desensitization procedure (option 4).
Desensitization can increase access to both living and deceased donor transplants and can be used individually or in combination with KPD.
Desensitization protocols have typically combined an approach of removing circulating DSA with plasmapheresis (PP) ,combined with agents that decrease antibody production, or ones that block their actions.
1-Plasmapheresis removes antibodies from the circulation. This technique is not specific for the removal of alloantibodies and therefore all plasma proteins are reduced including clotting factors. However, this removal is only short-lived with antibodies rebounding to pretreatment levels following re-equilibration between intravascular and interstitial compartments .More importantly, PP does not affect ongoing antibody production by plasma cells and, hence, is a poor treatment choice for desensitization as sole therapy. Its side effects include coagulopathy, hypocalcemia, thrombocytopenia, hypotension and catheter-related infection and sepsis.
2-Intravenous immunoglobulin (IVIg) derived from the gamma globulin fraction of plasma from pooled donors has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation .It was first utilized in combination with PP in crossmatch incompatible living donor kidney transplant candidates .
IVIg-based desensitization can be divided into two general approaches:
combined with alternate day PP at a low dose (100 mg/kg); or used at a high dose (1–2 g/kg).
a-Low-dose IVIg and PP protocols have been used for ESRD patients with living donors and high levels of DSA. Depending on the titres of antibodies patients undergo varying numbers of PP sessions (higher titres, more sessions of PP) followed with the infusion of IVIg. Using low-dose IVIg with PP, AMR has been reported to be as high as 36% with 100% 1-year graft survival [22]. The low-dose IVIg with PP, protocol was modified to include anti-thymocyte globulin for induction along with the addition of rituximab and splenectomy in an attempt to decrease high acute rejection rates .
b-High-dose IVIg-based protocols
c-Rituximab plus high-dose IVIg (2 g/kg) based regimen
Administration of IVIg was associated with a modest decrease in reactivity to both class I and II HLA antigens but did not significantly alter mean cPRA.
The effects of high-dose IVIG (2 g/ kg) and Rituximab were examined in a prospective study on desensitizing transplant candidates with a cPRA >50% waiting for a deceased donor kidney for more than 5 years. It showed no significant reduction in patients’ class I and II cPRA levels nor any change in the mean number of unacceptable antigens or their mean fluorescence intensity values . These studies question the ability of IVIg alone to meaningfully decrease sensitization status. The higher transplant rates noted could be due to non-anti-HLA lowering or immunomodulatory effects of IVIg such as inhibition of complement.
3-Bortezomib (BTZ) is a proteasome inhibitor (PI) that induces endoplasmic reticulum stress, NFjB inhibition and apoptosis in normal and transformed plasma cells.
4-Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation. It has been shown to be efficacious in the prevention AMR in renal transplant recipients who had a positive cross- match against their living donor.
5-Tocilizumab (TCZ) a humanized monoclonal antibody directed at the IL-6 receptor has also been studied as a potential desensitization agent.
Interleukin (IL)-6 is a pleiotropic cytokine that has powerful stimulatory effects on B cells and plasma cells and is responsible, in conjunction with other cytokines, for normal antibody production. It has also been recognized as an important mediator of allograft rejection .
6-IgG-degrading enzyme derived from Streptococcus pyo- genes (IdeS) that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization
7-Daratumumab is an IgG1j human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts.
Despite the availability of the above-described agents for desensitization, the quality of evidence comparing one to another is poor. There is no desensitization strategy that can universally allow transplantation in the presence of significant levels of anti-HLA antibody to the donor or a positive crossmatch. Despite combining the available therapies in different protocols abrogating the response of high levels of preformed DSA has posed a significant challenge with unacceptable rates of AMR after transplantation. This has led to a challenging ques- tion of whether sensitized patients are better of waiting on dialysis or undergoing desensitization.
Benefits of desensitization :
Higher survival rate when compared to patients on waiting list.
Long-term risks of desensitization :
1-Desensitization thera- pies add to overall immunosuppression raising the obvious concerns of infection and other immunosup- pression related complications including malignancies.
2-motor deficits, memory loss and other neurologic symptoms (to rule out reactivation of polyoma JC virus).
3-neurologic symptoms suggestive of progressive multifocal leukoen- cephalopathy, any viral infections [Cytomegalovirus (CMV), Epstein–Barr virus, parvovirus B-19 and BK polyomavirus]
Cost-effectiveness of desensitization :
these strategies are offer improved survival and are cost-effective given nationally accepted bench- marks.
CARLOS TADEU LEONIDIO
3 years ago
The different techniques of desensitisation
The desensitisation is divided into two moments:
– Removing circulating DAS: for this is utilized plasmapheresis
– Decrease antibody production or your block: When were utilized various drugs to inibited the action of antibodys
So there are several studies using these different drugs
Various techniques of desensitisation
There are varius techniques for decrease antibody production or your block and they vary according to the different protocols that are studied :
– Intravenous immunoglobulin (IVIg) ( Low dose X high dose): inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation.
– Eculizumab ( is a humanized monoclonal antibody) : blocks cleavage of the human complement component C5 and prevents terminal complement activation
– Tocilizumab (TCZ) ( humanized monoclonal antibody ): directed at the IL-6 receptor inhibiting your effects on B cells and plasma cells and is responsible, in conjunction with other cytokines, for normal antibody production
– Daratumumab (IgG1j human mAb): binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasma
Benefits of desensitization
It reduces the amount of circulating DSAs decreasing the risk of acute AMR. In US, recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group ( the waiting list ) at 1 year, 3 years, 5 years and 8 years (76.5% vs. 62.9% and 43.9%) (P < 0.001 for all comparisons with the two control groups.
Long-term risks of desensitization
Desensitization therapies increase overall immunosuppression by increasing concerns of infection and other complications related to immunosuppression, including malignancy. However, the rates of these events will vary according to each protocol employed.
Death and chronic rejection are other outcomes analyzed and the results tend to point out that desensitized recipients have worse responses.
Cost-effectiveness of desensitization
In addition to increasing the medical complexity of renal transplant, desensitization therapies significantly increase the cost of the transplant procedure. Some data that corroborate this statement are:
– Incompatible living donor transplant was associated with a 42% increase in the cost of care ($151 024 vs. $106 636 P < .001). The incremental cost was highest in patients with positive cytotoxic crossmatch (58% increase) compared with patients who had only flow positive crossmatch (38% increase).
– Medicare reimbursement was also increased, with mean payment (excluding the cost of organ acquisition) of $92 150 for incompatible vs. $58 084 for compatible transplant;
– Over 10 years, incompatible living donor kidney transplant was associated with a greater mean cost of care ($440 234 vs. $292 117
MOHAMED Elnafadi
3 years ago
The different techniques of desensitisation.
THE AIM OF DESENSITIZATION PROTOCOLS IS TO REMOVE PARTIALLY OR COMPLETLTY DSA THUS PREVENTING ACUTE OR CH REJECTION BY ONE THE FOLLOWING METHODS.
1.Plasmapheresis removes antibodies from the circulation, which is not specific for only alloantibodies but also to circulating plasma proteins even clotting factors.
considered apoor way for desensetaization as it doesnt affect the ongoing production of ab by plasmacells,
side effects include oagulopathy, hypocalcemia,thrombocytopenia, hypotension and catheter-related infection and sepsis.
2.Intravenous immunoglobulin (IVIg) it could be combined with alternate day PP at a low dose (100 mg/kg); or used at a high dose (1–2 g/kg) .
3.Bortezomib (BTZ) proteasome inhibitor results in depletion antibody-secreting long-lived
plasma cells and have an impact on DSA production.
4.Eculizumab, prevents complement activation. It helps in the prevention AMR in renal transplant recipients who had a positive cross- match against their living donor.
5.Tocilizumab (TCZ) directed at the IL-6 receptor has also been studied as a potential desensitization agent.
6.IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS):cleaves all four human subclasses of IgG has recently been used as an agent for desensitization
7.Daratumumab control the production of anti-HLA antibodies in a nonhuman primate was tested considered amedical challenge. Benefits of desensitization
PROVIDE AGOOD CHANCE FOR SEBSETIZED PATIENT FOR TRANSPLANTATION OPPORTUNITY.
REDUCTION OF WAITING LIST TIME. Long-term risks of desensitization
Immunosuppression used in desensitization raising the
chance of getting infection and other immunosuppression related complications including malignancies and systemic side effects incomarison to success or faliure.
Dalia Ali
3 years ago
1-A patient’s extent of sensitization is reflected in the calculated panel reactive antibody (cPRA) score that can range from 0% indicating no anti-HLA antibody, to 100% that predicts incompatibility with 100% of the donor pool
The presence of a cPRA greater than 80% creates difficulty in finding matched kidneys from compatible donors and low annual transplant rates
Desensitization treatments
*Plasmapheresis removes antibodies from the circulation. This technique is not specific for the removal of alloantibodies and therefore all plasma proteins are reduced including clotting factors. However, this removal is only short-lived with antibodies rebounding to pretreatment levels following re-equilibration between intravascular and interstitial compartments
PP does not affect ongoing antibody production by plasma cells and, hence, is a poor treatment choice for desensitization as sole therapy. Its side effects include coagulopathy, hypocalcemia, thrombocytopenia, hypotension and catheter-related infection and sepsis.
*Intravenous immunoglobulin (IVIg) derived from the gamma globulin fraction of plasma from pooled donors has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation
IVIg-based desensitization can be divided into two general approaches: combined with alternate day PP at a low dose (100 mg/kg); or used at a high dose (1–2 g/kg)
* Bortezomib (BTZ) is a proteasome inhibitor (PI)
might deplete antibody-secreting long-lived plasma cells and have an impact on DSA production
*Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation.
The incidence of AMR was 7.7% (2/26) in the eculizumab group compared to 41.2% (21/51) in the control group
*Tocilizumab (TCZ) a humanized monoclonal antibody directed at the IL-6 receptor has also been studied as a potential desensitization agent. A phase I/II pilot study was performed with TCZ and IVIg to reduce and eliminate anti-HLA antibodies as well as test its safety and efficacy in desensitization
*IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS) that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization
*Daratumumab is an IgG1j human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts. In this context, its potential to control the production of antiHLA antibodies in a nonhuman primate was tested.
2-Benefits of desensitization
Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year (95.0% vs. 94.0% for the waiting list
Decreased waiting time in waiting list in patients on dialysis
3-Long-term risks of desensitization
Desensitization therapies add to overall immunosuppression raising the obvious concerns of infection and other immunosuppression related complications including malignancies.
Monitoring for adverse events and serious adverse events was continued after transplantation for a mean of 22.1 +_6.0 months. No patients had neurologic symptoms suggestive of progressive multifocal leukoencephalopathy, nor [Cytomegalovirus were (CMV), any viral Epstein–Barr infections virus
parvovirus B-19 and BK polyomavirus] detected
Patient survival rate was reduced in patients who underwent incompatible transplants (ABO, HLA, ABO+HLA) compared to standard transplants. The most common cause of death was infection-related
4-Economic assessment of desensitization
desensitization therapies significantly increase the cost of the transplant procedure.
Incompatible living donor transplant was associated with a 42% increase in the cost of care ($151 024 vs. $106 636 P < .001). The incremental cost was highest in patients with positive cytotoxic crossmatch (58% increase) compared with patients who had only flow positive crossmatch (38% increase).
Thus, the incremental cost-effectiveness of desensitization was estimated to be $80 486 per quality-adjusted life year. In comparison, compatible living donor transplant was estimated to cost $39 939 per quality-adjusted life year.
Theepa Mariamutu
3 years ago
Desensitization strategies: is it worth it?
Narrative review: level 5 evidence
Desensitization protocol is to achieve a successful transplantation by preventing hyperacute rejection which involves preventing formation and action of antibodies as well as removing the formed antibodies from circulation.
Plasmapheresis alone: Nonspecific removal of antibodies, which is short lived (due to rebound) and hence not successful.
Intravenous immunoglobulin (IVIG): IVIG can be used in either low dose or high does.
Low dose IVIG (100 mg/kg) with Plasmapheresis: It has been shown to have AMR rates of 36% with 100% graft survival at 1 year.
Low dose IVIG with plasmapheresis and ATG, rituximab and splenectomy: It has been associated with AMR in 43% and 39% at 15 months and 22 months with graft survival of approximately 80% at 15 months.
High dose (2 g/kg) IVIG alone: It is used in cadaveric transplant program, associated with slight decrease in PRA levels and increased transplantation rates 2 years post therapy. AMR rates were 31% with high 2-year patient and graft survival.
High dose IVIG with rituximab: It is associated with 50% acute rejection and 30% AMR while the 2-year patient and graft survival is 95% and 84% respectively.
Low dose IVIG and plasmapheresis with or without rituximab has shown results superior to use of high dose IVIG alone.
Bortezomib:
proteasome inhibitor causing apoptosis of plasma cells.
use saw transplant of 43% of sensitized patients with 12.5% developing de novo DSAs and 18.8% acute rejection.
Eculizumab:
It is an antibody blocking cleavage of C5
used with IVIG and plasmapheresis, has shown risk of AMR in range of 7.7% to 11.8% as compared to 21.6% to 41.2% seen with IVIG and plasmapheresis
but with an increased risk of invasive infections.
Tocilizumab: It is an antibody against IL-2 receptor which, when used with IVIG in patients unresponsive to IVIG and rituximab, showed good results post-transplant with no AMR at 6 months and good graft function at 1-year post-transplant.
IgG degrading enzyme derived from Streptococcus pyogenes (IdeS): It causes proteolysis at Fc region of IgG. Its use has been shown to be associated with approximately 40% AMR which were treated. Long term effects including infections and malignancies need to be evaluated.
Daratumumab: It is a CD38 inhibitor and has been used in non-human primates showing marked reduction in antibody levels which was short-lived, hence associated with severe rejections.
Benefits of desensitization
helps a highly sensitized patient, who is otherwise not getting a living or cadaveric donor and is expected to remain on wait-list for a long time, to get a kidney transplant.
kidney transplant has been shown to be associated with better quality of life, as well as better survival rates with respect to patients remaining on wait-list
Long-term risks of desensitization
infections
malignancies
use of IVIG, plasmapheresis and rituximab desensitization has similar infection rates while eculizumab use increases the infection rates by 50%.
Reduced patient survival due to increased infections has been observed in large study
Cost-effectiveness of desensitization
Desensitization increases the cost of care by 42%, more so in a CDC positive patient by 58% than a flow cytometry crossmatch positive patient (38%).
increased mean cost of care in comparison to patients remaining on dialysis
Last edited 3 years ago by Theepa Mariamutu
Mohammed Sobair
3 years ago
The different techniques of desensitization:
Desensitization treatments:
The goal of desensitization is to reduce or eliminate DSA, thereby preventing
hperacute rejection and allowing a successful transplantation.
It combined an approach of removing circulating DSA with plasmapheresis (PP),
combined with agents that decrease antibody production, or ones that block their
actions.
Plasmapheresis:
Advantage:
Removes antibodies from the circulation.
Disadvantage:
Not specific for the removal of alloantibodies and therefore all plasma proteins are
reduced including clotting factor risk of coagulopathy
Removal is only short-lived with antibodies rebounding to pretreatment levels
following re-equilibration between intravascular and interstitial compartments.
More importantly, PP does not affect ongoing antibody production by plasma cells
and, hence, is a poor treatment choice for desensitization as sole therapy.
Other side its side include, hypocalcemia, thrombocytopenia, hypotension and
catheter-related infection and sepsis.
Intravenous immunoglobulin:
derived from the gamma globulin fraction of plasma from pooled donors has been
shown to inhibit T- and B-cell proliferation, cytokine production, maturation of
dendritic cells, induce B-cell apoptosis and inhibit complement activation .
IVIg-based desensitization:
Two general approaches:
Combined with alternate day PP at a low dose (100 mg/kg).
Used at a high dose (1–2 g/kg).
Other agents used in desensitization:
Bortezomib (BTZ):
PI that induces endoplasmic reticulum stress, NFjB inhibition and apoptosis .
In a study aimed to determine the safety and efficacy of 32 doses of BTZ in 10
highly sensitized kidney transplant candidates with alloantibodies against their
intended living donor, no patient developed a negative crossmatch against their
original intended donor, and the calculated panel reactive was unchanged in all
patients
Eculizumab:
Is a humanized monoclonal antibody that blocks cleavage of the human
complement component C5 and prevents terminal complement activation.
Potential benefit for Eculizumab compared with SOC in preventing acute AMR in
recipients sensitized to their living-donor kidney transplants groups.
Disadvantage:
It is unfortunately quite expensive with an average wholesale price of $21 000 per
dose.
Risk of development of invasive infections with encapsulated organisms during
Eculizumab therapy due to which certain vaccinations are pre requisite .
Tocilizumab (TCZ):
Humanized monoclonal antibody directed at the IL-6 receptor has also been
studied as a potential desensitization agent. Further studies needed.
IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS):
That cleaves all four human subclasses of IgG has recently been used as an agent
for desensitization.
Twenty-five highly HLA-sensitized patients at two international centres (Sweden
and Unites States) were administered IdeS before the transplantation of a kidney
from an HLA-incompatible donor. Out of the 25 patients, 22 had DSA present
before transplantation. IdeS reduced or eliminated DSAs and permitted
HLA incompatible transplantation in 24 of 25 patients. AMR occurred in 10 patients
at 2 weeks to 5 months after transplantation; all these patients had a response to
treatment. The difference in immunosuppressive regimens used is noteworthy.
Daratumumab:
Is an IgG1j human mAb that binds to CD 38 and inhibits the development of CD 38
expressing cells including plasma cells and plasmablasts? It raises the possibility
of another potential therapeutic strategy, it shows that the removal of pathogenic
HLA antibodies is still a considerable medical challenge.
Benefits of desensitization
Recipients of kidney transplants from incompatible live donors had a higher
survival rate than either control group at 1 year (95.0% vs. 94.0% for the waiting
list or transplant control group and 89.6% for the waiting list-only control group), 3
years (91.7% vs. 83.6% and 72.7%, respectively), 5 years (86.0% vs. 74.4% and
59.2%) and 8 years (76.5% vs. 62.9% and 43.9%) (P < 0.001 for all comparisons
with the two control groups).
Long-term risks of desensitization
Though comparative studies show no statistical difference in infectious and
malignant risk, still this risk should be considered as an additive to other IS used in
transplant.
Cost-effectiveness of desensitization:
Desensitization therapies significantly increase the cost of the transplant
procedure.
Incompatible living donor transplant was associated with a 42% increase in the cost
of care ($151 024 vs. $106 636 P < .001).
Medicare reimbursement was also increased, with mean payment (excluding the
cost of organ acquisition) of $92 150 for incompatible vs. $58 084 for compatible
transplant.
Economic impact needs to be considered in light of longer survival and a reduced
need for hemodialysis.
Hinda Hassan
3 years ago
The different techniques of desensitization
Desensitization get rid of DSA partially or completely to prevent rejection. Desensitization techniques include: 1- Removal of circulating DSA with plasmapheresis.this is short lived technique. Side effects are coagulopathy, hypocalcemia, thrombocytopenia, hypotension and catheter-related infection and sepsis. 2- Reduction of antibody production (rituximab, Bortezomib) 3- Blockage of antibodies actions through Intravenous immunoglobulin. IVIg inhibit lymphocytes proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation. This technique can be used combined with alternate day PP at a low dose (100 mg/kg); or used at a high dose (1–2 g/kg). Low-dose approach was associated with high risk of AMR approaching 36% with 100% 1-year graft survival. So anti-thymocyte globulin induction, rituximab and splenectomy were included but with no success in reducing the rate of AMR.High-dose IVIg-based protocols improve the rate of transplant at two years,with higher acute rejection rate .induction with Zenapax, alemtuzumab or Thymoglobulin showed no differences in the rates of AMR. Rituximab with high-dose IVIg (2 g/kg) was associated with 50% acute rejection episodes and 30% AMR. It did not significantly alter mean cPRA . Combinations of PP, low-dose IVIG and rituximab or combination of PP, lowdose IVIG, rituximab and pretransplant anti-thymocyte globulin can producea negative crossmatch at a rate of 84% and 88% with low acute AMR 37% and 29% respectively. Bortezomib induces endoplasmic reticulum stress, NFjB inhibition and apoptosis in normal and transformed plasma cells. It was associated with a low acute rejection rate (18.8%). Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation. It is associated with AMR rate of 7.7% but it is expensive ($21 000 per dose) and there is risk of developmentof invasive infections with encapsulated organisms. Interleukin (IL)-6 is a pleiotropic cytokine that has powerful stimulatory effects on B cells and plasma cells and is responsible, in conjunction with other cytokines, for normal antibody production and is a mediator of allograft rejection. Tocilizumab (TCZ) a humanized monoclonal antibody directed at the IL-6 receptor. TCZ and IVIg showed promising effects in in unresponsive patients to desensitization with IVIg and Rituximab. IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS) that cleaves all four human subclasses of IgG preventing IgG-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity. It induces the crossmatches to became negative. Daratumumab is an IgG1j human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts. Animals treated with daratumumab had significantly reduced DSA levels compared to untreated controls. However, the reduction was not maintained and rapid rebound of antibodies developed with profound rejection.
Benefits of desensitization
1. It reduce the time on waiting list 2. provide a chance for those who are highly sensitized 3. Due to limited number of organs, desensitization offer a chance for meeting the required organs
Long-term risks of desensitization
Desensitization is associated with higher rates of infection and immunosuppressant related complications including malignancies. The survival rate up to 8 years of recipient of incompatible live donors was better in a multi-centre analysis of 1025 patients when compared with those remained on the waiting list or received a transplant from a deceased donor (waiting list or transplant control group) and controls who remained on the waiting list but did not receive a transplant (waiting list only control group). A study in UK showed similar survival. There was selection bias in the former study. In spite of that, desensitization is not inferior to other options. Some studies found no difference in bacterial, viral, fungal or serious infections over an 18-month follow-up period . In general, Multivariable risk factor analysis showed that desensitization was significant risk factor for infection-related mortality. Compared to ABO or HLA incompatibility .
Cost-effectiveness of desensitization
Drawbacks are medical complexity, high cost with a 42% increase in the cost of care. Benefits are longer survival and a reduced need for haemodialysis. Over 10 years, the incremental cost-effectiveness of desensitization was $80 486 per quality-adjusted life year while compatible living donor cost $39 939 per quality-adjusted life year. The mean survival was longer in the incompatible living donor kidney transplant (5.47 years vs.4.03).
Ben Lomatayo
3 years ago
Desensitization is the techniques of reduction/elimination of DSAto prevent hyper-acute rejection and permit successful transplantation. Two process ; antibody removal by PP and use of agents to reduce antibody production or block their actions[16]
Desensitization techniques ;
Plasmapheresis(PP) ; Remove antibodies from circulation
Problems ; 1. Re-bound[16] 2. Doesn’t affect ongoing anti-body production by plasma cells 23. Cannot be used alone Complications ; 1. Catherter related problems 2.Hypo-tension 3. Coagulopathy( removal of clotting factors and other proteins) 4. Thrombocytopenae 5. Hypocalcemia
2.Intravenous immunoglobulin(IVIG) ; Inhibit lymphocytes proliferation,inhibit cytokine release, inhibit complement activation, apoptosis of B cells, anti-idiotypic antibodies[17,18] Two protocols ; 1.Low dose 100mg/kg use with alternate PP 2. High dose 2g/kg protocol was modified to include ATG + Rituximab + Splenectomy High dose IVIG causes small reduction in PRA levels ~ 10% compared to placebo.
3.Bortezomib(BTZ) ; Is a proteasome inhibitor(PI) that causes endoplasmic reticulum stress, NFkB inhibition , apoptosis of plasma cells. i.e depletes plasma cell and therefore prevent antibody production[39,40]. up now the evidence is not conclusive for the use of PI BZT
4.Eculizumab ; Inhibit C5 & prevent terminal complement activation. It demonstrated efficacy in the prevention of AMR in highly sensitized patients[42]
Limitaion ; 1. Very costly drug 21,000 US dollars per dose 2. High risk of infections with encapsulating organisms
5.Tocilizumab (TCZ) ; IL-6 inhibitor and potential de-sensitizing agents( IL-6 is a pleitropic cytokine with strong stimulatory effect on B cells & plasma cells and it is a key cytokine in anti-body production. IL-6 has been identified as a potential mediator of allograft rejection[46,47]. More studies are needed to confirm the efficay of TCZ
6.IgG-degrading enzyme derived from streptococcus pyogenes(IdeS) ; Cleaves IgG molecules at the FC region and thereby preventing two things ; 1. CDC 2. Ab -dependent cellular cyto-toxicity. This two mechanism are the bases of ABMR. Data from US & Sweden showed IdeS eliminated DSAs and allowed transplantation in almost all the participants. AMR occur in alomost 50% of the patients at week 2 to 5 months and all the patients responded well to treatment[50]
7.Daratumumab ; Anti-CD38 & inhibit the maturation of CD 38 expressing cells like plasma cells & plasma blast. It has been tried in animal studies(non-human primate)[51] it reduced DSA significantly but with rapid re-bound and severe rejection.
Benefits of desensitization ; In broad terms ;
1.Permit access to transplantation of highly sensitized patient 2.Improve survival & quality of life
Two large studies examined this matter one from USA & the the other one from UK. The USA cohort showed higher survival rate among desensitized group compared to control group(wait list or transplant group, or wait list only group). The UK data showed NO difference in survival among all groups. The difference could be due to ;
Differences in definition of desensitization
Different populations
Different matching methods
Different waiting time
Different survival rates of dialysis patients
Different patient selection criteria
Long-term risk of desensitization ; Most of data are short -termed regarding
desensitization, so it is not easy to make conclusion about the long -term risk of this technique.
Desensitization by it self is a form of extra or additional immunosuppression and therefore the valid concerns are ;
Risk of infections ( in one study prevalence of CMV & BKV was the same as in standard transplant recipient [25] )
Risk of malignancy
Cost-effectiveness of desensitization ;
Desensitization added 42% extra cost and this increase if CDC +ve (58%) compared to FCXM +ve (38%)
Incremental cost-effectiveness of desensitization was estimated to be 80,846 US dollars per quality-adjusted life year.
Compatible living donor transplant was estimated to cost 39,939 US dollars per quality-adjusted life year
When compared with long-term dialysis treatment, desensitization offer improved survival and are cost-effective given nationally accepted benchmarks
Tahani Ashmaig
3 years ago
☆Desensitization strategies: is it worth it?
_________________________________________
▪︎Desensitization therapies target removing and/or reducing donor- pecific antibodies (DSA) prior to transplantation.
■Desensitization protocols:
______________________________
1) Plasmapheresis (PP):
▪︎ It removes antibodies from the circulation. combined with low dose IVIG
▪︎ Does not affect ongoing antibody production by plasma cells and, hence, is a
poor treatment choice for desensitization as sole therapy.
▪︎Coagulopathy, hypocalcemia, thrombocytopenia, hypotension and catheter-related infection and sepsis are the main side effects of PP.
2) Intravenous Immunoglobulins (IVIgs)
▪︎ Inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation .
▪︎IVIg-based desensitization can be divided into two general approaches: combined
with alternate day PP at a low dose ; or used at a high dose
2.1) Low-dose IVIg (100mg/ kg) and Plasma
pharesis
▪︎ Used for ESRD patients with living donors and high levels of DSA.
▪︎Depending on the titres of antibodies patients undergo varying numbers of PP sessions (higher titres, more sessions of PP) followed with the infusion of IVIg.
▪︎Because of the risk of AMR, this protoco
was modified to:→ Low-dose IVIg and Plasma pharesis +Anti-thymocyte globulin + rituximab + splenectomy.
2.2) High-dose IVIg (1–2 g/kg)
▪︎ Used for highly sensitized patients (cPRA > 50%)
▪︎ High-dose IVIg (2 g/kg) + rituximab are used for more benefit.
●Notes: From the above protocols:
• PP/low-dose IVIG and rituximab demonstrated more success in abrogating positive crossmatch and lower acute rejection rates
• No regimen was completely effective in preventing AMR.
☆Other agents used in desensitization include:
_______________________________________________
1) Bortezomib (BTZ):
Is a proteasome inhibitor (PI) which might deplete antibody-secreting long-lived plasma cells and have an impact on DSA production.
2) Eculizumab:
Is a humanized monoclonal antibody that block C5 activation. But, it is unfortunately quite expensive and increase the risk of development of invasive infections with encapsulated organisms
3) Tocilizumab (TCZ) + IVIg:
– Reduce and eliminate anti-HLA antibodies
-TCZ is a humanized monoclonal antibody directed at the IL-6 receptor.
4) IgG-degrading enzyme:
– Derived from Streptococcus pyogenes (IdeS)
– Cleaves all four human subclasses of IgG.
5) Daratumumab:
Binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts.
■ Benefits of desensitization protocols:
___________________________________________
▪︎Can be considered for patients with rare HLA types, uncommon HLA antigens or very high sensitization levels, when no matches from kidney exchange programmes are forthcoming after a period of time, given the longer expected survival and improved quality of life.
▪︎Desensitization can increase access to both living and deceased donor transplants and can be used individually or in combination with kidney paired donation.
■Long-term risks of desensitization:
_____________________________________
More studies and long term follow up are needed to arrive at stronger conclusion that desensitization protocols increase the risk of infection and immunosuppression related complications including malignancies.
■Cost effectiveness:
_____________________
▪︎ Desensitization therapies increase the cost of the transplant procedure. But, when compared with long-term dialysis treatment, these strategies offer improved survival and are cost-effective given nationally accepted benchmarks.
Jamila Elamouri
3 years ago
Q1- The different techniques of desensitization?
1- Plasmapheresis:
Action: removes antibodies from the circulation
Disadvantage:
· it is not specific as it removes all plasma proteins
· its removal is only temporal, as antibodies rebound following re-equilibration between intravascular and interstitial compartments.
· It has no effect on the antibody-producing plasma cell. So it cannot be used as sole therapy
Side effects:
· Coagulopathy, hypocalcemia, thrombocytopenia, hypotension, and catheter-related infection
2- Intravenous immunoglobulin (IVIG):
Action:
a- inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, and complement activation.
b- Induce B-cell apoptosis
It is used with PP, and the IVIG- based desensitization can be divided into two general approaches:
i- Low dose (100 mg/kg) with alternate day PP
Used for ESRD with living donors and high DSA. The number of sessions depends on the DSA titer.
ii- High dose IVIG (2 g/kg): used for patients on the deceased donor waiting list, and highly sensitized.
Both regimes had been combined with rituximab which additive benefit. However; AMR is still high
3- Bortezomib (BTZ): is a proteasome inhibitor (PI)
Action: apoptosis in plasma cells. might deplete antibody-secreting long-lived plasma cells and have an impact on DSA production
4- Eculizumab: is a humanized monoclonal antibody
Action: blocks cleavage of C5 complement, so prevent terminal complement activation. Highly sensitized recipients receiving it posttransplant have a lower rate of AMR 7.7% vs 41.2% for PP protocol in one study.
Disadvantage: quite expensive, and high risk of infection with encapsulated organisms.
5- Tocilizumab (TCZ) monoclonal antibody directed against IL-6 receptor.
6- IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS)
Action: cleaves all four human subclasses of IgG and has recently been used as an agent for desensitization. Therefore interfere with receptor binding and complement binding.
It prevents the occurrence of IgG-mediated antibody-dependent cellular cytotoxicity and complement-mediated
cytotoxicity.
7- Daratumumab is an IgG1j human mAb
Action: it binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts.
The reduction of DSAs with it also was not maintained and rebound rapidly with profound rejection Q2- The benefit of desensitization:
It allows the transplantation of highly sensitized patients. Q3- Long term risks of desensitization
Risk of infection, malignancy, development of motor deficits, memory loss and other neurologic symptoms (to rule out reactivation of polyoma JC virus). Q4- Cost-effectiveness of desensitization?
While desensitization treatments increase the cost of transplants, the overall economic impact needs to be considered in light of longer survival and a reduced need for haemodialysis.
Radwa Ellisy
3 years ago
The different techniques of desensitization? 1-Plasmapheresis
*Mechanism: nonspecific removal of circulating Abs
*Drawbacks:
a. only short-lived + rebound increase of antibodies after equilibrium
b. coagulopathy,
c. hypocalcemia,
d. thrombocytopenia
e. hypotension
f. catheter-related infection and sepsis. 2- Intravenous immunoglobulin (IVIg):purified IgG from pooled donors
Mechanism:
*Induce B-cell apoptosis
* Inhibit
– T- and B-cell proliferation
– cytokine production
– dendritic cells maturation
– complement activation 3- rituximab: anti-CD-20
Other: 4- Bortezomib:
*Mechanism: proteasome inhibitor induces plasma cell endoplasmic reticulum stress, NFkB inhibition
and apoptosis i.e. depletion of long-lived plasma cell secreting abs 5-Eculizumab:
*Mechanism: monoclonal antibody blocks cleavage of C5 ( terminal complement activation).
-i.e. prevents AMR in recipients with positive crossmatch against their living donor compared to standard of care.
*Drawbacks:
a. Serious encapsulated organism infection
b. costly 6-Tocilizumab: a humanized monoclonal antibody directed at the IL-6 receptor to prevent the stimulatory effect on B cell
Studied with IVIG 7-IgG-degrading enzyme from Streptococcus pyogenes (IdeS) :
Mechanism: cleaves IgG subclasses 8- Daratumumab is ani CD38 (expressed in plasma cell and plasmablast)
protocols:
-plasmapheresis is not used alone high dose IVIG
-plasmapheresis with low dose IVIG (100mg/Kg):
-plasmapheresis with low dose IVIG (100mg/Kg) +rituximab
-plasmapheresis with low dose IVIG (100mg/Kg) +rituximab+ ATG In conclusion: the quality of evidence comparing one protocol for sensitization to another is poor, no universal desensitization strategy that allows transplantation in recipients with significant levels of anti-HLA antibody to their intended donor or a positive crossmatch. Benefits of desensitization:
Of value in patients with high cPRA >80%
Better survival than being on dialysis or receiving a deceased donor`s graft Long-term risks of desensitization
-The most common cause of death was infection-related.
-Higher rate for AMR, poorer graft survival compared to non-sensitized patient Cost-effectiveness of desensitization:
Incompatible living donor transplant was associated with a 42% increase in the cost of care, especially in positive CDC XM this is weighted against the longer survival and dialysis-free period. Paired kidney donation is preferred as cost-effective and
Alternatives to desensitization: kidney paired donation
Weam Elnazer
3 years ago
The various desensitization approaches are as follows:
Plasmapheresis is a procedure that removes plasma from the bloodstream.
This procedure eliminates antibodies from the bloodstream at the same time as other plasma proteins that function as clotting factors, resulting in adverse effects such as coagulopathy, hypocalcemia, thrombocytopenia, hypotension, catheter-related infection, and sepsis, among others.
Inhibition of T- and B-cell proliferation, cytokine generation, maturation of dendritic cells, and inhibition of complement activation are some of the ways IVIG works.
According to research released by the Mayo Clinic, the combination of PP/low-dose IVIG and rituximab resulted in decreased incidence of AMR when compared to other regimens.
In the meantime, there is no exact regimen that may be prescribed.
Bortezomib (BTZ) is a proteasome inhibitor that works by reducing antibody-secreting plasma cells, which in turn affects DSA synthesis, among other things.
There was no evidence of a decrease in c PRA levels.
Eculizumab is a humanized monoclonal antibody that inhibits the cleavage of C5 and prevents the activation of the terminal complement cascade in the body.
It protected kidney transplant patients who had a positive crossmatch against their live donor from developing antimicrobial resistance (AMR).
Its most serious adverse effect is the risk of infection with encapsulated organisms, as well as the fact that it is a costly medication.
Tocilizumab (TCZ) is a humanized monoclonal antibody directed against the interleukin-6 (IL-6) receptor. The combination of TCZ and IVIg seems to have favourable effects on desensitization.
It is produced from Streptococcus pyrogenes and acts on FC receptors of IgG to inhibit antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity caused by IgG. It is also used to treat autoimmune diseases.
Its promising agent has been tested in two large centres in a desensitization protocol for highly HLA sensitized patients, with successful depletion of DSA but with a risk of DSA rebound and AMR reported in a significant number of recipients. Ides were used with different induction protocols, including hoarse ATG from a European centre and alemtuzumab from a US centre, all of whom received homogenous triple maintenance therapy.
The advantages of desensitization:
some centres have reported good early graft and patient survival within 1-3 years after desensitization, while others have reported no difference in graft survival when compared to the matched sensitized control group; this diversity in the results is due to the heterogeneity of these studies by using different definitions of desensitization.
The risk of desensitisation/;
immunosuppression raising the obvious concerns of infection, CMV, BK
immunosuppression related complications including malignancies.
Desensitization is a cost-effective treatment option:
It was discovered that an incompatible live donor transplant resulted in an increase in the cost of treatment.
When comparing patients with positive cytotoxic crossmatch to those with positive flow crossmatch, the cost was higher in the former group.
MICHAEL Farag
3 years ago
The different techniques of desensitisation
Desensitization protocols have typically combined an approach of removing circulating DSA with plasmapheresis (PP) , combined with agents that decrease antibody production, or ones that block their actions as
1-Intravenous immunoglobulin (IVIg)
inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells,
induce B-cell apoptosis and inhibit complement activation. IVIg-based desensitization
can be divided into two general approaches:
– Combined with alternate day PP at a low dose (100 mg/kg); used for ESRD patients with living donors and high levels of DSA. Depending on the titres of antibodies patients undergo varying numbers of PP sessions (higher titres, more sessions of PP) followed with the infusion of IVIg. The low-dose IVIg with PP, protocol was modified to include anti-thymocyte globulin for induction along with the addition of rituximab and splenectomy in an attempt to decrease high acute rejection rates.
– High-dose IVIg-based protocols (2 g/kg)
2- Bortezomib (BTZ) is a proteasome inhibitor (PI) that induces endoplasmic reticulum stress, NFkB inhibition and apoptosis in normal and transformed plasma cells
3- Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation. It has been shown to be efficacious in the prevention AMR in renal transplant recipients who had a positive crossmatch against their living donor.
4- Interleukin (IL)-6 is a pleiotropic cytokine that has powerful stimulatory effects on B cells and plasma cells and is responsible, in conjunction with other cytokines, for normal antibody production. It has also been recognized as an important mediator of allograft rejection
5- Tocilizumab (TCZ) a humanized monoclonal antibody directed at the IL-6 receptor has also been studied as a potential desensitization agent.
6- IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS) that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization.
7- Daratumumab is an IgG1k human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts but still under experiments.
Benefits of desensitization
Reduce/eliminate DSA, thereby preventing hyperacute rejection and allowing a successful transplantation.
In a study at US, recipients of kidney transplants from incompatible live donors had a higher survival rate than either the group who remained on the waiting list or received a transplant from a deceased donor, or, the group who remained on the waiting list but did not receive a transplant. While the study in UK didn’t show any difference. However; Comparing these two studies is difficult due to many of considerations. So still the overall benefits from desensitization need more studies.
Long-term risks of desensitization
– the risk of development of invasive infections with encapsulated organisms during eculizumab therapy due to which certain vaccinations are pre requisite. Desensitization increases the risk of infection in general
– malignancies
long-term risks from desensitization still needs more thorough and long term follow up studies.
Cost-effectiveness of desensitization
While desensitization treatments increase the cost of transplant, the overall economic impact needs to be considered in light of longer survival and a reduced need for hemodialysis.
Drtalib Salman
3 years ago
The different techniques of desensitization:
-Plasmapheresis:
removes antibodies from the circulation.
Intravenous immunoglobulin (IVIg)
Has been shown to inhibit T- and B-cell proliferation.
-Rituximab
The authors concluded that PP/low-dose IVIG and rituximab demonstrated more success in abrogating positive crossmatch and lower acute rejection rates, but no regimen was completely effective in preventing AMR. —Bortezomib (BTZ) :
is a proteasome inhibitor (PI) that induces endoplasmic reticulum stress, NFjB inhibition
more study need for there safety and efficacy .
Eculizumab
is a humanized monoclonal antibody , It has been shown to be efficacious in the prevention AMR in renal transplant recipients ,It is unfortunately quite expensive , Another consideration is the risk of development of invasive infections with encapsulated organisms .
Tocilizumab(TCZ) :
a humanized monoclonal antibody directed at the IL-6 receptor has also been studied as a potential desensitization agent. A phase I/II pilot study was performed with TCZ and IVIg to reduce and eliminate anti-HLA antibodies as well as test its safety and efficacy in desensitization.
-IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS):
Cleaves all four human subclasses of IgG has recently been used as an agent for desensitization, different study all crossmatches became negative post-IdeS and the patients underwent successful transplantation.
Benefits of desensitization:
A multi-center analysis on the survival ,the results across 22 centers in the US with 1025 recipients . Their outcomes were matched with controls who remained on the waiting list or received a transplant from a deceased donor (waiting list or transplant control group) and controls who remained on the waiting list but did not receive a transplant (waiting list only control group). Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year.
Long-term risks of desensitization:
Risk for malignancy.
Infection related mortality.
Cost-effectiveness of desensitization:
The cost of desensitization transplant regimen 40 percent more than transplantation of non sensitized patient but still lower than those stay on hemodialysis .
Heba Wagdy
3 years ago
The different techniques of desensitization.
Plasmapheresis:
Removes antibodies from circulation with subsequent decrease in all plasma proteins including clotting factors
Can’t be used alone as has no impact on antibody production by plasma cells
Antibodies rebound shortly due to re-equilibration between intravascular and interstitial compartments.
Side effects include, coagulopathy, hypocalcemia, thrombocytopenia sepsis and catheter relayed infections. IVIG:
Low dose IVIG and plasmapheresis: was associated with high incidence of acute AMR
High dose IVIG: The efficacy of IVIG alone is not well determined and was shown to be inferior to plasmapheresis and low dose IVIG Plasmapheresis, low dose IVIG and rituximab:
more successful in rendering positive crossmatch negative with lower acute rejection rates. Bortezomib (BTZ):
Proteasome inhibitor, It is suggested that BTZ may deplete antibody secreting long lived plasma cells and affect DSA production, but it couldn’t change cPRA in sensitized recipients. Eculizumab:
Monoclonal antibody, blocks cleavage of C5 and prevent terminal complement activation.
It was efficient in prevention of AMR in recipients with positive crossmatch against their live donor.
Quite expensive and is associated with risk of infection with encapsulated organism Tocilizumab (TCZ):
Humanized monoclonal antibody directed at IL-6 receptor
Large control studies are needed to determine its efficacy. IgG degrading enzyme derived from streptococcus pyogenes (IdeS):
Prevent IgG mediated antibody dependent cellular cytotoxicity and complement mediated cytotoxicity
2 studies showed that it could reduce or eliminate DSA and permit HLA incompatible transplant in highly sensitized patients. Daratumumab:
Monoclonal antibody, still tested in nonhuman primate .
Benefits of desensitization
A multi-center analysis showed that patients who had HLA incompatible transplant had higher survival rates than patients who remained on dialysis and than those who remained on waiting list and received deceased donor transplant
Another analysis showed no difference in survival between patients who had HLA incompatible transplant and patients who remained on waiting list.
Long-term risks of desensitization:
Determination of long term risks is not possible as most studies are short termed
A nationwide cohort analysis showed lower survival rate in incompatible transplants compared to standard transplant, the most common cause was infection related mortality
Desensitization attempts were more significant risk factor for infection than ABO and HLA incompatibility.
Further studies are needed to determine long term risks.
Cost-effectiveness of desensitization
Desensitization significantly increase the cost of transplantation, however the longer survival and reduced need for hemodialysis should be considered
Incompatible living donor kidney transplant is associated with greater mean cost of care and longer mean survival.
Mohamed Mohamed
3 years ago
III. Desensitization strategies: is it worth it?
Discuss the following: Various techniques of desensitisation Introduction: Transplant options for highly sensitized patients: 1. Waiting for a compatible deceased donor (may take years without a suitable donor ever being found) 2. Living donor transplant if the immunological barrier can be successfully dealt with. 3. Enrolling in KPD program 4. Undergo a desensitization procedure.
Techniques of Desensitization A. Plasmapheresis (PP):
– Removes antibodies from the circulation.
– All plasma proteins are also reduced
– Antibodies can rebound to pretreatment levels
– Does not prevent antibody production by plasma cells &(not suitable as a sole therapy)
– Adverse effects: i. Coagulopathy ii. Hypocalcemia iii. Thrombocytopenia iv. Hypotension v. Catheter-related infection & sepsis. B. Intravenous immunoglobulin (IVIg) :
– Derived from the gamma globulin fraction of plasma from pooled donors
– Inhibits T- & B-cell proliferation, cytokine production & inhibit complement activation
– IVIg-based desensitization approaches: (i) Combined with alternate day PP at a low dose (100 mg/kg); or at high dose (1–2 g/kg). (ii) Modified low-dose IVIg with PP protocol to include ATG for induction + rituximab & splenectomy to reduce high rejection rates. C. Other agents used in desensitization: 1. Anti-CD 20 monoclonal antibodies – Rituximab depletes B cells & minimize the memory response. – Reduce the PRA & increase the rate of transplantation – Reduce FCMX MCS. – 50% develop early AMR(<30 days posttransplant) – Obinutuzumab, a 3rd generation anti-CD20, has recently been studied in desensitization. It is more potent in depleating B cells. 2. Bortezomib is a reversible proteasome inhibitor. It depletes plasma cells causing modest antibody reductions. Carfilzomib, an irreversible proteasome inhibitor, has similar but transient effects. 3. Complement Inhibitors Eculizumab is a terminal complement inhibitor(anti C5). It is very costly & carries the risk of invasive infections. 4.Tocilizumab, an IL-6 receptor blocker humanized monoclonal antibody, has been studied as a potential desensitization agent. 5.Imlifidase, an IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS) that cleaves all 4 human subclasses of IgG has recently been used for de- sensitization 6.Daratumumab, an ant-CD 38 monoclonal antibody has been tested in non human primates. Challenges with the described desensitization agents: – Poor quality of evidence comparing one agent to another. – No single strategy that can universally allow transplantation in the face of significant levels of DSAs or a positive crossmatch. – Unacceptable rates of AMR are reported. – A challenging question is which is better for sensitized patients? To wait on dialysis or undergo desensitization. Benefits of desensitization: 1. Increases sensitized patients access to transplantation by decreasing cPRA & the number of unacceptable antigens for listing. 2. Patients with a cPRA of > 99.9% have the greatest need for desensitization. 3. Patients with a cPRA < 98% with an incompatible living donor or those on the waiting list for several years may also benefit from desensitization.
4. Decreases DSA prior transplantation in patients with positive XM to reduce the risk of immediate graft loss from hyperacute rejection. Long-term risks of desensitization: Difficult to determine because most of the studies that looked into this issue were short term. Overall immunosuppression raises concerns of infections & malignancies. Reduced survival, mostly related to infections, also reported. Cost-effectiveness of desensitization: There is increased cost imposed by desensitization treatments, however considering longer survival & reduced need for dialysis makes it cost effective.
amiri elaf
3 years ago
The different techniques of desensitisation
# Desensitization protocols have typically combined an approach of removing circulating DSA with plasmapheresis (PP) combined with agents that decrease antibody production, or ones that block their actions.
# Plasmapheresis :
– Removes antibodies from the circulation, this removal is only short lived with antibodies rebounding to pretreatment levels
– PP does not affect ongoing antibody production by plasma cells .
– poor treatment choice for desensitization if used alone .
# Intravenous immunoglobulin (IVIg)
-Inhibit T and B cell proliferation, cytokine production, maturation of dendritic cells, induce B cell apoptosis and inhibit complement activation
– It is use in combination with PP in crossmatch incompatible living donor
transplant .
– IVIG can be divided into two :
* combined with alternate day PP at a low dose (100 mg/kg)
* used at a high dose (2 g/kg).
– Low dose IVIg and PP protocols have been used for patients with living donors and high levels of DSA.
* Using low dose IVIg with PP, AMR has been reported to be as high as 36% with 100% 1 year graft survival
* The low dose IVIg with PP protocol was modified to include ATG, rituximab and splenectomy to decrease high acute rejection rates.
* A report from the Mayo clinic concluded that PP/low-dose IVIG and rituximab are more success in lower acute rejection rates, but no regimen was completely effective in preventing AMR.
# Bortezomib (BTZ) :
– is a proteasome inhibitor that induces endoplasmic reticulum stress, NFjB inhibition and apoptosis in normal and transformed plasma cells and might deplete antibody secreting long lived plasma cells and have an impact on DSA production.
– studies showed use of many sessions of BTZ, non developed a negative cross match and the cPRA was unchanged in all patients.
# Eculizumab:
– is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation.
– It has been shown to be efficacious in the prevention AMR in recipients who had a positive crossmatch against their living donor.
-Study showed benefit for eculizumab compared with standard of care (SOC) in preventing acute AMR in senitized recipients.
– It expensive and has risk ofdevelopment of invasive infections with encapsulated organisms so vaccinations are pre requisite.
# Tocilizumab (TCZ) :
-A humanized monoclonal antibody directed at the IL-6 receptor has also been studied as a potential desensitization agent.
# IgG-degrading enzyme:
– Derived from Streptococcus pyogenes (IdeS) that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization.
– In study IdeS reduced or eliminated DSAs and permitted HLAincompatible transplantation in 24 of 25 patients. AMR
occurred in 10 patients at 2 weeks to 5 months after transplantation.
# Daratumumab :
– Is an IgG1j human mAb that binds to
CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts.
– There is no desensitization strategy that can universally allow transplantation in the presence of significant levels of anti-HLA antibody to the donor or a positive crossmatch.
# Benefits of desensitization:
– Despite the challenging that facing highly sensitized patients it is better for going to desensitization than waiting on dialysis , it given the longer expected survival and improved quality of life.
– Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year, 3 years, 5 years and 8 years.
#Long-term risks of desensitization
-Infection: bacterial, viral, fungal or serious infections
– malignancies
# Cost-effectiveness of desensitization
While desensitization treatments increase the cost of transplant, the overall economic impact needs to be considered in light of longer survival and a reduced need for haemodialysis.
Amit Sharma
3 years ago
The different techniques of desensitization
The aim of any desensitization protocol is to achieve a successful transplantation by preventing hyperacute rejection. This involves preventing formation and action of antibodies as well as removing the formed antibodies from circulation. Various methods used for desensitization include:
1) Plasmapheresis alone: Non specific removal of antibodies, which is short lived (due to rebound) and hence not successful.
2) Intravenous immunoglobulin (IVIG): IVIG can be used in either low dose or high does. a) Low dose IVIG (100 mg/kg) with Plasmapheresis: It has been shown to have AMR rates of 36% with 100% graft survival at 1 year. b) Low dose IVIG with plasmapheresis and ATG, rituximab and splenectomy: It has been associated with AMR in 43% and 39% at 15 months and 22 months with graft survival of approximately 80% at 15 months. c) High dose (2 g/kg) IVIG alone: It is used in cadaveric transplant program, associated with slight decrease in PRA levels and increased transplantation rates 2 years post therapy. AMR rates were 31% with high 2 year patient and graft survival. d) High dose IVIG with rituximab: It is associated with 50% acute rejection and 30% AMR while the 2 year patient and graft survival is 95% and 84% respectively.
Low dose IVIG and plasmapheresis with or without rituximab has shown results superior to use of high dose IVIG alone.
3) Bortezomib: It is a proteasome inhibitor causing apoptosis of plasma cells. Its use saw transplant of 43% of sensitized patients with 12.5% developing de novo DSAs and 18.8% acute rejection.
4) Eculizumab: It is an antibody blocking cleavage of C5. If used in addition to IVIG and plasmapheresis, has shown risk of AMR in range of 7.7% to 11.8% as compared to 21.6% to 41.2% seen with IVIG and plasmapheresis, but with an increased risk of invasive infections.
5) Tocilizumab: It is an antibody against IL-2 receptor which, when used with IVIG in patients unresponsive to IVIG and rituximab, showed good results post-transplant with no AMR at 6 months and good graft function at 1 year post-transplant.
6) IgG degrading enzyme derived from Streptococcus pyogenes (IdeS): It causes proteolysis at Fc region of IgG. Its use has been shown to be associated with approximately 40% AMR which were treated. Long term effects including infections and malignancies need to be evaluated.
7) Daratumumab: It is a CD38 inhibitor and has been used in non-human primates showing marked reduction in antibody levels which was short-lived, hence associated with severe rejections.
Benefits of desensitization
Desensitization helps a highly sensitized patient, who is otherwise not getting a living or cadaveric donor and is expected to remain on wait-list for a long time, to get a kidney transplant. A kidney transplant has been shown to be associated with better quality of life, as well as better survival rates with respect to patients remaining on wait-list.
Long-term risks of desensitization
The most important long-term concerns with desensitization include infections and malignancies. In comparison to non-desensitized patients, use of IVIG, plasmapheresis and rituximab desensitization has similar infection rates while eculizumab use increases the infection rates by 50%. Reduced patient survival due to increased infections has been observed in a large study.
Cost-effectiveness of desensitization
Desensitization increases the cost of care by 42%, more so in a CDC positive patient (by 58%) than a flow cytometry crossmatch positive patient (38%). There is an increased mean cost of care in comparison to patients remaining on dialysis.
Mahmud Islam
3 years ago
The different techniques of desensitization:
plasmapheresis, IVIG (low dose 100 mg/kg combined with plasmapheresis or high dose alone 2 g/kg, Rituximab, Bortezomib, Eculizumab, Tocilizumab, IgG-degrading enzyme)
plasmapheresis removes preformed antibodies but a rebound is seen later as it does not affect ongoing production of antibodies
IVIG: inhibits proliferation of T and B cells as well as inhibition of dendritic cells and complement activation.
Bortezomib. affects plasma cells responsible for antibody production
eculizumab inhibits complement
Tocilizumab inhibits IL-6 which is a powerful B and T cell stimulator
Benifits of desensitization: shortening of waiting on waiting lists give the chance for patients who are of low chance due to high sensitization
Long-term risks of desensitization
increased incidence of infection and malignancy due to high dose immunosuppression
Cost-effectiveness of desensitization :
The cost is doubled in comparison to the acceptable or compatible donor (as per year)
Ibrahim Omar
3 years ago
The different techniques of desensitisation :
1- palsmapharesis :
an extracorporeal removal of related allo-antibodies.
short-lived with antibodies rebounding.
no effect on ongoing antibody production.
serious side effects including coagulopathy, hypocalcemia, thrombocytopenia, hypotension and catheter related infections.
2- IVIG :
it is derived from gamma globulin fraction of plasma.
it has the following therapeutic effects :
a- inhibition of T-cell and B-cell proliferation.
b- decreasing cytokine production.
c- inducing B-cell apoptosis.
d- inhibition of maturation of dentritic cells.
e- inhibition of complement activation.
it was 1st used in combination with plasmapharesis in incompatible living related grafts
3- Rituximab:
it is a monoclonal antibody, acting as anti-CD20 on plasma cells.
4- ATG :
it is polyclonal antibodies, acting as a T-cell depleting agent.
5- Borteozomab :
it is a proteosome inhibitor, acting by causing endoplasmic reticulum stress.
6- Eculizumab :
acting by blocking cleavage of the human complement component C5 and so prevention of terminal complement activation.
7- Tocilizumab :
it works by blocking IL-6 receptor.
8- IgG-degrading enzyme :
it is derived from strept. pyogenes.
it works by cleaving all 4 human classes of IgG.
9- Paratumumab :
it works by blocking CD38 in plasma cells and so decreasing antibody production.
Benefits of desensitization :
it offers the best hope of transplantation for very highly sensitized patients and those without living donors.
it results in an improvement in patient survival as compared to maintenance hemodialysis/peritoneal dialysis
Long-term risks of desensitization :
the 2 main risks are similar to those of other immunosuppressive therapies.
1- more susceptibility to infections and flare up of latent viral infections as CMV, EBV,BK polyoma virus, JC virus, Parvovirus-19,…
2- more incidence of malignancies.
Cost-effectiveness of desensitization :
despite the cost of desensitization is very high, the cost-benefit ratio is favourable as compared with maintenance hemodialysis with its side effects, morbidities and higher mortalities.
Filipe prohaska Batista
3 years ago
The different techniques of desensitisation
Plasma Exchange
IVIg high and low dosis
Rituximab
Bortezomib
Eculizumab
IgG-degradating enzyme derived from Streptococcus pyogenes (IdeS)
Tocilizumab
Daratumumab
The combination of these protocols must be individualized depending on the immunological status of the patient and the peculiarities of the graft and local protocols and the availability of institutional costs.
Classically, the combination of rituximab, IVIg and plasma exchange is currently the most used and is more consistent in the literature.
Benefits of desensitization
Need to decrease DSA in patients with high rates of antibodies to antigens in organs available for donation. Patients are usually on the waiting list for a long period, low quality of life, high risk of hemodialysis catheter infections, unnecessary invasive manipulation, high cost, and poor survival.
Long-term risks of desensitization
The possibility of risks of infection and neoplasms in the long term is considered. Although rituximab and plasma exchange are related to infections, immunoglobulin tends to compensate for the humoral response, especially against viruses. Eculizumab is closely related to serious infections by encapsulated bacteria, for this reason vaccination and quinolone prophylaxis are necessary to minimize this risk. De novo lesions in the renal graft by costimulation by B and T lymphocytes tend to appear after the first year of transplantation and should be considered in case of worsening renal function.
Cost-effectiveness of desensitization
Despite the higher initial cost of desensitizing the patient with high-cost medications, two important facts should be kept in mind. The first is that the cost of remaining on hemodialysis waiting for an organ that may become available is much higher in the long term. The second is the quality of life gain associated with prolonged survival.
Mohamed Saad
3 years ago
Desensitization strategies: is –it worth it? 1-Techniques of desensitization:
Desensitization is simply depends on removal of performed DSA pre-transplant by PEX and to prevent /or reduce the formation of other antibodies.
=Plasmapheresis is depending on removal of antibodies from circulation and re-bounding of antibodies occur again from interstitial and others from plasma cells, side effects mainly from removal of all plasma proteins.
=Intravenous immunoglobulin (IVIg):two protocol low and high based IVIg with PEX.
A-Low-dose IVIg and PP protocols (100 mg/kg).
B-High-dose IVIg and PP protocols (1-2gm/kg) .
=IVIg + PP protocols +Rituximab.
=Bortezomib (BTZ): deplete antibody-secreting long-lived plasma cells and have an impact on DSA production.
=Eculizumab: prevent terminal complement activation by blocking cleavage of C5, has a good role in preventing AMR in highly sensitized patients but still so costly and associated with high risk if encapsulated organism infection.
=Tocilizumab (TCZ) and IVIg.
=IgG-degrading enzyme derived from Streptococcus pyogenes (Ides).
=Daratumumab is an IgG1j human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasma blasts. 2-Benefits of desensitization.
Recipients of kidney transplants from incompatible live donors had a higher survival rate than either who remained on the waiting list or received a transplant from a deceased donor. 3-Long-term risks of desensitization
Infection and malignancy is considered the most common long-term risks of desensitization but still need more studies with long term follow up. 4-Cost-effectiveness of desensitization:
Desensitization protocols increase cost of transplant procedure but still we should keep in mind the longer survival and reducing duration of hemodialysis.
Last edited 3 years ago by Mohamed Saad
Wael Jebur
3 years ago
Techniques of desensitization:
Generally desensitization procedure involve removal of the DSAs from the serum of receipts who are highly sensitized with cPRA of more than 80%.As highly sensitized patients have high risk of AMR, early graft loss and higher chance of being removed from or dying on a waiting list.
Desensitization is one of the option to make transplantation possible.Basically by reducing or eliminating DSAs ,hyperacute rejection risk minimized ,allowing for successful transplantation. Different protocols were endeavoured to overcome this immunologic barrier. Each with different outcomes and disadvantages.
Plasmapheresis PP:
Removing DSAs from circulation. It’s non specific for antibodies removal, all plasma proteins are removed including clotting factors.
The removal of DSAs is short lived with DSAs rebounding to pre treatment level following re_equlibration between intravascular and interstitial compartments.
It dose not affect ongoing DSAs production by plasma cells hence its poor choice for desensitization as sole therapy.
It’s side effects include coagulopathy,hypocalcemia, thrombocytopenia,hypotension and catheter related infection.
Therefore IVIg was added to PP.
Intravenous immunoglobuline IVIg derived from gamma globular fraction of plasma from pooled donors.
Its mode of action include:
1) Inhibit T and B cell proliferation
2) Inhibit cytokine production.
3)Inhibit complement activation
4) Inhibit maturation of dendritic cells.
5) Induce B_cells apposite.
The protocol for combination of IVIg and PP divided into 2 approaches
a) alternate day PP (no. Of sessions depend on titer of DSAs ) combined with low dose IVIg( 100 mg/kg).
b) PP alternating days with high dose IVIg (1_2 gm/kg).
Low dose IVIg with PP:
AMR , has been reported to be as high as 36%, with 100 % one year graft survival.
This protocol was modified to improve the high risk of AMR ,with the inclusion of ATG for induction,along with Rituximab and splenectomy. Despite that modification, AMR was still high with 43% and graft survival of 78% at 15 months. Same incidence risk was reported with a median follow up of 22 months.
One single center analysis compared 8 years survival in 211 desensitized patients with this protocol and underwent living donor transplant. Survival was compared to two other groups of patients (Dialysis only group ) and (Dialysis or HLA matched transplantation group). The result of this study provided evidence that this desensitization protocol could help overcome incompatibility barriers in live donor transplantation with a better graft and patient survival.
Being single center study ,it’s result can’t be generalized.
High dose IVIg 1_2 gm/kg with PP:
AMR was seen in 31% and 7% lost the allograft secondary to rejection.
Induction protocol with Daclizumab, ATG or Alemtuzumab dose not affect the AMR incidence risk.
High dose IVIg, PP and Rituximab:
Due to high rate of acute AMR ,Rituximab ,as a B_lymphocytes depleting agents ,targeting CD20 ,was added to the desensitization regimen.
In conclusion
The AMR was high regardless of which PP/low dose IVIg or high dose IVIg was applied or which type of induction agent was used(Daclizumab,ATG or Alemtuzumab).
The addition of Rituximab or splenectomy did not appear to decrease the incidence of AMR.
Bortizomib based desensitization:
Bortizomib as it might deplete antibody secreting long lived plasma cells and have an impact on DSAs production. Results are inconclusive.
Eculizumab based desensitization protocol:
It’s monoclonal antibody that block cleavage of complement C5 and prevent terminal complement activation. It’s effective in preventing AMR in highly sensitized patients. It’s main issues are ,highly expensive and associated with risk of invasive encapsulated organism.
Tocilizumab( IL_6 inhibitor) based desensitization protocol: As IL6 has powerful stimulators effect on B lymphocytes and Plasma cells. Tocilizumab was advocated to be used in highly sensitized patients. Larger controlled trial needed to verify its potency in this field.
IgG_degrading enzym derived from streptococcus prognosis (IdeS) dependent desensitization:
It cleaves all four subclasses of IgG,,since Fc region ofIgG is critical for interaction with Fc receptor and Complement binding,proteolytic activity at this site prevent the occurrence of IgG dependent cellular toxicity and complement mediated cytotoxicity. Thereby preventing AMR.,Those patients who respond initially experienced rebound of DSAs and AMR..
As it’s noticed ,several protocols for desensitization are available ,Several issues linked to desensitization raised;
1)the quality of evidence comparing one to another is poor.
2)There is no desensitization protocol that permit transplantation in the presence of DSAs or positive cross match.
3)Despite combining the different therapies in several protocols has abrogated the response of high level of preformed DSAs.the higher rate of AMR posed a real challenge to desensitization programs.
These debatable issues raised the question of whether desensitization is superior to waiting on Dialysis.
Benefit of desensitization:
One multi _center study conducted in USA to explore the long term graft and survival rate ,concluded superior result in desensitization group in comparison to HLA matched and waiting on HD patients.A result that was verified by a UK study which showed comparable survival rate.larger cohort controlled studies are needed to answer this question.
Long term complications of desensitization:
Patients survival was reduced in transplanted patient after desensitization, with most common cause of death was infection as per Korean transplant registry data.Sim8larly other study revealed higher infection rate with administration of Eculizumab post transplant.On the other hand ,comparable risk of infection was found in desensitized and in HLA matched recipients.More studies are required to arrive at stronger conclusion.
The other drawback of desensitization transplantation Is the high economic cost ,
Cost effectiveness of desensitization:
In patients with rare HLA typs, uncommon HLA antigens or very high sensitization level (cPRA of more than 95%),when no match from kidney exchange programs(like KPD) are forthcoming after a period of time,desensitization hold be considered given the longer expected survival in comparison to Dialysis and better quality of life.
Reem Younis
3 years ago
The different techniques of desensitization:
Aim of desensitization:
1. Removing circulating DSA with plasmapheresis.
2. Reduce Abs production
3. Inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation.
1. Plasmapheresis(PP): removes antibodies from the circulation.
-This technique is not specific to the removal of alloantibodies and therefore all plasma proteins are reduced including clotting factors.
– PP does not affect ongoing antibody production by plasma cells. Its side effects include coagulopathy, hypocalcemia, thrombocytopenia, hypotension, catheter-related infection, and sepsis.
2. Intravenous immunoglobulin (IVIg) derived from the gamma globulin fraction of plasma from pooled donors has been shown to inhibit T- and B-cell proliferation, cytokine production, and maturation of dendritic cells induce B-cell apoptosis, and inhibit complement activation.
– IVIg-based desensitization can be divided into two general approaches: combined with alternate day PP at a low dose (100 mg/kg), or used at a high dose (1–2 g/kg) .
-Low-dose IVIg and PP protocols have been used for ESRD patients with living donors and high levels of DSA. attempt to decrease high acute rejection rates.
– PP/low-dose IVIG and rituximab are more successful in abrogating positive crossmatch and lower acute rejection rates.
3. Bortezomib (BTZ) is a proteasome inhibitor (PI) that induces endoplasmic reticulum stress, NFkB inhibition, and apoptosis in normal and transformed plasma cells.
4. Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation.
5. Tocilizumab (TCZ) a humanized monoclonal antibody directed at the IL-6 receptor has also been studied as a potential desensitization agent.
6. IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS) that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization.
6. Daratumumab is an IgG1j human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts.
There is no desensitization strategy that can universally allow transplantation in the presence of significant levels of anti-HLA antibody to the donor or a positive crossmatch. Benefits of desensitization
-Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year compared to patients or recipients who received a transplant from a deceased donor. Long-term risks of desensitization
– Desensitization therapies are associated with infections and malignancies.
-Patient survival rate was reduced in patients who underwent incompatible transplants (ABO, HLA, ABO+HLA) compared to standard transplants. The most common cause of death was infection-related. Economic assessment of desensitization
-Desensitization therapies significantly increase the cost of the transplant procedure and the medical complexity of renal transplant
-Incompatible living donor transplant was associated with a 42% increase in the
cost of care than compatible living donor transplant.
MOHAMMED GAFAR medi913911@gmail.com
3 years ago
The presence of a cPRA greater than 80% creates difficulty in finding matched kidneys from compatible donors and low annual transplant rates .
highly sensitized patients have higher rates of antibody-mediated rejection (AMR), early graft loss and a higher chance of being removed from or dying on the waiting list .
Four transplant possibilities are currently available for this disadvantaged group of dialysis patients.
The first is to wait for a compatible deceased donor transplant, which may take years without a suitable donor ever being identified ,
ones who have a living donor can undergo transplantation if the immunological barrier can be successfully crossed,
Patients for whom a living donor transplantation is not possible due to unacceptable antibodies, have the option of enrolling in a kidney paired dona- tion (KPD) programme ,
undergoing a desensitization procedure .
DESENTIZATION STRATIGES
1-reduce and eliminate DSA. 2-decreasing antibody production. 3-blocking action of antibodies.
DESENTIZATION PRTOCOLS
Plasmapheresis ,
removes antibodies from the circula- tion
PP does not affect ongoing antibody production by plasma cells and, hence, is a poor treatment choice for desensitization as sole therapy .
side effects include coagulopathy, hypocalcemia, thrombocytopenia, hypotension and catheter-related infection and sepsis.
2.Intravenous immunoglobulin (IVIg) ,
inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activa- tion
IVIg-based desensitization can be divided into two general approaches: combined with alternate day PP at a low dose (100 mg/kg); or used at a high dose (1–2 g/kg) .
3.Low-dose IVIg and PP protocols ,
used for ESRD patients with living donors and high levels of DSA.
Depending on the titres of antibodies patients undergo varying numbers of PP sessions (higher titres, more sessions of PP) followed with the infusion of IVIg. Using low-dose IVIg with PP.
4.High-dose IVIg-based protocols ,
high-dose IVIg-based desensitization (2 g/kg) for patients on the deceased donor induced a small decrease (approximately 10%) in PRA levels .
5.Rituximab Chimeric monoclonal AB, act on B cell depletion but not plasma cells, used in combination with plasmapheresis, IVIG,
6.Bortezomib (BTZ) is a proteasome inhibitor (PI ,
BTZ might deplete antibody-secreting long-lived plasma cells and have an impact on DSA production .
7.Eculizumab ,
effictive in the prevention AMR in renal transplant recipients who had a positive cross- match against their living donor .
It is unfortunately quite expensive .
8.Interleukin (IL)-6 ,
is a pleiotropic cytokine that has powerful stimulatory effects on B cells and plasma cells and is responsible, in conjunction with other cytokines, for normal antibody production .
9.IgG-degrading enzyme derived from Streptococcus pyo- genes (IdeS) ,
Its promising agent as tested in two large centers in desensitization protocol for highly HLA sensitized patients with successful depletion of DSA but still the risk of DSA rebound and AMR was reported in good numbers of recipients, Ides used with different induction protocols, hoarse ATG from European center, and alemtuzumab in US center with rituximab and IVIG, all received homogenous triple maintenance therapy.
10.Daratumumab ,
gG1j human mAb that binds to CD 38 and inhibits the development of CD 38 express- ing cells including plasma cells and plasmablasts .
BENFITS OF DESENTIZATION
Recipients of kidney transplants from incompatible live donors had a higher survival rate than patients on the waiting list at 1 year, 3 years, 5 years and 8 year.
LONG TERM RISK OF DESENTIZAION
immunosuppression raising the obvious concerns of infection ,CMV,BK,PARVO B19 VIRUS
immunosup- pression related complications including malignancies .
Cost-effectiveness of desensitization
The incremental cost-effectiveness of desen-sitization was estimated to be $80 486 per quality ad justed life year. In comparison, compatible living donor transplant was estimated to cost $39 939 per quality-ad- justed life year.
saja Mohammed
3 years ago
The different techniques of desensitization
1- Remove the antibodies from the circulation by plasmapheresis or immunoadsorption (IA).
2- Inhibition of antibodies production
3- Block further formation of ABS by inhibition of the memory B, plasma cells.
Various techniques of desensitisation
1-Plasmapheresis, used to remove the antibodies from the circulation with the risk of eliminating protein binding clotting factors lead to coagulopathy with increase risk of bleeding, hypocalcemia and infection, with this technique there is a risk of antibodies rebound and cannot prevent the production of ABs from plasma cells so it’s of transient benefits and should be used as part of combination desensitization protocol not alone.
2-Intravenous immunoglobulin, prepared from plasma fraction of pooled donors, it acts as immunomodulating agent through inhibition of both T and B proliferation, reduced cytokines production, induce B cells apoptosis and complement inhibition. Can be used alone or in combination with PP for ABOI desensitization protocol.IVIG, high dose 2gmlkg or low dose 100mg lkg alternating with PP and rituximab 375mg / m2.
3-Rituximab Chimeric monoclonal AB, act on B cell depletion but not plasma cells, used in combination with plasmapheresis, IVIG, its associated with risk of infections.
4- Bortezomib (BTZ) is a proteasome inhibitor (plasma cells depleting agent)
Promising agent different doses density and induction therapy, associated with lower rate of AR ( 18%), and lower denovo AB production( 12.5%) , used in combination with PP, IVIG .
5-Eculuzemab humanized monoclonal AB act on C5 complement inhibition, its use for treatment of AMR based on evidence from small studies its use limited due to the cost , and also risk of meningococcal infection with encapsulated microorganism so need vaccination two weeks prior to its use and antibacterial prophylaxis.
6- 1L 6 inhibitor tocilizumab(TCZ), IL6 Is
pleotropic cytokine with stimulatory effect on both B and plasma cells and interact with other cytokines to produce more antibodies so tocilizumab is humanized monoclonal antibody that act as 1l-6 receptor inhibitor so it help in reduce and inhibit the production of HLA antibodies , its use for desensitization limited to pilot studies with promising results to prevent AMR in combination with IVIG , need more large studies to confirm its potency .
7-(IdeS) IgG-degrading enzyme derived from Streptococcus pyogenes, act on FC receptors of IgG-and stop the IgG mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity
Its promising agent as tested in two large centers in desensitization protocol for highly HLA sensitized patients with successful depletion of DSA but still the risk of DSA rebound and AMR was reported in good numbers of recipients, Ides used with different induction protocols, hoarse ATG from European center, and alemtuzumab in US center with rituximab and IVIG, all received homogenous triple maintenance therapy.
8-daratumumab it’s an IgG 1k monoclonal AB, that bind and inhibit the cd38 expressing cells including plasma and plasmoblasts still under investigation from animal study .
The most common protocals used including the combination of PP alternating with low dose IVIG , rituximab
Benefits of desensitization
according to the evidnece from multicenter experiences-based analysis the benefit of desensitization in HLA incompatible donors not yet determined, some centers reported good early graft and patient survival with 1-3 years after desensitization while other they did not show any difference in graft survival compared to matched sensitized control group, this diversity in the results due to the heterogenicity of these studies by using different definition of desensitization , different methodologyand different population so we need more studies to confirm its potency, but overall still can be used with limitation and accept the risk of complications including AMR ,serious infections like BV , cmv malignancy including PTLD and skin tumors .
Cost-effectiveness of desensitization:
desensitization protocals associated with high cost.
Last edited 3 years ago by saja Mohammed
Abdul Rahim Khan
3 years ago
Techniques of desensitization
These include:
Plasmaphresis
It involves removing Circulating DSA from circulation. The effect is usually short term and there can be reboundand should usually be combined with IVIG
Rituximab
It causes B cell depletion thus decreasing DSA formation.
IVIG
This blocks the effect of preformed DSA and also inhibits T& B cell proliferation , compliment activation and cytokine release.
Bortezomib– Inhibits antibody producing B cells
Eclulizumab- Quite effective but can have serios complications like infection. Vaccination is mandatory before start of treatment
Tocilizumab-anti IL6 antibodies used along with IVIG
Dartatumumab-
Ides– Enzyme derived from strept pyogenes and prevents IgG dependent cytotoxicity. It removes all DSA but can be immunogenic and there is risk of rebound rise in DSA
It can be concluded that plasmaphresis should be included in all desensitization protocol . All protocols without plasmaphresis have failed to decrease PRA. IVIG alone is not recommended . Adding Rituximab to plasmaphresis and IVIG is questionable. Splenectomy does not confer significant advantage. The most common protocol involves combination of Plasmaphresis , low dose IVIG and Rituximab. Plasamphresis is done on alternate days and can vary from 5 to more sessions and each session followed by IVIG at 100 mg/kg followed by Rituximab 375 mg m2 after 1 week
Benefits of Desensitization Options in highly sensitized patients include, Long term Dialysis, kidney paired donation or wait for compatible donor as with improvement of KAS waiting time has decreased.
Desensitisation make transplantation possible in incompatible donors with those with high PRA even >80% . Risks of Desensitization.
Higher risk of acute rejection as desensitization removes DSA but memory cell are not removed.
Higher risk of infections
Cost effectiveness
Because of high risk of acute rejection more cost is incurred on monitoring , protocol biopsies and costly treatment. Transplantation in positive CDC crossmatch patients is more expensive than positive FCXM .
Future Directions
Improvement of kidney allocation system for deceased donors.
Paired kidney donation and exchange
Shereen Yousef
3 years ago
DSAs remain a major risk for successful transplantation for very highly sensitized recipients
For living donor paired exchange programme had improved chances for sensitized patients
Desensitization despite allowed transplantation in highly sensitized patients but results are still inferior to compatible transplant. Desensitization therapies target removing DSA prior to transplantation and block their production or action .
●Desensitization treatments:
*Plasmapheresis : it removes antibodies from the circulation it is not specific for Ab only and offers only short term solution and doesn’t affect Ab production so its not effective alone.
*Intravenous immunoglobulin (IVIg)
Inhibit T-and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation .
IVIg-based desensitization can be divided into two general approaches: combined with alternate day PP at a low dose (100 mg/kg); or used at a high dose (1–2 g/kg) .
*Combined Low-dose IVIg and PP protocols have been used for desensitization
AMR has been reported to be as high as 36% with 100% 1-year graft survival
* The low-dose IVIg with PP, protocol was added to anti-thymocyte globulin for induction with addition of rituximab and splenectomy in an attempt to decrease high acute rejection rates results showed acute AMR rate was 43% with a 78% graft survival at 15 months.
*High-dose IVIg-based protocols 2 g/kg was also tried for desensitization with little effect on cPRA ,better chances for transplantation and higher acut rejection rates .
*Examination of AMR rates using different antibody induction regimens (Zenapax or Thymoglobulin) in patients with desensitized with IVIG (2 g/kg) showed no difference.
*rituximab with high-dose IVIg (2 g/kg) :patients 30% of patients experiencing AMR in early post-transplant period.
*Bortezomib (BTZ) is a proteasome inhibitor (PI) that induces endoplasmic reticulum stress, apoptosis in normal and transformed plasma cells it depletes antibody-secreting long-lived plasma cells.
In a study aimed to determine the safety and efficacy of 32 doses of BTZ in 10 highly sensitized kidney transplant candidates with alloantibodies against their living donor, no patient developed a negative crossmatch against their original intended donor, and the calculated panel reactive was unchanged in all patients.
*Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation.its result in preventing AMR in sensitized patients results are promising but its very expensive and It increased the risk of development of invasive infections with encapsulated organisms .
* Tocilizumab (TCZ) a humanized monoclonal antibody directed at the IL-6 receptor ( recognized as an important mediator of allograft rejection) has also been studied as a potential desensitization agent. TCZ and IVIg were used to reduce and eliminate anti-HLA antibodies with good resullts in desensitization and AMR was seen on protocol biopsies performed at 6 months.
This combination might be promising but more studies are needed.
*IgG-degrading enzyme derived from Streptococcus pyo genes (IdeS) ;
It cleaves all four human subclasses of IgG . Since the Fc region of IgG is critical for interaction with Fc receptors and complement binding, proteolytic activity on IgG molecules at this site prevents the occurrence of IgG-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity, two processes that are critical for AMR.
*Daratumumab is an IgG1k human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts it was tried on animal ,reduction in DSA was not maintained and rapid rebound of antibodies developed with profound rejection.
●Various techniques of desensitisation ?
1Low dose of intravenous immunoglobulin + plasma exchange.
2 Low dose of intravenous immunoglobulin + plasma exchange+ rituximab with or without splenectomy .
3 High dose of intravenous immunoglobulin+ rituximab.
3 Low dose of intravenous immunoglobulin + plasma exchange after ATG induction.
4 daclizumab +ATG or alemtuzumab .
5 Low dose of intravenous immunoglobulin + plasma exchange+Bortezomib.
●Benefits of desensitization
Desensitization offered more chances for sensitized patient to be transplanted so improved patient’s survival
Recipients of kidney transplants from incompatible live donors had a higher survival rate than patients on the waiting list at 1 year, 3 years, 5 years and 8 years.
Long-term risks of desensitization :most published studies are short-term.
1 it is associated with Higher incidence of infection and malignancy as other immunosuppression comparison of infectious complications between kidney transplant recipients desensitized with Rituximab and IVIg and nondesensitized patients showed no difference in bacterial, viral, fungal or serious infections over an 18-month follow-up period
Patient survival rate was reduced in patients who underwent incompatible transplants (ABO, HLA, ABO+HLA) compared to standard transplants.
Cost-effectiveness of desensitization
Desensitization therapies significantly increase the cost of the transplant procedure. Incompatible living donor transplant was associated with a 42% increase in the cost of care in National cohort study. incremental cost-effectiveness of desensitization was estimated to be $80 486 per quality-adjusted life year. In comparison, compatible living donor transplant was estimated to cost $39 939 per quality-adjusted life year
Doaa Elwasly
3 years ago
The different techniques of desensitisation
Plasma pheresis This technique removes antibodies temporally along other plasma proteins as clotting factors , causing side effects as coagulopathy, hypocalcemia, thrombocytopenia, hypotension and catheter-related infection and sepsis. IVIG Acts by inhibiting T- and B-cell proliferation, cytokine production, maturation of dendritic cells and inhibit complement activation . Mayo clinic study published that PP/low-dose IVIG and rituximab combination gave lower rates of AMR compared to other regimens. Mean while no specific regimen can be standerdised. Bortezomib (BTZ) A proteosome inhibitor act by depleting antibody-secreting plasma cells affecting DSA production, It did not show any decline in c PRA levels Eculizumab is a humanized monoclonal antibody that blocks cleavage of C5 and prevents terminal complement activation It prevented AMR in renal transplant recipients who had a positive crossmatch against their living donor. It’s main side effect is the liability of infection with encapsulated organisms and being an expensive drug as well. Tocilizumab (TCZ) a humanized monoclonal antibody against IL-6 receptor.TCZ with IVIg seemed to have beneficial effects on desensitization. IdeS IgG-degrading enzyme derived from Streptococcus pyogenes that cleaves all four human subclasses of IgG preventing IgG-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity, thereby preventing AMR. It reduced or eliminated DSAs allowing HLA incompatible transplantation . Daratumumab an IgG1j human mAb acts by inhibiting the development of CD 38 expressing cells as plasma cells and plasma blasts. It reduced DSA levels compared to untreated controls but rebound increase in Ab levels occurred with rejection.
Various techniques of desensitisation
o low dose (100 mg/kg)on alternate day with PP which was applied for cases having living donors and high levels of DSA. o anti-thymocyte globulin with low dose IVIG , PP ,rituximab and splenectomy . o IVIG ,with PP with rituximab o a high dose IVIG (1–2 g/kg) lead to high AMR rates
o High dose IVIG with rituximab yet the results was not acceptable.
Benefits of desensitization
-better long term survival rates -better quality of life with less waiting list time burden. -Over all economic wise can be cost effective ,decreasing the financial dialysis burden
Long-term risks of desensitization
More studies are needed to assess it . · But it includes infection as viral infections as Cytomegalovirus (CMV), Epstein–Barr virus,parvovirus B-19 and BK polyomavirus and other immunosuppression related complications including malignancy ,progressive multifocal leukoencephalopathy. · AMR rate is high in desensitised cases. · It is an expensive method.
Cost-effectiveness of desensitization
Incompatible living donor transplant was associated with a 42% increase in the cost of care. The cost was highest in patients with positive cytotoxic crossmatch compared with those with flow positive crossmatch . While desensitization treatments increase the cost of transplant, the overall economic impact needs to be considered regarding the longer survival and reducedneed for haemodialysis.
Mohamad Habli
3 years ago
Renal transplantation is the best treatment for patients with ESRD. DSAs are major obstacle to access to transplantation for many transplant patients. Sensitized patients have the option of enrolling in a kidney paired donation programme or undergoing a desensitization procedure. Desensitization therapies target: Removing preformed DSA Decrease antibody production, or ones that block their actions. Desensitization treatments Plasmapheresis removes antibodies from the circulation. This technique removes all plasma proteins including clotting factors. However, this removal is only short-lived with antibodies rebounding to pretreatment levels following re-equilibration between intravascular and interstitial compartments. IVIg has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation .Low-dose IVIg have been used complementary to PP protocols for ESRD patients with living donors and high levels of DSA. IVIg-based desensitization can be divided into two general approaches: combined with alternate day PP at a low dose (100 mg/kg); or used at a high dose (1–2 g/kg). Rituximab in combination with high-dose IVIg (2 g/kg) or PP Bortezomib is a proteasome inhibitor that induces endoplasmic reticulum stress, NFjB inhibition and apoptosis in normal and transformed plasma cells. Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation. The efficacy of eculizumab was demonstrated few studies, when added to conventional desensitization protocol. It was shown it was associated with lower risk of AMR. risk of development of invasive infections with encapsulated organisms during eculizumab therapy. Eculizumab 21,000 $ per dose. Tocilizumab a humanized monoclonal antibody directed at the IL-6 receptor, cytokine that has powerful stimulatory effects on B cells and plasma cells, has also been studied as a potential desensitization agent. TCZ with IVIg appears to be an additional agent with potential in desensitization. IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS) that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization. IdeS prevents the occurrence of IgG-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity. Daratumumab is an IgG1k human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts. However, the reduction was not maintained and rapid rebound of antibodies developed with profound rejection. Various protocols of desensitization a- Plasmapheresis + low dose IVIG b- High dose IVIG (2 gm/kg) c- High dose IVIG (2 gm/kg ) + Rituximab d- Plasmapheresis + low dose IVIG + Rituximab e- Plasmapheresis + low dose IVIG + Rituximab + splenectomy f- Plasmapheresis + low dose IVIG + Bortezomib g- Alemtezumab + low dose IVIG+ Ides h- Low dose IVIG+ Tocilizumab Benefits of desensitization Recipients of kidney transplants from incompatible live donors had a higher survival rate than patients on the waiting list at 1 year, 3 years, 5 years and 8 years. Long-term risks of desensitization Desensitization improves the short term graft and patient survival but associated with: 1- Increased risk of acute rejection 3 fold higher than in non-sensitized patients · 2- Higher incidence of infection risk 3- Increased risk of malignancy, in particular skin and hematologic malignancies. Cost-effectiveness of desensitization Desensitization therapies significantly increase the cost of the transplant procedure. Incompatible living donor transplant was associated with a 42% increase in the cost of care in National cohort study. Over 10 years, incompatible living donor kidney transplant was associated with a greater mean cost of care ($440 234 vs. $292 117) and longer mean survival.
Ban Mezher
3 years ago
Different techniques of desensitization:
removing of DSA by PP
reduce Abs production
blocking of Abs action
Various techniques of desensitization:
PP: non specific removal of plasma proteins from blood including clotting factors. The Abs can rapidly rebound to baseline level. It had no effect on plasma cells so it is not effective alone as treatment & need combination with PP. Had several complication e.g. coagulopathy, hypocalcemia, hypotension, thrombocytopenia & catheter related infection & sepsis.
IVIg: prevent Abs production by inducing B cells apoptosis & inhibition of complement activation. Usually used with PP either as (a) low dose IVIg 100mg/kgfor patient with living donor & high DSA. It can be modified to include ATG with rituximab & splenectomy to reduce high acute rejection rate. (b) High dose IVIg (2g/kg) used for patient with deceased donor & PRA >50%. It associated wit high rate of acute rejection.
Proteosome inhibitor ( bortezomib): It act through apoptosis of normal & transformed plasma cells.
Eculizumab: effective in AR prevention among sensitized recipient who require desensitization, but it very expensive & associated with high risk of infection.
IL-6 receptor blockers (Tocilizumab): effective in desensitization when combined with IVIg.
IdeS: effective in conversion of positive cross match to negative, high rate of AR but well responding to treatment.
Daratumumab: CD38 blocker. used in animal models ( not used in human). Result show rapid rebound of Abs with high rate of AR.
There was a conflict about the benefit of desensitization. In USA studies proved that desensitization of positive cross match & incompatible donor had better survival than patient remain on waiting list while UK result was the opposite ( no survival benefit).
The long term risk of desensitization can’t be predicted because all the studies were short term study.
Using of desensitization protocol was associated with increased cost in around 40%. This increase in cost should be considered with longer survival. The cost effectiveness of incompatible living donor transplant around 80486$/ quality adjusted life year while in compatible living donor around 39939$/ year.
Sahar elkharraz
3 years ago
Different techniques of desensitisation?
The goal of desensitisation is remove circulating DSA and inhibition production of antibodies and blocking action of antibodies.
1. Plasma exchange to remove circulating DSA but may remove plasma protein and it’s side effects coagulopathy, leukopenia hypocalcemia and hypotension
2. intravenous immunoglobulin for inhibition T and B cell proliferation/ reduce cytokines production and maturation of dentric cell / induce B cell apotosis and inhibition of complement activation.
3. Anti thymoglobulin antibodies
4. Rituximab is monoclonal antibody against CD 20
5. splenectomy plus rituximab
6. Bortezomib is proteasome inhibitors that induce endoplasmic reticulum NfkB inhibition and apoptosis
7. Eculizumab C5 inhibitors
8. Interleukin (IL-6) pleiotropic cytokine that has powerful stimulating effects on B cell & plasma cell
9. Tocilizumab humanized monoclonal antibody directed at IL6 receptor
10. IgG degradation enzymes derived from streptococcus pyrogens.
Various techniques of desensitisation ?
1. Low dose of intravenous immunoglobulin plus plasma exchange plus rituximab
2. High dose of intravenous immunoglobulin plus rituximab
3. Low dose of intravenous immunoglobulin plus plasma exchange plus ATG
4. Splenectomy plus rituximab
5. daclizumab plus ATG or alemtuzumab .
Benefits of desensitisation:
2 studies done on outcome of survival graft in incompatible donor transplant shows different results and different definition of desensitisation and matching method for patients waiting transplant.
one study shows the outcome of patients receiving incompatible donor has higher survival rate than patients on waiting list.
Other study shows no difference in survival was noticed between patients who underwent HLA incompatible transplant in comparison to patients on waiting list.
Long term risk:
desensitisation patients underwent transplant have risk of serious infection and malignancy and desensitisation protocol has short term and production of DSA may appear post transplant with long term of graft leading to failure of graft despite using high dose of immunosuppressive drug.
Patients survival rate reduced who underwent ABO / HLA incompatible.
Cost effectiveness:
desensitisation treatment and cost care very high in comparison to compatible patients.
Abdulrahman Ishag
3 years ago
The different techniques of desensitization;
1-Removal of circulating DSA
2- Decrease antibody production
3- Block antibody actions
Various techniques of desensitization;
1-Plasmapheresis; Removes antibodies from the circulation. Its side effects include coagulopathy , hypocalcemia, thrombocytopenia, hypotension and catheter-related infection and sepsis.
2-Intravenous immunoglobulin (IVIg); inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation . IVIg-based desensitization can be divided into two general approaches:
1-combined with alternate day PP at a low dose (100 mg/kg)
2- used at a high dose (1–2 g/kg) [20,21]
3-Bortezomib (BTZ) is a proteasome inhibitor (PI) that induces endoplasmic reticulum stress, NFjB inhibition and apoptosis in normal and transformed plasma cells . PI BTZ might deplete antibody-secreting long-lived plasma cells and have an impact on DSA production.
4-Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation. It is increased the risk of development of invasive infections with encapsulated organisms .
5- Interleukin (IL)-6 is a pleiotropic cytokine that has powerful stimulatory effects on B cells and plasma cells and is responsible, in conjunction with other cytokines, for normal antibody production. It has also been recognized as an important mediator of allograft rejection.
– Tocilizumab (TCZ) a humanized monoclonal antibody directed at the IL-6 receptor has also been studied as a potential desensitization agent. A phase I/II pilot study was performed with TCZ and IVIg to reduce and eliminate anti-HLA antibodies as well as test its safety and efficacy in desensitization.
6- IgG-degrading enzyme derived from Streptococcus pyo genes (IdeS) ;
that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization . Since the Fc region of IgG is critical for interaction with Fc receptors and complement binding, proteolytic activity on IgG molecules at this site prevents the occurrence of IgG-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity, two processes that are critical for AMR.
7- Daratumumab is an IgG1k human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts.
Desensitization can increase access to both living and deceased donor transplants and can be used individually or in combination with KPD.
Long-term risks of desensitization;
1-Desensitization therapies add to overall immunosuppression raising the obvious concerns of infection and other immunosuppression related complications including malignancies.
2-Patient survival rate was reduced in patients who underwent incompatible transplants (ABO, HLA, ABO+HLA) compared to standard transplants.
Cost-effectiveness of desensitization;
The incremental cost-effectiveness of desensitization was estimated to be $80 486 per quality-adjusted life year. In comparison, compatible living donor transplant was estimated to cost $39 939 per quality adjusted life year.
Batool Butt
3 years ago
1-The different techniques of desensitization
The goal of desensitization is to reduce or eliminate DSA to prevent hyperacute rejection. Desensitization protocols combine antibody elimination by PE and decrease antibody production or block their action. 2-Various techniques of desensitization Plasmapheresis has short term effects and removes not only circulating DSA but also all plasma proteins including clotting factors, with post treatment rebound if used alone. Intravenous immunoglobulin (IVIg): inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation. Two protocols have been studied so far :low dose IVIG (100mg/kg) with alternate day PLEX or high dose(1-2g/kg)combined with alternate day PP . Administration of IVIG was associated with a modest decrease in reactivity to both class I and II HLA antigens so need to be used in combination with other modalities. Rituximab: monoclonal antibody against CD20 : ABMR still occur in 29% of the patients if used in combination with high dose IVIG , with patient and graft survival of 95% & 84% respectively at 02 years.
Other agents used includes Bortezomib(proteasome inhibitor-no role in desensitization ), Eculizumab (a humanized monoclonal antibody against C5-is expensive, may show some benefit but have risk of meningococcal infection and also needs vaccination prior to transplant ), Tocilizumab (a humanized monoclonal antibody against IL-6 receptor -under investigation but may have potential role), and IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS) (Prevent IgG dependent (cellular cytotoxicity and complement mediated toxicity, has promising results but need more studies)and Daratumumab (IgG1j –a human monoclonal antibody that binds to CD 38 and inhibits the development of plasma cells and plasmablasts-reduce DSA level but causes rebound rise of antibodies). Various protocols of desensitization
a- High dose IVIG (2 gm/kg)
b- High dose IVIG (2 gm/kg ) + Rituximab
c- Plasmapheresis + low dose IVIG
d- Plasmapheresis + low dose IVIG+ Rituximab
e- Plasmapheresis + low dose IVIG+ Rituximab + splenectomy 3-Benefits of desensitization
Transplantation in highly sensitized patients is very difficult and challenging. Desensitization removes preformed DSA and allow to proceed with transplant and prevent hyperacute rejection and enhances transplantability of highly sensitized patient on the waiting list of deceased kidney transplantation and provide him better QOL than to stay on dialysis. .4-Long-term risks of desensitization
Desensitization recipients has high risk of rejection episodes ,infection rates and other immunosuppression related complications including malignancies. Also had reduced graft and patient survival ) compared to standard transplant patients. 5-Cost-effectiveness of desensitization
Desensitization therapies significantly increase the expenses of the transplant procedure, accounting for about 42% increase in its according to one study. But still the overall economic impact needs to be considered in light of longer survival and a reduced need for hemodialysis. Alternatives to desensitization: kidney paired donation:
Kidney allocation system for deceased donor. And Paired kidney donation and exchange between living donors should be encouraged to improve outcomes and prevent graft failure.
fakhriya Alalawi
3 years ago
Desensitization therapies target removing and/or reducing donor-specific antibodies (DSA) prior to transplantation, thereby preventing hyperacute rejection and allowing a successful transplantation
.
The different techniques of desensitization
Desensitization protocols have typically combined an approach of removing circulating DSA with plasmapheresis (PP), combined with agents that decrease antibody production, or ones that block their actions.
Plasmapheresis removes antibodies from the circulation. This technique is not specific for the removal of alloantibodies and this removal is only short-lived with antibodies rebounding to pre-treatment levels following re-equilibration between intravascular and interstitial compartments. More importantly, PP does not affect ongoing antibody production by plasma cells and, hence, is a poor treatment choice for desensitization as sole therapy. Its side effects include coagulopathy, hypocalcemia, thrombocytopenia, hypotension and catheter-related infection and sepsis.
Intravenous immunoglobulin (IVIg) has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation. IVIg-based desensitization can be divided into two general approaches: combined with alternate day PP at a low dose (100 mg/kg); or used at a high dose (1–2 g/kg). Despite the modification in the dose, the acute AMR rate is still high. Luminex single-antigen testing was performed before and after IVIg. Administration of IVIg was associated with a modest decrease in reactivity to both class I and II HLA antigens but did not significantly alter mean cPRA.
The effects of high-dose IVIG (2 g/ kg) and Rituximab were examined in a prospective study on desensitizing transplant candidates with a cPRA >50% waiting for a deceased donor kidney for more than 5 years. It showed no significant reduction in patients’ class I and II cPRA levels, nor any change in the mean number of unacceptable antigens or their mean fluorescence intensity values.
The addition of rituximab or splenectomy did not appear to decrease the acute AMR rate.
Bortezomib (BTZ): is a proteasome inhibitor (PI) that induces endoplasmic reticulum stress, NFjB inhibition and apoptosis in normal and transformed plasma cells. In different studies of patients who used many sessions of BTZ, non-developed a negative cross-match against their original intended donor, and the calculated panel reactive was unchanged in all patients.
Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation. It has been shown to be efficacious in the prevention AMR in renal transplant recipients who had a positive crossmatch against their living donor with a significant reduction in the rates of AMR. However, it’s of high cost, with an average wholesale price of $21 000 per dose. Another consideration is the risk of the development of invasive infections with encapsulated organisms during eculizumab therapy due to which certain vaccinations are prerequisites.
Tocilizumab (TCZ) a humanized monoclonal antibody directed at the IL-6 receptor has also been studied as a potential desensitization agent. Looks promising agent in reducing AMR, however, larger controlled studies are essential to better study its efficacy.
IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS) that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization. Out of the 25 patients, 22 had DSA present before transplantation. IdeS reduced or eliminated DSAs and permitted HLA incompatible transplantation in 24 of 25 patients. AMR occurred in 10 patients from 2 weeks to 5 months after transplantation; all of these patients had a response to treatment.
Daratumumab is an IgG1j human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts. Its use is still experimental. Animals treated with daratumumab had significantly reduced DSA levels compared to untreated controls (57.9% vs. 13%). However, the reduction was not maintained and a rapid rebound of antibodies developed with profound rejection.
· Benefits of desensitization
Recipients of kidney transplants from incompatible live donors had higher survival, though results are controversial between different analyses.
· Long-term risks of desensitization
Desensitization therapies lead to an increase in the rate of infection and other immunosuppression related complications including malignancies.
The patient survival rate was reduced in patients who underwent incompatible transplants (ABO, HLA, ABO+HLA) compared to standard transplants.
· Cost-effectiveness of desensitization
In addition to increasing the medical complexity of renal transplants, desensitization therapies significantly increase the cost of the transplant procedure. In Axelrod et al. study Incompatible living donor transplant was associated with a 42% increase in the cost of care ($151 024 vs. $106 636 P < .001). Medicare reimbursement was also increased, with a mean payment (excluding the cost of organ acquisition) of $92 150 for incompatible vs. $58 084 for compatible transplants. However, While desensitization treatments increase the cost of the transplant, the overall economic impact needs to be considered in light of longer survival and a reducedneed for haemodialysis
Alternative to desensitization is kidney paired donation which can provide access to organs where the immunological barrier can be avoided. KPD is associated with better outcomes and lower costs.
mai shawky
3 years ago
Ø Available desensitization agents:
o Plasmapheresis: remove all antibodies, but unfortunately
§ Short lasting effect and rebound DSA after treatment due to redistribution between intravascular compartment and interstitial spaces, so it can not be used alone.
§ Not prevent new DSA formation from plasma cells.
§ Adverse effects: coagulopathy, hypocalcemia, complications of central line as infection and thrombosis.
o IVIG: neutralizes DSA, prevent T and B cell maturation and decrease cytokines production.
§ Either low dose (100 mg/kg) or large dose (2 gm/kg).
§ Usually follow PEX therapy on alternate days.
§ Combined PEX and low dose IvIg is better than high dose IvIg alone.
o Rituximab: chimeric molecule against CD 20, deplete B cells (precursor of antibody producing plasma cells)
o Bortezomib:
§ Inhibit anti body producing plasma cells.
§ Failed to turn XM negative and decrease cPRA
§ Need further studies.
o Eculizimab:
§ May be effective, but very expensive and can lead to serious infections by encapsulated organism (vaccination prior to transplant is mandatory).
o Anti IL-6 r antibodies (tocilizumab): just add on therapy with IvIg and still under investigations.
o IdeS:
§ an enzyme derived from strept pyogens that can cleave all 4 subtypes of human IgG.
§ Prevent IgG dependent (cellular cytotoxicity and complement mediated toxicity).
§ Can remove all DSA and turn +ve XM to -ve.
§ However, it is immunogenic that antibodies formed against it
§ Also associated with rebound DSA with AMR, fortunately responded to standard of care therapy as (PEX and IvIg).
Ø The most commonly used protocol is combined PE, low dose IVIG and Rituximab (5 sessions of plasmapheresis on alternate days (more sessions can be done according to titer of DSA), followed by low dose of IVIG 100 mg/kg after each session and 1 dose of Rituximab 375 mg/m2 1 week later).
Ø Benefits of desensitization
§ Transplantation in the context of positive crossmatch and high level of detected DSA and cPRA > 80% is very challenging and can be done by:
§ In living donor: kidney paired donation system for exchange of donors between couples.
§ Deceased donor: no time for KPD, so only available option is desensitization to proceed to transplantation. Other options, unlimited waiting for another deceased donor or keep on dialysis.
§ Sensitization enhance transplantability of highly sensitized host on the waiting list of deceased kidney transplantation and provide him better QOL than to stay on dialysis.
§ Desensitization remove preformed DSA and turn XM to be negative to allow transplant and prevent hyperacute rejection.
Ø Long-term risks of desensitization
§ Acute rejection can still occur 3 times higher in desensitized recipients than non sensitized regardless the regimen used for desensitization and induction therapy. This is coasty and associated with worse long term graft survival. This can be explained by formation of memory cells
§ Risk of infections and malignancy after those immune depleting regimens can not be neglected.
Ø Cost-effectiveness of desensitization
§ The cost of desensitization protocols + cost of treatment of inevitable close monitoring as protocol biopsy and DSA monitoring + cost of treatment of expected acute rejection in case of HLA -incompatible transplantation represent a major burden.
§ This cost may overweigh short term benefit of trasplantability of some patients with very high risk of rejection ( impossible transplant without desensitization)
§ So , desensitization protocol should be used only for those who has been on waiting list for long time and no suitable deceased donor.
§ The direction must be toward improvement of:
o Kidney allocation system for deceased donor.
o Paired kidney donation and exchange between living donors.
Riham Marzouk
3 years ago
Renal transplantation is the best option for ESRD on regular dialysis to decrease comorbidities and for better quality of life.
HLA mismatch is the biggest barrier against renal transplantation, also sensitized patient to HLA antigens following pregnancy, blood transfusion or previous transplant usually have higher calculated panel reactive antibody and may reach 100%, which means decrease chance to meet compatible matched donor , and also highly sensitized patient have more chance to develop antibody mediated rejection and decrease graft survival and ends by graft loss.
Desensitization protocol in spite of being expensive but should be done to desensitize the patient or remove DSA and block its production:
Plasmapheresis PP : not used as single treatment as it removed circulating antibodies and not specific to alloantibodies but also it removes plasma proteins including clotting factors , and also has no effect on ongoing antibody production by plasma cells so rebound can be done early, so not used alone.
Side effects including infection, bleeding disorders
Intravenous immunoglobulin (IVIg) it inhibits T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation. Can be used combined with alternate day PP at a low dose (100 mg/kg), or used at a high dose (1–2 g/kg)
Low-dose IVIg and PP protocols used for the patients with living donors and high levels of DSA. higher titre of DSA, more sessions of PP, followed with the infusion of IVIg. Here, AMR incidence is 36% with 100% 1-year graft survival.
In spite of a lot of trials (use ATG as induction, addition of rituximab to desensitization protocol, and splenectomy) to decrease incidence of AMR, the incidence of AMR remains high as 43% with 78% graft survival at 15 months.
Use of high dose IVIg has variable results in variable studies.
Bortezomib (BTZ) is a proteasome inhibitor (PI) that induces endoplasmic reticulum stress, NFjB inhibition and apoptosis in normal and transformed plasma cells. treatment with the PI BTZ might deplete antibody-secreting long-lived plasma cells and have an impact on DSA production.
Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation. It has been shown to be efficacious in the prevention AMR in renal transplant recipients who had a positive crossmatch against their living donor.
Tocilizumab (TCZ) a humanized monoclonal antibody directed at the IL-6 receptor has also been studied as a potential desensitization agent. IL-6 is a pleiotropic cytokine that has powerful stimulatory effects on B cells and plasma cells and is responsible, in conjunction with other cytokines, for normal antibody production. It has also been recognized as an important mediator of allograft rejection.
IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS) that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization.
Daratumumab is an IgG1 human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts.
Desensitization protocol is expensive and has long term complications added to complications of immunosuppression drugs , also there is no standard protocol can decrease DSA and decrease incidence of AMR.
Kidney exchange donor program KPD (kidney paired donation) is the best option for living donation, can solve many problems of the recipients.
Sherif Yusuf
3 years ago
The different techniques of desensitization
3 main lines are available for desensitization
· Plasmapharesis which remove circulating DSA , it provide short term removal of antibodies, with post treatment rebound if used alone.
· Rituximab which decrease the production of DSA by producing B cell depletion
· IVIG which block the effect of preformed DSA and cause inhibition of T cell, B cell proliferation, cytokine release, complement activation and promote B cell apoptosis
Other agents used includes Bortezomib (no rule), Eculizumab (potentioal benefit, expensive, risk of meningiococcal infection), Tocilizumab (may have potential rule-needs more studies), Daratumumab (rebound rise of antibodies) and IdeS (promising, need more studies)
· Plasmapheresis should be included in any regimen used for desensitization since all regimens that did not contain plasmapheresis fail to decrease PRA and obtain negative cross match
· Addition of rituximab to plasmapharesis and IVIG is debatable
· Splenectomy offer no advantage in desensitization protocols
· Use of high dose IVIG alone is not recommended
– The most commonly used protocol is combined PE, low dose IVIG and Rituximab. 5 sessions of plasmapheresis are done on alternate days (more sessions can be done according to titre of DSA), each session is followed by low dose of IVIG 100 mg/kg and 1 week later give 1 dose of Riuximab 375 mg/m2. Benefits of desensitization
Highly sensitized transplant candidate who cannot find suitable donor has one of the following possibilities:
1- Keeping the patient on hemodialysis which is associated with higher mortality
2- Try to find compatible living kidney donor, it may be difficult but because of KPD (local or preferred national) any recipient with a living donor even if ABO or HLA incompatible can exchange donor with another pairs
3- Wait for compatible deceased donor and this will take very long time, but because of improvement of the kidney allocation system (KAS), wait list was reduced from > 19 years to around 3 years
4- Desensitization to render incompatible donor possible for transplantation
Desensitization offer a good transplant opportunity and survival advatage for highly sensitized recipient with cPRA> 80% who has very low likehood to get a transplant (living or deceased) due to positive cross match
The goal of desensitization is to remove preformed DSA that cause positive cross match with the doner and are associated with hyper acute rejection with immediate loss of the graft upon transplantation
The main indication of desensitization nowadays is a recipient with no living donor and highly sensitized so cannot find deceased offer and expected to be waitlisted for long time Long-term risks of desensitization
· Desensitization was found to improve short term graft and patient survival, but rate of acute rejection is more than 3 fold higher than in non sensitized patients regardless of the regimen used for desensitization and induction and this may affect long term graft survival
· Higher incidence of acute rejection may be explained by the effect of desensitization which remove or decrease production of DSA but will not remove memory cells which are capable of producing strong rejection later on.
· The most important concern when using desensitization strategies is infection risk, some found increase in the risk of infection but other failed to find this finding Cost-effectiveness of desensitization
· Desensitization was found to improve short term graft and patient survival, but rate of acute rejection is high adding more cost due to aggressive monitoring, protocol biopsies and cost of treatment
· Desensitization is expensive, the cost of transplanting incompatible donors with positive CDC cross match is the highest, followed by those with positive FCM and negative CDC then patients kept on hemodialysis and lastly compatible kidney transplantation which offers the least cost
Desensitization in Kidney Transplant: A Risky (but Necessary?) Endeavor for Those With Limited Options
· The development of good allocation system and national kidney paired donation facilitates deceased and living kidney transplantation and decrease the need for desensitization.
· The main indication of desensitization nowadays is a recipient with no living donor and highly sensitized so cannot find deceased offer and expected to be waitlisted for long time
· Desensitization is associated with higher acute rejection and infection rate, and is expensive
· So the author recommends avoidance of HLA incompatible transplantation whenever possible due to cost and risks associated with this strategy.
Huda Al-Taee
3 years ago
The different techniques of desensitisation
The goal of desensitization is to reduce or eliminate DSA to prevent hyperacute rejection. Desensitization protocols combine antibody elimination by PE and decrease antibody production or block their action.
Various techniques of desensitisation
Plasmapheresis: removes antibodies from the circulation. It removes the antibodies and other proteins, including clotting factors; this removal is short-lived with antibody rebounding. It does not affect antibody production by plasma cells, and therefore, it can not be used solely for desensitization. SE: coagulopathy, hypocalcemia, thrombocytopenia, hypotension, and catheter-related infection and sepsis.
IVIG: shown to inhibit B & T cell proliferation, cytokine production, maturation of dendritic cells, induce B cell apoptosis and inhibit complement activation. It can be divided into 2 general approaches either combined with alternate day PE in a low dose (100 mg/kg) or used at a high dose (1-2g/kg). A. low dose IVIG: depending on the antibodies titer, a number of PE sessions followed IVIG, this protocol was modified to include ATG for induction along with rituximab and splenectomy. Despite this modification, the ABMR rate was high. B. high dose IVIG: reported in many single-centre experiences with variables results. In an RCT, it produces a small decrease in PRA level in highly sensitized patients.
Rituximab: with high dose IVIG, large experience showed that ABMR happened in 29% of the patients with patient and graft survival of 95% & 84% respectively at 24 months.
Bortezomib: in a study evaluating the efficacy of bortezomib, about 43% of the desensitized patients can be transplanted but they had a low rejection risk.
Eculizumab: it has been shown to be effective in preventing ABMR in patients who had a positive crossmatch.
IL-6: Tocilizumab a humanized monoclonal antibody, has been studied as a potential desensitization agent. In phase I/II study, most of the involved patients were able to be transplanted with negative cross matches and no ABMR were seen in protocol biopsies 6 months later. larger studies are required.
IgG-degrading enzyme derived from streptococcus pyogenes ( Ides): cleaves all four human classes of IgG. In 2 international centers studies, Ides reduced or eliminated DSAs and permitted HLA incompatible transplantation in 24 out of 25 patients.AMR occurred in 10 patients from 2 weeks to 5 months, and all had responded to treatment.
Daratumumab: an IgG1 k human mAb that binds to CD38 and inhibits the development of CD38 expressing cells including plasma cells and plasmablasts. animal studies showed a significant reduction of DSA levels but this reduction was not maintained and there was antibodies rebound.
Benefits of desensitization
in multi-center analysis: recipients of a kidney transplant from incompatible live donors had a high survival rate than those who remain on dialysis or on the waiting list for a deceased donor.
in the UK study: No difference in survival was noted between patients who underwent an HLA-incompatible transplant compared with the listed only group, or listed or transplant group.
Comparing the two studies are difficult as they have different definition of sensitization, different matching methods, different population, different waiting time, and different socioeconomic factors.
Long-term risks of desensitization
Most published studies are short term studies, so it is difficult to determine the long term effect of desensitization. there is a concern about infection and malignancy risks. In a study that evaluated the risk of CMV & BK virus infection in patients desensitized with IVIG+ PE+ Rituximab, the risk of these infections was similar to that observed in standard transplant recipients. larger studies are needed to arrive at a stronger conclusion.
Cost-effectiveness of desensitization
Desensitization therapies significantly increase the cost of transplantation.
Incompatible living donor transplant was associated with a 42% increase in the cost of care according to a cohort. The overall economic impact needs to be considered in light of longer survival and a reduced need for haemodialysis. An incompatible living donor kidney transplant was associated with a greater cost of care ($440 234) and longer mean survival. In comparison, a compatible living donor transplant was estimated to cost $39 939 per quality-adjusted life-year.
Plasmapheresis
removes antibodies from the circulation
not specific for the removal of alloantibodies
all plasma proteins are reduced including clotting factors. removal is only short-lived
PP does not affect ongoing antibody production by plasma cells
side effects
coagulopathy
hypocalcemia
thrombocytopenia
hypotension
catheter-related infection
sepsis.
Intravenous immunoglobulin (IVIg)
inhibit T- and B-cell proliferation
cytokine production
maturation of dendritic cells
induce B-cell apoptosis
inhibit complement activation
can be divided into two general approaches:
combined with alternate day PP
at a low dose (100 mg/kg)
patients undergo varying numbers of PP sessions (higher titres, more sessions of PP) followed with the infusion of IVIg.
Using low-dose IVIg with PP, AMR has been reported to be as high as 36%.
The low-dose IVIg with PP, protocol was modified to include anti-thymocyte globulin for induction along with the addition of rituximab and splenectomy.
Despite the modification, acute AMR rate was 43%.
at a high dose (1–2 g/kg)
use in both living and deceased donors
IVIg (2 g/kg) was given to cross- match-positive recipients.
In addition various induction agents like thymoglobulin, alemtuzumab used
As AMR rates remained high despite pretreatment intervention rituximab was added to high-dose IVIg (2 g/kg) based regimen.
studies question the ability of IVIg alone to meaningfully decrease sensitization status.
Mayo clinic authors in their single centre study concluded that PP/low-dose IVIG and rituximab demonstrated more success in abrogating positive crossmatch and lower acute rejection rates, but no regimen was completely effective in preventing AMR.
Other agents used-
Bortezomib
Forty-four patients received 52 desensitization courses. Only 19 out of 44 patients (43.2%) could be transplanted low acute rejection rate (18.8%)
12.5% of subjects had de novo DSA formation
Eculizumab
One hundred and two patients underwent desensitization. Post-transplant, 51 patients received standard of care (SOC) and 51 received eculizumab. Treatment failure rates were 11.8% and 21.6% for the eculizumab and SOC.
Quite expensive
risk of develop- ment of invasive infections with encapsulated organisms.
Tocilizumab
Tocilizumab with IVIg appears to be an additional agent with potential in desensitization.
IgG-degrading enzyme derived from Streptococcus pyo- genes (IdeS)
Since the Fc region of IgG is critical for inter- action with Fc receptors and complement binding, proteolytic activity on IgG molecules at this site pre- vents the occurrence of IgG-mediated antibody-depen- dent cellular cytotoxicity and complement-mediated cytotoxicity, two processes that are critical for AMR.
Daratumumab
IgG1 human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts.
Studied in primates
Benefits of desensitization
A multi-centre analysis on the survival benefit of kidney transplants from HLA-incompatible live donors exam- ined the results across 22 centres in the US with 1025 recipients.
Their outcomes were matched with controls who remained on the waiting list or received a transplant from a deceased donor (waiting list or transplant control group) and controls who remained on the waiting list but did not receive a transplant.
Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year (95.0% vs. 94.0% for the waiting list or transplant control group and 89.6% for the waiting list-only control group)
3 years (91.7% vs. 83.6% and 72.7%, respectively)
5 years (86.0% vs. 74.4% and 59.2%)
8 years (76.5% vs. 62.9% and 43.9%
Analysis of the UK adult transplant waiting list –
compared the patient survival of crossmatch- positive living donor HLA-incompatible kidney transplant with that of similarly sensitized patients awaiting a compatible organ . Two hundred and thirteen patients who underwent HLA-incompatible transplant were matched in a 1:4 ratio with similarly sensitized patients listed for a transplant across the same time period.
No difference in survival was noted between patients who underwent a HLA-incompatible transplant compared with the listed only group, or listed or transplant group.
Long-term risks of desensitization
Infection
Malignancies
Cost-effectiveness of desensitization
Incompatible living donor transplant was associated with a 42% increase in the cost of care.
Desensitization involves removal of pre existing donor specific antibodies from the plasma combined with agents that inhibit their further production or alter their binding capacity..
Desensitization is essential to prevent hyperacute rejections in case of pre existing DSA which can interfere with graft function…Anti HLA antibodies are formed after blood transfusions, pregnancy and after repeat transplantations…These patients are classified as highly sensitized….
Plasmapheresis: removes pre existing antibodies from the circulation. It is not specific as it removes other plasma proteins, immunoglobulins. It is not effective as a sole therapy as antibody levels rebound after apheresis…There are 2 types which can be done – membrane based and centrifugal based apheresis techniques…
Intravenous Immunoglobulin (IVig) – inhibit T and B cell proliferation, binds to the Fc portion of anti HLA antibody altering its binding capacity, inhibits cytokine production and inhibits complement activation..There are 2 protocols using IVIg – Low dose (0.5-1g/kg) whch i sused after every PP and the high dose IvIG protocol 2gm/day..Mayo clinic have published their results of comparison of the low dose and the high dose IvIG and found that High dose IVIG alone is not useful and the best results of desensitization is seen with Low dose IVIG +PP, Inj Rituximab and triple immunosuppression. The use of ATG as induction agents was also described as a part of the protocol with Low dose IVIG, else there was high rate of AMR which was described…
Other novel agents used in desensitization are Bortezomib, Eculizumab, Toclizumab, Ides (Ig derived streptococcus enzyme), daratumumab….
Benefits of desensitization:
Various trials across USA, show that renal transplant carried out after desensitization in HLAi renal transplants had better 1 year, 2 year and 5 year graft survival as compared to waiting on hemodialysis which has a higher mortality. On the other hand trials from UK showed no difference in the overall survival between HLAi renal transplants as compared to those who are on the waiting list…Unfortunately these 2 studies cannot be compared as they are across different continents with different population groups..
Long term consequences of desensitization:
While most studies of desensitization are short lived, theoretical concerns about over immunosuppression is always there. Patients need to be on Cotrimoxazle prophylaxsis and Valganciclovir prophylaxsis. Further long term studies are needed to ascertain their safety
Desensitization is not cost effective..the overall cumulative cost is more on desensitization as compared to staying on dialysis..
Different techniques of desensitization
The goal of desensitization is to reduce/eliminate DSA, thereby preventing hyperacute rejection and allowing a successful transplantation
Desensitization protocols have typically combined an approach of removing circulating DSA with plasmapheresis (PP) , combined with agents that decrease antibody production, or ones that block their actions.
IVIg-based desensitization can be divided into two general approaches: combined with alternate day PP at a low dose ; or used at a high dose
Low-dose IVIg and PP protocols have been used for ESRD patients with living donors and high levels of DSA.The low-dose IVIg with PP, protocol was modified to include anti-thymocyte globulin for induction along with the addition of rituximab and splenectomy to decrease rate of acute rejection
High dose IVIG showed higher rate of AMR, so Rituximab was added
3.Other agents used in desensitization include :
Benefits of desensitization
Multi-centre study in the US on the survival benefit of kidney transplant from HLA-incompatible live donors showed that recipient of kidney transplant from in-computable live donor had a higher survival rate than waiting list or transplant from deceased donor at 1 year, 3 years, 5 years and 8 years.
Study in UK adult transplant centre showed no difference in survival between patients who underwent a HLA-incompatible transplant compared with the listed only group, or listed or transplant group
Comparing these two studies is difficult as two studies have different definitions of sensitization have different matching methods for patients awaiting a transplant. Study different population different so go economic factors and different study period in two populations
Long-term risks of desensitization
It is difficult to determine the impact desensitization therapies have on the long-term health since most published studies are short-termed.
Desensitization therapies add to overall immunosuppression raising the obvious concerns of infection and other immunosuppression related complications including malignancies.
Some of studies showed high prevalence of infection and other no so it is important to recognize that infection-related mortality is a risk factor to desensitization
More studies are necessary to arrive at stronger conclusion.
Cost-effectiveness of desensitization
Desensitization therapies significantly increase the cost of the transplant procedure.
While desensitization treatments increase the cost of transplant, the overall economic impact needs to be considered in light of longer survival and a reduced need for haemodialysis.
The cost-effectiveness of incompatible living donor transplant was assessed using a discrete event simulation model . Over 10 years, incompatible living donor kidney transplant was associated with a greater mean cost of care ($440 234 vs. $292 117) and longer mean survival (5.47 years vs. 4.03). Thus, the incremental cost-effectiveness of desensitization was estimated to be $80 486 per quality-adjusted life year. In comparison, compatible living donor transplant was estimated to cost $39 939 per quality-adjusted life year.
The different techniques of desensitisation.
Plasmapheresis involve the removal of antibodies in the body. Plasmapharesis is only short-lived. The antibodies rebounding to pretreatment levels following re-equilibration between intravascular and interstitial compartments. It does not affect ongoing antibody production. Thus, it is a poor treatment choice for desensitization as sole therapy. The side effects include coagulopathy, hypocalcemia, thrombocytopenia, hypotension and CRBSI and infection.
Intravenous immunoglobulin (IVIg) inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation . IVIg-based desensitization can be divided into two general approaches: combined with alternate day PP at a low dose (100 mg/kg); or used at a high dose (1–2 g/kg) . Low-dose IVIg and PP protocols have been used for ESRD patients with living donors and high levels of DSA. Depending on the titres of antibodies patients undergo varying numbers of PP sessions (higher titres, more sessions of PP) followed with the infusion of IVIg. Using low-dose IVIg with PP, AMR has been reported to be as high as 36% with 100% 1-year graft survival. The low-dose IVIg with PP, protocol was modified to include anti-thymocyte globulin for induction along with the addition of rituximab and splenectomy in an attempt to reduce the rejection rate. High-dose IVIg-based protocols for desensitization have been reported in many single centre experiences with variable results.
Other agents used in desensitization list as following:
1. Bortezomib (BTZ) is a proteasome inhibitor.
2. Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation.
3. Interleukin (IL)-6 is a pleiotropic cytokine that has powerful stimulatory effects on B cells and plasma cells.
4. Tocilizumab (TCZ) a humanized monoclonal antibody directed at the IL-6 receptor.
5. IgG-degrading enzyme derived from Streptococcus pyogenes .
6. Daratumumab is an IgG1j human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts.
Benefits of desensitization
The benefits of desensitization in term of survival rate were controversial due to the different definitions of sensitisation and matching methods for patients awaiting a transplant.
Long-term risks of desensitization
Infection.
Malignancy.
Cost-effectiveness of desensitization
The arbitrary incremental cost-effectiveness of desensitization was estimated to be $80 486 per quality-adjusted life year. In comparison, compatible living donor transplant was estimated to cost $39 939 per quality-adjusted life year. Generally, the incompatible living donor kidney transplant was associated with a greater mean cost of care and longer mean survival.
Summary
Introduction
Sensitization can occur through blood transfusions, pregnancy or a previous transplantation. This can be a barrier to a good outcome. The extent of sensitization is calculated using cPRA, wherein 0% indicates no anti-HLA antibody, while 100% indicates incompatibility with the donor pool. This is crucial, since sensitization can lead to AMR, early loss of graft, and a higher chance of death while on waiting list.
Different techniques of desensitization
The goal of sensitization is to reduce DSA and thereby prevent hyper acute rejection, increasing the chances of a good outcome.
Desensitization protocols combine removing circulating DSA with plasmapheresis with agents that decrease antibody production or block their actions.
IVIG inhibits T and B cell proliferation, cytokine production, maturation of dendritic cells and induce B cell apoptosis and inhibit complement activation.
Other drugs used in desensitization include :
Benefits of desensitization
Long term risks of desensitization
Cost effectiveness of desensitization
Conclusion
Patients with DSA and high levels of HLA antibodies can go for desensitization in order to have good outcome post transplant. The cost is higher for patients requiring desensitization. IVIG and plasma exchange form the cornerstone of desensitization with other agents available as well. An alternative to desensitization is kidney paired donation programmes. KPD is associated with better outcomes and lower costs while providing access to organs where immunological barrier can be avoided. If KPD is not possible then desensitization should be considered.
Newer medications to modify antibody mediated graft injury post transplant are being researched for better outcome for more patients.
🍁Transplant candidates with a cPRA 98% are in a dire situation, as mortality rates on dialysis exceed those of most forms of cancer
🍁Four transplant possibilities are currently available for this high cPRA more than 98% group of dialysis patients :
*wait for poper donor (takes very long time)
*Cross immuno barrier
*kidney paired donation program
*Desensitization
🍁The authors concluded that PP/low-dose IVIG and rituximab demonstrated more success in abrogating positive crossmatch and lower acute rejection rates, but no regimen was completely effective in preventing AMR.
🍁the PI BTZ might deplete antibody-secreting long-lived plasma cells and have an impact on DSA production
🍁Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation
🍁Interleukin (IL)-6 is a pleiotropic cytokine that has powerful stimulatory effects on B cells and plasma cells and is responsible, in conjunction with other cytokines, for normal antibody production. It has also been recognized as an important mediator of allograft rejection
🍁IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS) that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization
Since the Fc region of IgG is critical for interaction with Fc receptors and complement binding, proteolytic activity on IgG molecules at this site prevents the occurrence of IgG-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity,
🍁Daratumumab is an IgG1j human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts.
🍁There is no desensitization strategy that can universally allow transplantation in the presence of significant levels of anti-HLA antibody to the donor or a positive crossmatch.
🍁Desensitization therapies add to overall immunosuppression raising the obvious concerns of infection and other immunosuppression related complications including malignancies.
🍁desensitization therapies significantly increase the cost of the transplant procedure.
🍁Alternatives to desensitization: kidney paired donation
-Desensitiztion in kidney transplant=A risky (but necessary)
What is the take-home message advised by this article?
Highly sensitized patients without living donors where pared exchange is not possible and expected wait time is considered unacceptable so proceeding with desensitization may be reasonable consideration
So those patients at the highest risk of posttransplant immunologic injury following desensitization and emphasizes the importance of careful antibody maintaining throughout the post renal transplant period
Desensitization strategies: is it worth it?
Discuss the following:
· The difference techniques of desensitization
· Benefits of desensitization
· Long-term of desensitization
· Cost effectiveness of desensitization
Difference techniques of desensitization:
1. Plasmapheresis:
Non-specific removal of antibodies including clotting factors
Disadvantages: short-lived with antibodies rebounding and PP does not affect ongoing antibody production by plasma cells.
Side effects include: coagulopathy, hypocalcaemia, thrombocytopenia, hypotension and catheter-related infection and sepsis.
2. Intravenous immunoglobulin (IVIG)
· Inhibit B and T-cell proliferation
· Cytokines production
· Maturation of dendritic cells
· B-cell apoptosis
· Inhibit complement activation
IVIG based desensitization can be divided in two:
1) Alternative day PP at a low dose 100mg/kg
2) High dose 1-2 gm/kg
· Combination of IVIG and PP used for ESRD patients with living donors and high levels of DSA
· Combination of PP, low dose IVIG, and Rituximab is lower the pastime crossmatch and outcome rejection rate compare to high dose IVIG
3. Bortezomib (BTZ):
Is a proteasome inhibitor and cause inhibition and apoptosis of normal and transformed plasma cells.
Had more study and trials to be evaluated
4. Eculizumab:
Humanized monoclonal antibody that blocks cleavage of human complement C5 and prevent terminal complement activation
Expensive medication
Pre dose vaccination for encapsulated organisms
It is effective in prevention AMR in renal transplant recipient who had positive crossmatch against their living donor
5. Interleukin (IL-6):
Is a pleiotropic cytokine that has powerful stimulating effects on B cells and plasma cells and is responsible in conjunction with other cytokines for normal antibody production?
6. Tocilizumab (TCZ):
A humanized monoclonal antibody direct at the IL-6 receptor
Phase 1,2 pilot study was performed with TCZ and IVIG to eliminate anti-HLA antibodies as well as test its safety and efficacy in desensitization agent.
Larger controlled studies are essential to better study its efficacy
7. Ides:
IgG-degrading enzyme derived from streptococcus pyrogens
Fc region of IgG. Is critical for interaction with Fc receptors and complement binding activity of IgG molecules at this site prevent the occurrence of IgG mediated antibody-depend cellular cytotoxicity and complement mediated cytotoxicity
2 processes are critical for AMR:
Need more studies and trials for efficiency and potential long-term complication
8. Daratumumab:
Is an IgG1k human mAb that binds to CD 38 and inhibit the development of CD 38 expressing cells and plasmablast
However, the reduction of DSA treated animals was not maintained and rapid rebound of antibodies develop with profound rejection
There is no desensitization study that can universally allow transplantation in the presence of significant level of anti-HLA antibody to the donor or appositive crossmatch
Challenge question of whether sensitized patients are better of waiting on dialysis or undergoing desensitization
2 large multi-centre studies have attempted to answer this different dilemma
Benefit of desensitization:
Multi-centre analysis on the survival benefit of kidney transplant from HLA-incompatible live donors examined .the result across 22 centre in the US with 1025 recipient
The result that recipient of kidney transplant from incomputable live donor had a higher survival rate than waiting list or transplant from deceased donor
Study in UK adult transplant centre
Result of study in this centre no difference in survival was noted between patients who underwent a HLA-incompatible transplant compared with the listed early group
Comparing these two studies is difficult as two studies have different definitions of sensitization have different matching methods for patients awaiting a transplant. Study different population different so go economic factors and different study period in two populations
Long-term risk of desensitization:
It is difficult to determine the impact desensitization therapies have on the long-term health since most published studies are short-termed
Desensitization therapy add to are all immunosuppression raising 2 risks for recipient transplant patient:
1) Infection
2) Malignancies
Some of studies showed high prevalence of infection and other no so it is important to recognize that infection-related mortality is a risk factor to desensitization
More studies are necessary to arrive at stronger conclusion
Economic assessment of desensitization:
Desensitization therapies significantly increase the cost of the transplant
Desensitization treatment increase the cost of transplant the overall economic impact need to considered in hight of longer survival and reduced need for haemodialysis
The cost-effectiveness of incompatible living donor was assessed using a discrete event stimulation model over 10 years incompatible living donor kidney transplant was associated with a greater mean cost of care
$440.234
$292.117
Mean survival==years vs 4-0-3
In comparison, compatible living donor transplant was estimated to cost $39.9 regularly adjust life year to $ 80.48 regularly adjust life year
Conclusion:
The choice of desensitization or not remaining difficult and should be approach individually rather than group.
For patients with DSAs and high level of HLA antibodies paired donor exchange programme and transplant chains can provide access to organs where immunological barrier can be avoided.
Introduction
Renal transplantation is the preferred treatment of choice as
ü it improves their survival,
ü quality of life
ü costs lower after the first year compared to dialysis
sensitization to (HLA) from
o blood transfusions,
o pregnancy or
o aprevious transplantation
is an additional barrier to successful outcomes.
extent of sensitization is reflected in the calculated panel reactive antibody
(cPRA) score that can range from 0% indicating no anti-HLA antibody, to 100% that predicts incompatibility with 100% of the donor pool.
The presence of a cPRA <80% creates difficulty in finding matched kidneys
highly sensitized patients have
ü higher rates of (ABMR),
ü early graft loss
ü a higher chance of being removed from or dying on the waiting list.
Transplant candidates with a cPRA 98% are in a bad situation, as mortality rates on dialysis exceed those of most forms of cancer.
Four transplant possibilities are currently available for dialysis patients.
1.to wait for deceased donor transplant,
2.a living donor
3.a kidney paired donation (KPD) programme
4.desensitization procedure.
Desensitization can increase access to both living and deceased donor transplants and can be used individually or in combination with KPD.
Desensitization treatments
The goal of desensitization is to reduce/eliminate DSA, thereby preventing hyperacute rejection and allowing a successful transplantation.
Desensitization protocols have typically combined an approach of removing circulating DSA with plasmapheresis (PP) ,combined with agents that decrease antibody production, or ones that block their actions.
Plasmapheresis removes antibodies from the circulation.
It is not specific for the removal of alloantibodies and all plasma proteins are reduced including clotting factors.
But the removal is only short-lived with antibodies rebounding occur .
PP does not affect ongoing antibody production by plasma cells therefore it is a poor treatment choice for desensitization as sole therapy.
Its side effects include
1. coagulopathy,
2. hypocalcemia,
3. thrombocytopenia,
4. hypotension
5. catheter-relatedinfection and sepsis.
Intravenous immunoglobulin (IVIg) derived from the gamma globulin fraction of plasma from pooled donors
Action :-
inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells,induce B-cell apoptosis and inhibit complement activation
IVIg-based desensitization can be divided into two general approaches: combined with alternate day PP at a low dose (100 mg/kg); or
used at a high dose (1–2 g/kg) .
conclusion: IVIg ( both low and high dose )as a sole treatment is not adequate for treatment of high sensitized patients.
If combined with PP may produce better transplant outcome , although the ABMR is still higher ( around 30%) with lower patient and graft survival than in patient without sensitization .
In another study the conclusion was, that PP/low-dose IVIG and rituximab
demonstrated more success in abrogating positive crossmatch and lower acute rejection rates, but no regi men was completely effective in preventing AMR.
The addition of rituximab or splenectomy did not appear to decrease the acute AMR rate.
Another study to assess the role of IVIg to reduce DSA shows , IVIg was associated with a modest decrease in reactivity to both class I and II HLA antigens but did not significantly alter mean cPRA.
Bortezomib (BTZ) is a proteasome inhibitor (PI) that induces apoptosis in normal and transformed plasma cells. PI BTZ might deplete antibody-secreting long-lived plasma cells and have an impact on DSA production.
One study shows – no patient developed a negative crossmatch against their original intended donor, and the calculated panel reactive was unchanged in all patients .
Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation.
It has been shown to be efficacious in the prevention AMR in renal transplant recipients who had a positive crossmatch against their living donor.
Side effects : infection with encapsulated microorganisim, costs ( it is very costy )
Interleukin (IL)-6 is a pleiotropic cytokine that has powerful stimulatory effects on B cells and plasma cells and is responsible, in conjunction with other cytokines, for normal antibody production.
It has also been recognized as an important mediator of allograft rejection.
The conclusion of one study — TCZ with IVIg appears to be an additional agent with potential in desensitization.
IgG-degrading enzyme derived from Streptococcus pyogenes(IdeS)
that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization.
It prevents the occurrence of IgG-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity .
Result :
IdeS reduced or eliminated DSAs and permitted HLA incompatible transplantation in 24 of 25 patients. AMR occurred in 10 patients at 2 weeks to 5 months after transplantation; all these patients had a response to treatment.
Daratumumab is an IgG1j human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts.
Evidence weak only animal studies .
Despite the availability of the above-described agents for desensitization, the quality of evidence comparing one to another is poor.
Benefits of desensitization
whether sensitized patients are better of waiting on dialysis or undergoing desensitization ?
two study try to answer this question .
first study showed the beneficial effect of transplantation of highly sensitized patient with desensitization , regarding patient and graft survival second study shows no benefit over remaining on dialysis .
Long-term risks of desensitization
Desensitization thera pies add to overall immunosuppression raising the obvious concerns of infection and other immunosup pression
related complications including malignancies.
Economic assessment of desensitization
desensitization therapies significantl increase the cost (42%) of the transplant procedure
Alternatives to desensitization: kidney paired donation
Inits simplest form, KPD is an exchange of donors between two incompatible pairs such that they are now compatible.
Traditionally pairs were entered into the registry due to ABO incompatibility but the use of KPD has extended and now commonly involves highly sensitized recipients.
Different techniques of desensitization
The aim of desensitization is to reduce DSA and prevent rejection.
Desensitization protocols:
–Plasmapheresis:
It removes antibodies also clotting factors
Disadvantages:
Transient effect and antibodies rebounding as it doesn’t affect antibody production by plasma cells.
Coagulopathy , electrolyte disturbance
-Intravenous immunoglobulin (IVIG)
it Inhibits B and T-cell proliferation, cytokines release, maturation of dendritic cells and complement activatio
Other drugs used in desensitization include :
*Bortezomib
*Eculizumab
*Tocilizumab
Benefits of desensitization:
–Allowing highly sensitized patient to doing renal transplant
-less expensive if compared with continuing on dialysis
Long term risks of desensitization:
–infection
-Malignancy
Cost effectiveness of desensitization
-Desensitization increases the total cost of the transplant but provide better quality of life also longer survival .
Cost-effectiveness of desensitization:
– While desensitization treatments increase the cost of transplant, the overall economic impact needs to be considered in light of longer survival and a reduced need for dialysis.
– Desensitisation cost of care 42% , CDC positive 58 % and Flowcytometry crossmatch positive 38 % in comparison to mean cost of care than remaining on dialysis.
Long-term risks of desensitization
– raising the obvious concerns of infection and other immunosuppression related complications including malignancies.
– The most common cause of death was
infection-related. Multivariable risk factor analysis
revealed that desensitization attempts rather than ABO or HLA incompatibility were more significant risk factors for infection-related mortality.
Benefits of desensitization :
Helps highly desensitised patients who not getting cadaveric or living donor and expected for long waiting list which leads best quality of life reflecting on patient and graft survival.
The different techniques of desensitisation:
– The goal of desensitization is to reduce/eliminate DSA, thereby preventing hyperacute rejection and allowing a successful transplantation.
– different methods for desensitisation:
1- PLASMAPHERESIS ALONE :
removes antibodies from the circulation. This technique is not specific for the removal of
alloantibodies and therefore all plasma proteins are reduced including clotting factors. However, this removal is only short-lived with antibodies rebounding to pretreatment levels following re-equilibration between intravascular and interstitial compartments. More importantly, PP does not affect ongoing antibody production by plasma cells and, hence, is a poor treatment choice for desensitization as sole therapy. Its side effects include coagulopathy, hypocalcemia,
thrombocytopenia, hypotension and catheter-related infection and sepsis.
2- IVIG:
– derived from the gamma globulin fraction of plasma from pooled donors has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells,
induce B-cell apoptosis and inhibit complement activation.
* either :
a – low dose ( 100 mg/ kg ) with plasmapheresis.
( it shows AMR 36 % with 100 % graft survival)
b – low dose IVIG with plasmapheresis, ATG ,rituximab and splenectomy.
( acute AMR rate was 43% with
a 78% graft survival at 15 months. A similar high incidence of acute AMR of 39% and graft survival of 89%was noted with a median follow-up of 22 months )
c- High dose of IVIG ( 2g/kg) :
used in cadaveric transplant with slight decrease in PRA level .
e- high dose of IVIG Alone with rituximab .
3- Bortezomib (BTZ)
is a proteasome inhibitor (PI) that induces endoplasmic reticulum stress, NFjB inhibition and apoptosis in normal and transformed plasma cells. This led to the hypothesis that treatment with the PI BTZ might deplete antibody-secreting long-lived plasma cells and have an impact on DSA production.
– no patient developed a negative crossmatch against their original intended donor, and the calculated panel reactive was unchanged in all
patients.
4- Eculizumab
– is a humanized monoclonal antibody that
blocks cleavage of the human complement component C5 and prevents terminal complement activation. It has been shown to be efficacious in the prevention AMR in renal transplant recipients who had a positive crossmatch against their living donor.
– It is unfortunately quite expensive with an average wholesale price of $21 000 per
dose . Another consideration is the risk of development of invasive infections with encapsulated organisms during eculizumab therapy due to which certain vaccinations are pre requisite .
5- Tocilizumab (TCZ)
IL 6 antagonist, a humanized monoclonal
antibody directed at the IL-6 receptor has also been studied as a potential desensitization agent. A phase I/II pilot study was performed with TCZ and IVIg to reduce and eliminate anti-HLA antibodies as well as test its safety and efficacy in desensitization.
6- IgG-degrading enzyme :
derived from Streptococcus pyogenes (IdeS) that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization .Since the Fc region of IgG is critical for interaction with Fc receptors and complement binding, proteolytic activity on IgG molecules at this site prevents the occurrence of IgG-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity, two processes that are critical for AMR.
– All crossmatches became negative post- IdeS and the patients underwent successful transplantation. Three patients had DSA rebound and AMR, which responded to SOC therapies. At a median follow-up of 235 days, all patients had a functioning renal allograft.
7- Daratumumab
– is an IgG1j human mAb that binds to
CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts. In this context, its potential to control the production of antiHLA antibodies in a nonhuman primate was tested.
The different techniques of desensitisation :
Four transplant options are currently available for this disadvantaged group of dialysis patients. The first is to wait for a compatible deceased donor transplant, which may take years without a suitable donor ever being identified .Fortunate ones who have a living donor can undergo transplantation if the immunological barrier can be successfully crossed (option 2). Patients for whom a living donor transplantation is not possible due to unacceptable antibodies, have the option of enrolling in a kidney paired donation (KPD) programme (option 3) or undergoing a desensitization procedure (option 4).
Desensitization therapies target removing and/or reducing donor-specific antibodies (DSA) prior to transplantation.
Desensitization can increase access to both living and deceased donor transplants and can be used individually or in combination with KPD.
Desensitization protocols have typically combined an approach of removing circulating DSA with plasmapheresis (PP) ,combined with agents that decrease antibody production, or ones that block their actions.
1-Plasmapheresis removes antibodies from the circulation. This technique is not specific for the removal of alloantibodies and therefore all plasma proteins are reduced including clotting factors. However, this removal is only short-lived with antibodies rebounding to pretreatment levels following re-equilibration between intravascular and interstitial compartments .More importantly, PP does not affect ongoing antibody production by plasma cells and, hence, is a poor treatment choice for desensitization as sole therapy. Its side effects include coagulopathy, hypocalcemia, thrombocytopenia, hypotension and catheter-related infection and sepsis.
2-Intravenous immunoglobulin (IVIg) derived from the gamma globulin fraction of plasma from pooled donors has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation .It was first utilized in combination with PP in crossmatch incompatible living donor kidney transplant candidates .
IVIg-based desensitization can be divided into two general approaches:
combined with alternate day PP at a low dose (100 mg/kg); or used at a high dose (1–2 g/kg).
a-Low-dose IVIg and PP protocols have been used for ESRD patients with living donors and high levels of DSA. Depending on the titres of antibodies patients undergo varying numbers of PP sessions (higher titres, more sessions of PP) followed with the infusion of IVIg. Using low-dose IVIg with PP, AMR has been reported to be as high as 36% with 100% 1-year graft survival [22]. The low-dose IVIg with PP, protocol was modified to include anti-thymocyte globulin for induction along with the addition of rituximab and splenectomy in an attempt to decrease high acute rejection rates .
b-High-dose IVIg-based protocols
c-Rituximab plus high-dose IVIg (2 g/kg) based regimen
Administration of IVIg was associated with a modest decrease in reactivity to both class I and II HLA antigens but did not significantly alter mean cPRA.
The effects of high-dose IVIG (2 g/ kg) and Rituximab were examined in a prospective study on desensitizing transplant candidates with a cPRA >50% waiting for a deceased donor kidney for more than 5 years. It showed no significant reduction in patients’ class I and II cPRA levels nor any change in the mean number of unacceptable antigens or their mean fluorescence intensity values . These studies question the ability of IVIg alone to meaningfully decrease sensitization status. The higher transplant rates noted could be due to non-anti-HLA lowering or immunomodulatory effects of IVIg such as inhibition of complement.
3-Bortezomib (BTZ) is a proteasome inhibitor (PI) that induces endoplasmic reticulum stress, NFjB inhibition and apoptosis in normal and transformed plasma cells.
4-Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation. It has been shown to be efficacious in the prevention AMR in renal transplant recipients who had a positive cross- match against their living donor.
5-Tocilizumab (TCZ) a humanized monoclonal antibody directed at the IL-6 receptor has also been studied as a potential desensitization agent.
Interleukin (IL)-6 is a pleiotropic cytokine that has powerful stimulatory effects on B cells and plasma cells and is responsible, in conjunction with other cytokines, for normal antibody production. It has also been recognized as an important mediator of allograft rejection .
6-IgG-degrading enzyme derived from Streptococcus pyo- genes (IdeS) that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization
7-Daratumumab is an IgG1j human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts.
Despite the availability of the above-described agents for desensitization, the quality of evidence comparing one to another is poor. There is no desensitization strategy that can universally allow transplantation in the presence of significant levels of anti-HLA antibody to the donor or a positive crossmatch. Despite combining the available therapies in different protocols abrogating the response of high levels of preformed DSA has posed a significant challenge with unacceptable rates of AMR after transplantation. This has led to a challenging ques- tion of whether sensitized patients are better of waiting on dialysis or undergoing desensitization.
Benefits of desensitization :
Higher survival rate when compared to patients on waiting list.
Long-term risks of desensitization :
1-Desensitization thera- pies add to overall immunosuppression raising the obvious concerns of infection and other immunosup- pression related complications including malignancies.
2-motor deficits, memory loss and other neurologic symptoms (to rule out reactivation of polyoma JC virus).
3-neurologic symptoms suggestive of progressive multifocal leukoen- cephalopathy, any viral infections [Cytomegalovirus (CMV), Epstein–Barr virus, parvovirus B-19 and BK polyomavirus]
Cost-effectiveness of desensitization :
these strategies are offer improved survival and are cost-effective given nationally accepted bench- marks.
The desensitisation is divided into two moments:
– Removing circulating DAS: for this is utilized plasmapheresis
– Decrease antibody production or your block: When were utilized various drugs to inibited the action of antibodys
So there are several studies using these different drugs
There are varius techniques for decrease antibody production or your block and they vary according to the different protocols that are studied :
– Intravenous immunoglobulin (IVIg) ( Low dose X high dose): inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation.
– Eculizumab ( is a humanized monoclonal antibody) : blocks cleavage of the human complement component C5 and prevents terminal complement activation
– Tocilizumab (TCZ) ( humanized monoclonal antibody ): directed at the IL-6 receptor inhibiting your effects on B cells and plasma cells and is responsible, in conjunction with other cytokines, for normal antibody production
– Daratumumab (IgG1j human mAb): binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasma
It reduces the amount of circulating DSAs decreasing the risk of acute AMR. In US, recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group ( the waiting list ) at 1 year, 3 years, 5 years and 8 years (76.5% vs. 62.9% and 43.9%) (P < 0.001 for all comparisons with the two control groups.
Desensitization therapies increase overall immunosuppression by increasing concerns of infection and other complications related to immunosuppression, including malignancy. However, the rates of these events will vary according to each protocol employed.
Death and chronic rejection are other outcomes analyzed and the results tend to point out that desensitized recipients have worse responses.
In addition to increasing the medical complexity of renal transplant, desensitization therapies significantly increase the cost of the transplant procedure. Some data that corroborate this statement are:
– Incompatible living donor transplant was associated with a 42% increase in the cost of care ($151 024 vs. $106 636 P < .001). The incremental cost was highest in patients with positive cytotoxic crossmatch (58% increase) compared with patients who had only flow positive crossmatch (38% increase).
– Medicare reimbursement was also increased, with mean payment (excluding the cost of organ acquisition) of $92 150 for incompatible vs. $58 084 for compatible transplant;
– Over 10 years, incompatible living donor kidney transplant was associated with a greater mean cost of care ($440 234 vs. $292 117
The different techniques of desensitisation.
THE AIM OF DESENSITIZATION PROTOCOLS IS TO REMOVE PARTIALLY OR COMPLETLTY DSA THUS PREVENTING ACUTE OR CH REJECTION BY ONE THE FOLLOWING METHODS.
1.Plasmapheresis removes antibodies from the circulation, which is not specific for only alloantibodies but also to circulating plasma proteins even clotting factors.
considered apoor way for desensetaization as it doesnt affect the ongoing production of ab by plasmacells,
side effects include oagulopathy, hypocalcemia,thrombocytopenia, hypotension and catheter-related infection and sepsis.
2.Intravenous immunoglobulin (IVIg) it could be combined with alternate day PP at a low dose (100 mg/kg); or used at a high dose (1–2 g/kg) .
3.Bortezomib (BTZ) proteasome inhibitor results in depletion antibody-secreting long-lived
plasma cells and have an impact on DSA production.
4.Eculizumab, prevents complement activation. It helps in the prevention AMR in renal transplant recipients who had a positive cross- match against their living donor.
5.Tocilizumab (TCZ) directed at the IL-6 receptor has also been studied as a potential desensitization agent.
6.IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS):cleaves all four human subclasses of IgG has recently been used as an agent for desensitization
7.Daratumumab control the production of anti-HLA antibodies in a nonhuman primate was tested considered amedical challenge.
Benefits of desensitization
PROVIDE AGOOD CHANCE FOR SEBSETIZED PATIENT FOR TRANSPLANTATION OPPORTUNITY.
REDUCTION OF WAITING LIST TIME.
Long-term risks of desensitization
Immunosuppression used in desensitization raising the
chance of getting infection and other immunosuppression related complications including malignancies and systemic side effects incomarison to success or faliure.
1-A patient’s extent of sensitization is reflected in the calculated panel reactive antibody (cPRA) score that can range from 0% indicating no anti-HLA antibody, to 100% that predicts incompatibility with 100% of the donor pool
The presence of a cPRA greater than 80% creates difficulty in finding matched kidneys from compatible donors and low annual transplant rates
Desensitization treatments
*Plasmapheresis removes antibodies from the circulation. This technique is not specific for the removal of alloantibodies and therefore all plasma proteins are reduced including clotting factors. However, this removal is only short-lived with antibodies rebounding to pretreatment levels following re-equilibration between intravascular and interstitial compartments
PP does not affect ongoing antibody production by plasma cells and, hence, is a poor treatment choice for desensitization as sole therapy. Its side effects include coagulopathy, hypocalcemia, thrombocytopenia, hypotension and catheter-related infection and sepsis.
*Intravenous immunoglobulin (IVIg) derived from the gamma globulin fraction of plasma from pooled donors has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation
IVIg-based desensitization can be divided into two general approaches: combined with alternate day PP at a low dose (100 mg/kg); or used at a high dose (1–2 g/kg)
* Bortezomib (BTZ) is a proteasome inhibitor (PI)
might deplete antibody-secreting long-lived plasma cells and have an impact on DSA production
*Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation.
The incidence of AMR was 7.7% (2/26) in the eculizumab group compared to 41.2% (21/51) in the control group
*Tocilizumab (TCZ) a humanized monoclonal antibody directed at the IL-6 receptor has also been studied as a potential desensitization agent. A phase I/II pilot study was performed with TCZ and IVIg to reduce and eliminate anti-HLA antibodies as well as test its safety and efficacy in desensitization
*IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS) that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization
*Daratumumab is an IgG1j human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts. In this context, its potential to control the production of antiHLA antibodies in a nonhuman primate was tested.
2-Benefits of desensitization
Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year (95.0% vs. 94.0% for the waiting list
Decreased waiting time in waiting list in patients on dialysis
3-Long-term risks of desensitization
Desensitization therapies add to overall immunosuppression raising the obvious concerns of infection and other immunosuppression related complications including malignancies.
Monitoring for adverse events and serious adverse events was continued after transplantation for a mean of 22.1 +_6.0 months. No patients had neurologic symptoms suggestive of progressive multifocal leukoencephalopathy, nor [Cytomegalovirus were (CMV), any viral Epstein–Barr infections virus
parvovirus B-19 and BK polyomavirus] detected
Patient survival rate was reduced in patients who underwent incompatible transplants (ABO, HLA, ABO+HLA) compared to standard transplants. The most common cause of death was infection-related
4-Economic assessment of desensitization
desensitization therapies significantly increase the cost of the transplant procedure.
Incompatible living donor transplant was associated with a 42% increase in the cost of care ($151 024 vs. $106 636 P < .001). The incremental cost was highest in patients with positive cytotoxic crossmatch (58% increase) compared with patients who had only flow positive crossmatch (38% increase).
Thus, the incremental cost-effectiveness of desensitization was estimated to be $80 486 per quality-adjusted life year. In comparison, compatible living donor transplant was estimated to cost $39 939 per quality-adjusted life year.
Desensitization strategies: is it worth it?
Narrative review: level 5 evidence
Desensitization protocol is to achieve a successful transplantation by preventing hyperacute rejection which involves preventing formation and action of antibodies as well as removing the formed antibodies from circulation.
Plasmapheresis alone: Nonspecific removal of antibodies, which is short lived (due to rebound) and hence not successful.
Intravenous immunoglobulin (IVIG): IVIG can be used in either low dose or high does.
Low dose IVIG and plasmapheresis with or without rituximab has shown results superior to use of high dose IVIG alone.
Bortezomib:
Eculizumab:
Tocilizumab: It is an antibody against IL-2 receptor which, when used with IVIG in patients unresponsive to IVIG and rituximab, showed good results post-transplant with no AMR at 6 months and good graft function at 1-year post-transplant.
IgG degrading enzyme derived from Streptococcus pyogenes (IdeS): It causes proteolysis at Fc region of IgG. Its use has been shown to be associated with approximately 40% AMR which were treated. Long term effects including infections and malignancies need to be evaluated.
Daratumumab: It is a CD38 inhibitor and has been used in non-human primates showing marked reduction in antibody levels which was short-lived, hence associated with severe rejections.
Benefits of desensitization
Long-term risks of desensitization
use of IVIG, plasmapheresis and rituximab desensitization has similar infection rates while eculizumab use increases the infection rates by 50%.
Reduced patient survival due to increased infections has been observed in large study
Cost-effectiveness of desensitization
Desensitization treatments:
The goal of desensitization is to reduce or eliminate DSA, thereby preventing
hperacute rejection and allowing a successful transplantation.
It combined an approach of removing circulating DSA with plasmapheresis (PP),
combined with agents that decrease antibody production, or ones that block their
actions.
Plasmapheresis:
Advantage:
Removes antibodies from the circulation.
Disadvantage:
Not specific for the removal of alloantibodies and therefore all plasma proteins are
reduced including clotting factor risk of coagulopathy
Removal is only short-lived with antibodies rebounding to pretreatment levels
following re-equilibration between intravascular and interstitial compartments.
More importantly, PP does not affect ongoing antibody production by plasma cells
and, hence, is a poor treatment choice for desensitization as sole therapy.
Other side its side include, hypocalcemia, thrombocytopenia, hypotension and
catheter-related infection and sepsis.
Intravenous immunoglobulin:
derived from the gamma globulin fraction of plasma from pooled donors has been
shown to inhibit T- and B-cell proliferation, cytokine production, maturation of
dendritic cells, induce B-cell apoptosis and inhibit complement activation .
IVIg-based desensitization:
Two general approaches:
Combined with alternate day PP at a low dose (100 mg/kg).
Used at a high dose (1–2 g/kg).
Other agents used in desensitization:
Bortezomib (BTZ):
PI that induces endoplasmic reticulum stress, NFjB inhibition and apoptosis .
In a study aimed to determine the safety and efficacy of 32 doses of BTZ in 10
highly sensitized kidney transplant candidates with alloantibodies against their
intended living donor, no patient developed a negative crossmatch against their
original intended donor, and the calculated panel reactive was unchanged in all
patients
Eculizumab:
Is a humanized monoclonal antibody that blocks cleavage of the human
complement component C5 and prevents terminal complement activation.
Potential benefit for Eculizumab compared with SOC in preventing acute AMR in
recipients sensitized to their living-donor kidney transplants groups.
Disadvantage:
It is unfortunately quite expensive with an average wholesale price of $21 000 per
dose.
Risk of development of invasive infections with encapsulated organisms during
Eculizumab therapy due to which certain vaccinations are pre requisite .
Tocilizumab (TCZ):
Humanized monoclonal antibody directed at the IL-6 receptor has also been
studied as a potential desensitization agent. Further studies needed.
IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS):
That cleaves all four human subclasses of IgG has recently been used as an agent
for desensitization.
Twenty-five highly HLA-sensitized patients at two international centres (Sweden
and Unites States) were administered IdeS before the transplantation of a kidney
from an HLA-incompatible donor. Out of the 25 patients, 22 had DSA present
before transplantation. IdeS reduced or eliminated DSAs and permitted
HLA incompatible transplantation in 24 of 25 patients. AMR occurred in 10 patients
at 2 weeks to 5 months after transplantation; all these patients had a response to
treatment. The difference in immunosuppressive regimens used is noteworthy.
Daratumumab:
Is an IgG1j human mAb that binds to CD 38 and inhibits the development of CD 38
expressing cells including plasma cells and plasmablasts? It raises the possibility
of another potential therapeutic strategy, it shows that the removal of pathogenic
HLA antibodies is still a considerable medical challenge.
Recipients of kidney transplants from incompatible live donors had a higher
survival rate than either control group at 1 year (95.0% vs. 94.0% for the waiting
list or transplant control group and 89.6% for the waiting list-only control group), 3
years (91.7% vs. 83.6% and 72.7%, respectively), 5 years (86.0% vs. 74.4% and
59.2%) and 8 years (76.5% vs. 62.9% and 43.9%) (P < 0.001 for all comparisons
with the two control groups).
Though comparative studies show no statistical difference in infectious and
malignant risk, still this risk should be considered as an additive to other IS used in
transplant.
Desensitization therapies significantly increase the cost of the transplant
procedure.
Incompatible living donor transplant was associated with a 42% increase in the cost
of care ($151 024 vs. $106 636 P < .001).
Medicare reimbursement was also increased, with mean payment (excluding the
cost of organ acquisition) of $92 150 for incompatible vs. $58 084 for compatible
transplant.
Economic impact needs to be considered in light of longer survival and a reduced
need for hemodialysis.
Desensitization get rid of DSA partially or completely to prevent rejection.
Desensitization techniques include:
1- Removal of circulating DSA with plasmapheresis.this is short lived technique. Side effects are coagulopathy, hypocalcemia, thrombocytopenia, hypotension and catheter-related infection and sepsis.
2- Reduction of antibody production (rituximab, Bortezomib)
3- Blockage of antibodies actions through Intravenous immunoglobulin. IVIg inhibit lymphocytes proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation. This technique can be used combined with alternate day PP at a low dose (100 mg/kg); or used at a high dose (1–2 g/kg). Low-dose approach was associated with high risk of AMR approaching 36% with 100% 1-year graft survival. So anti-thymocyte globulin induction, rituximab and splenectomy were included but with no success in reducing the rate of AMR.High-dose IVIg-based protocols improve the rate of transplant at two years,with higher acute rejection rate .induction with Zenapax, alemtuzumab or Thymoglobulin showed no differences in the rates of AMR.
Rituximab with high-dose IVIg (2 g/kg) was associated with 50% acute rejection episodes and 30% AMR. It did not significantly alter mean cPRA .
Combinations of PP, low-dose IVIG and rituximab or combination of PP, lowdose IVIG, rituximab and pretransplant anti-thymocyte globulin can producea negative crossmatch at a rate of 84% and 88% with low acute AMR 37% and 29% respectively.
Bortezomib induces endoplasmic reticulum stress, NFjB inhibition and apoptosis in normal and transformed plasma cells. It was associated with a low acute rejection rate (18.8%).
Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation. It is associated with AMR rate of 7.7% but it is expensive ($21 000 per dose) and there is risk of developmentof invasive infections with encapsulated organisms.
Interleukin (IL)-6 is a pleiotropic cytokine that has powerful stimulatory effects on B cells and plasma cells and is responsible, in conjunction with other cytokines, for normal antibody production and is a mediator of allograft rejection.
Tocilizumab (TCZ) a humanized monoclonal antibody directed at the IL-6 receptor. TCZ and IVIg showed promising effects in in unresponsive patients to desensitization with IVIg and Rituximab.
IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS) that cleaves all four human subclasses of IgG preventing IgG-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity. It induces the crossmatches to became negative.
Daratumumab is an IgG1j human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts. Animals treated with daratumumab had significantly reduced DSA levels compared to untreated controls. However, the reduction was not maintained and rapid rebound of antibodies developed with profound rejection.
1. It reduce the time on waiting list
2. provide a chance for those who are highly sensitized
3. Due to limited number of organs, desensitization offer a chance for meeting the required organs
Desensitization is associated with higher rates of infection and immunosuppressant related complications including malignancies.
The survival rate up to 8 years of recipient of incompatible live donors was better in a multi-centre analysis of 1025 patients when compared with those remained on the waiting list or received a transplant from a deceased donor (waiting list or transplant control group) and controls who remained on the waiting list but did not receive a transplant (waiting list only control group).
A study in UK showed similar survival. There was selection bias in the former study. In spite of that, desensitization is not inferior to other options.
Some studies found no difference in bacterial, viral, fungal or serious infections over an 18-month follow-up period . In general, Multivariable risk factor analysis showed that desensitization was significant risk factor for infection-related mortality. Compared to ABO or HLA incompatibility .
Drawbacks are medical complexity, high cost with a 42% increase in the cost of care. Benefits are longer survival and a reduced need for haemodialysis. Over 10 years, the incremental cost-effectiveness of desensitization was $80 486 per quality-adjusted life year while compatible living donor cost $39 939 per quality-adjusted life year. The mean survival was longer in the incompatible living donor kidney transplant (5.47 years vs.4.03).
Desensitization is the techniques of reduction/elimination of DSAto prevent hyper-acute rejection and permit successful transplantation. Two process ; antibody removal by PP and use of agents to reduce antibody production or block their actions[16]
Desensitization techniques ;
Problems ; 1. Re-bound[16] 2. Doesn’t affect ongoing anti-body production by plasma cells 23. Cannot be used alone
Complications ; 1. Catherter related problems 2.Hypo-tension 3. Coagulopathy( removal of clotting factors and other proteins) 4. Thrombocytopenae 5. Hypocalcemia
2.Intravenous immunoglobulin(IVIG) ; Inhibit lymphocytes proliferation,inhibit cytokine release, inhibit complement activation, apoptosis of B cells, anti-idiotypic antibodies[17,18]
Two protocols ; 1.Low dose 100mg/kg use with alternate PP 2. High dose 2g/kg
protocol was modified to include ATG + Rituximab + Splenectomy
High dose IVIG causes small reduction in PRA levels ~ 10% compared to placebo.
3.Bortezomib(BTZ) ; Is a proteasome inhibitor(PI) that causes endoplasmic reticulum stress, NFkB inhibition , apoptosis of plasma cells. i.e depletes plasma cell and therefore prevent antibody production[39,40]. up now the evidence is not conclusive for the use of PI BZT
4.Eculizumab ; Inhibit C5 & prevent terminal complement activation. It demonstrated efficacy in the prevention of AMR in highly sensitized patients[42]
Limitaion ; 1. Very costly drug 21,000 US dollars per dose 2. High risk of infections with encapsulating organisms
5.Tocilizumab (TCZ) ; IL-6 inhibitor and potential de-sensitizing agents( IL-6 is a pleitropic cytokine with strong stimulatory effect on B cells & plasma cells and it is a key cytokine in anti-body production. IL-6 has been identified as a potential mediator of allograft rejection[46,47]. More studies are needed to confirm the efficay of TCZ
6.IgG-degrading enzyme derived from streptococcus pyogenes(IdeS) ; Cleaves IgG molecules at the FC region and thereby preventing two things ; 1. CDC 2. Ab -dependent cellular cyto-toxicity. This two mechanism are the bases of ABMR. Data from US & Sweden showed IdeS eliminated DSAs and allowed transplantation in almost all the participants. AMR occur in alomost 50% of the patients at week 2 to 5 months and all the patients responded well to treatment[50]
7.Daratumumab ; Anti-CD38 & inhibit the maturation of CD 38 expressing cells like plasma cells & plasma blast.
It has been tried in animal studies(non-human primate)[51]
it reduced DSA significantly but with rapid re-bound and severe rejection.
Benefits of desensitization ; In broad terms ;
1.Permit access to transplantation of highly sensitized patient
2.Improve survival & quality of life
Two large studies examined this matter one from USA & the the other one from UK. The USA cohort showed higher survival rate among desensitized group compared to control group(wait list or transplant group, or wait list only group). The UK data showed NO difference in survival among all groups. The difference could be due to ;
Long-term risk of desensitization ; Most of data are short -termed regarding
desensitization, so it is not easy to make conclusion about the long -term risk of this technique.
Desensitization by it self is a form of extra or additional immunosuppression and therefore the valid concerns are ;
Cost-effectiveness of desensitization ;
☆Desensitization strategies: is it worth it?
_________________________________________
▪︎Desensitization therapies target removing and/or reducing donor- pecific antibodies (DSA) prior to transplantation.
■Desensitization protocols:
______________________________
1) Plasmapheresis (PP):
▪︎ It removes antibodies from the circulation. combined with low dose IVIG
▪︎ Does not affect ongoing antibody production by plasma cells and, hence, is a
poor treatment choice for desensitization as sole therapy.
▪︎Coagulopathy, hypocalcemia, thrombocytopenia, hypotension and catheter-related infection and sepsis are the main side effects of PP.
2) Intravenous Immunoglobulins (IVIgs)
▪︎ Inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation .
▪︎IVIg-based desensitization can be divided into two general approaches: combined
with alternate day PP at a low dose ; or used at a high dose
2.1) Low-dose IVIg (100mg/ kg) and Plasma
pharesis
▪︎ Used for ESRD patients with living donors and high levels of DSA.
▪︎Depending on the titres of antibodies patients undergo varying numbers of PP sessions (higher titres, more sessions of PP) followed with the infusion of IVIg.
▪︎Because of the risk of AMR, this protoco
was modified to:→ Low-dose IVIg and Plasma pharesis +Anti-thymocyte globulin + rituximab + splenectomy.
2.2) High-dose IVIg (1–2 g/kg)
▪︎ Used for highly sensitized patients (cPRA > 50%)
▪︎ High-dose IVIg (2 g/kg) + rituximab are used for more benefit.
●Notes: From the above protocols:
• PP/low-dose IVIG and rituximab demonstrated more success in abrogating positive crossmatch and lower acute rejection rates
• No regimen was completely effective in preventing AMR.
☆Other agents used in desensitization include:
_______________________________________________
1) Bortezomib (BTZ):
Is a proteasome inhibitor (PI) which might deplete antibody-secreting long-lived plasma cells and have an impact on DSA production.
2) Eculizumab:
Is a humanized monoclonal antibody that block C5 activation. But, it is unfortunately quite expensive and increase the risk of development of invasive infections with encapsulated organisms
3) Tocilizumab (TCZ) + IVIg:
– Reduce and eliminate anti-HLA antibodies
-TCZ is a humanized monoclonal antibody directed at the IL-6 receptor.
4) IgG-degrading enzyme:
– Derived from Streptococcus pyogenes (IdeS)
– Cleaves all four human subclasses of IgG.
5) Daratumumab:
Binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts.
■ Benefits of desensitization protocols:
___________________________________________
▪︎Can be considered for patients with rare HLA types, uncommon HLA antigens or very high sensitization levels, when no matches from kidney exchange programmes are forthcoming after a period of time, given the longer expected survival and improved quality of life.
▪︎Desensitization can increase access to both living and deceased donor transplants and can be used individually or in combination with kidney paired donation.
■Long-term risks of desensitization:
_____________________________________
More studies and long term follow up are needed to arrive at stronger conclusion that desensitization protocols increase the risk of infection and immunosuppression related complications including malignancies.
■Cost effectiveness:
_____________________
▪︎ Desensitization therapies increase the cost of the transplant procedure. But, when compared with long-term dialysis treatment, these strategies offer improved survival and are cost-effective given nationally accepted benchmarks.
Q1- The different techniques of desensitization?
1- Plasmapheresis:
Action: removes antibodies from the circulation
Disadvantage:
· it is not specific as it removes all plasma proteins
· its removal is only temporal, as antibodies rebound following re-equilibration between intravascular and interstitial compartments.
· It has no effect on the antibody-producing plasma cell. So it cannot be used as sole therapy
Side effects:
· Coagulopathy, hypocalcemia, thrombocytopenia, hypotension, and catheter-related infection
2- Intravenous immunoglobulin (IVIG):
Action:
a- inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, and complement activation.
b- Induce B-cell apoptosis
It is used with PP, and the IVIG- based desensitization can be divided into two general approaches:
i- Low dose (100 mg/kg) with alternate day PP
Used for ESRD with living donors and high DSA. The number of sessions depends on the DSA titer.
ii- High dose IVIG (2 g/kg): used for patients on the deceased donor waiting list, and highly sensitized.
Both regimes had been combined with rituximab which additive benefit. However; AMR is still high
3- Bortezomib (BTZ): is a proteasome inhibitor (PI)
Action: apoptosis in plasma cells. might deplete antibody-secreting long-lived plasma cells and have an impact on DSA production
4- Eculizumab: is a humanized monoclonal antibody
Action: blocks cleavage of C5 complement, so prevent terminal complement activation. Highly sensitized recipients receiving it posttransplant have a lower rate of AMR 7.7% vs 41.2% for PP protocol in one study.
Disadvantage: quite expensive, and high risk of infection with encapsulated organisms.
5- Tocilizumab (TCZ) monoclonal antibody directed against IL-6 receptor.
6- IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS)
Action: cleaves all four human subclasses of IgG and has recently been used as an agent for desensitization. Therefore interfere with receptor binding and complement binding.
It prevents the occurrence of IgG-mediated antibody-dependent cellular cytotoxicity and complement-mediated
cytotoxicity.
7- Daratumumab is an IgG1j human mAb
Action: it binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts.
The reduction of DSAs with it also was not maintained and rebound rapidly with profound rejection
Q2- The benefit of desensitization:
It allows the transplantation of highly sensitized patients.
Q3- Long term risks of desensitization
Risk of infection, malignancy, development of motor deficits, memory loss and other neurologic symptoms (to rule out reactivation of polyoma JC virus).
Q4- Cost-effectiveness of desensitization?
While desensitization treatments increase the cost of transplants, the overall economic impact needs to be considered in light of longer survival and a reduced need for haemodialysis.
The different techniques of desensitization?
1-Plasmapheresis
*Mechanism: nonspecific removal of circulating Abs
*Drawbacks:
a. only short-lived + rebound increase of antibodies after equilibrium
b. coagulopathy,
c. hypocalcemia,
d. thrombocytopenia
e. hypotension
f. catheter-related infection and sepsis.
2- Intravenous immunoglobulin (IVIg): purified IgG from pooled donors
Mechanism:
*Induce B-cell apoptosis
* Inhibit
– T- and B-cell proliferation
– cytokine production
– dendritic cells maturation
– complement activation
3- rituximab: anti-CD-20
Other:
4- Bortezomib:
*Mechanism: proteasome inhibitor induces plasma cell endoplasmic reticulum stress, NFkB inhibition
and apoptosis i.e. depletion of long-lived plasma cell secreting abs
5-Eculizumab:
*Mechanism: monoclonal antibody blocks cleavage of C5 ( terminal complement activation).
-i.e. prevents AMR in recipients with positive crossmatch against their living donor compared to standard of care.
*Drawbacks:
a. Serious encapsulated organism infection
b. costly
6-Tocilizumab: a humanized monoclonal antibody directed at the IL-6 receptor to prevent the stimulatory effect on B cell
Studied with IVIG
7-IgG-degrading enzyme from Streptococcus pyogenes (IdeS) :
Mechanism: cleaves IgG subclasses
8- Daratumumab is ani CD38 (expressed in plasma cell and plasmablast)
protocols:
-plasmapheresis is not used alone high dose IVIG
-plasmapheresis with low dose IVIG (100mg/Kg):
-plasmapheresis with low dose IVIG (100mg/Kg) +rituximab
-plasmapheresis with low dose IVIG (100mg/Kg) +rituximab+ ATG
In conclusion: the quality of evidence comparing one protocol for sensitization to another is poor, no universal desensitization strategy that allows transplantation in recipients with significant levels of anti-HLA antibody to their intended donor or a positive crossmatch.
Benefits of desensitization:
Of value in patients with high cPRA >80%
Better survival than being on dialysis or receiving a deceased donor`s graft
Long-term risks of desensitization
-The most common cause of death was infection-related.
-Higher rate for AMR, poorer graft survival compared to non-sensitized patient
Cost-effectiveness of desensitization:
Incompatible living donor transplant was associated with a 42% increase in the cost of care, especially in positive CDC XM this is weighted against the longer survival and dialysis-free period. Paired kidney donation is preferred as cost-effective and
Alternatives to desensitization: kidney paired donation
The various desensitization approaches are as follows:
Plasmapheresis is a procedure that removes plasma from the bloodstream.
This procedure eliminates antibodies from the bloodstream at the same time as other plasma proteins that function as clotting factors, resulting in adverse effects such as coagulopathy, hypocalcemia, thrombocytopenia, hypotension, catheter-related infection, and sepsis, among others.
Inhibition of T- and B-cell proliferation, cytokine generation, maturation of dendritic cells, and inhibition of complement activation are some of the ways IVIG works.
According to research released by the Mayo Clinic, the combination of PP/low-dose IVIG and rituximab resulted in decreased incidence of AMR when compared to other regimens.
In the meantime, there is no exact regimen that may be prescribed.
Bortezomib (BTZ) is a proteasome inhibitor that works by reducing antibody-secreting plasma cells, which in turn affects DSA synthesis, among other things.
There was no evidence of a decrease in c PRA levels.
Eculizumab is a humanized monoclonal antibody that inhibits the cleavage of C5 and prevents the activation of the terminal complement cascade in the body.
It protected kidney transplant patients who had a positive crossmatch against their live donor from developing antimicrobial resistance (AMR).
Its most serious adverse effect is the risk of infection with encapsulated organisms, as well as the fact that it is a costly medication.
Tocilizumab (TCZ) is a humanized monoclonal antibody directed against the interleukin-6 (IL-6) receptor. The combination of TCZ and IVIg seems to have favourable effects on desensitization.
It is produced from Streptococcus pyrogenes and acts on FC receptors of IgG to inhibit antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity caused by IgG. It is also used to treat autoimmune diseases.
Its promising agent has been tested in two large centres in a desensitization protocol for highly HLA sensitized patients, with successful depletion of DSA but with a risk of DSA rebound and AMR reported in a significant number of recipients. Ides were used with different induction protocols, including hoarse ATG from a European centre and alemtuzumab from a US centre, all of whom received homogenous triple maintenance therapy.
The advantages of desensitization:
some centres have reported good early graft and patient survival within 1-3 years after desensitization, while others have reported no difference in graft survival when compared to the matched sensitized control group; this diversity in the results is due to the heterogeneity of these studies by using different definitions of desensitization.
The risk of desensitisation/;
Desensitization is a cost-effective treatment option:
It was discovered that an incompatible live donor transplant resulted in an increase in the cost of treatment.
When comparing patients with positive cytotoxic crossmatch to those with positive flow crossmatch, the cost was higher in the former group.
Desensitization protocols have typically combined an approach of removing circulating DSA with plasmapheresis (PP) , combined with agents that decrease antibody production, or ones that block their actions as
1-Intravenous immunoglobulin (IVIg)
inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells,
induce B-cell apoptosis and inhibit complement activation. IVIg-based desensitization
can be divided into two general approaches:
– Combined with alternate day PP at a low dose (100 mg/kg); used for ESRD patients with living donors and high levels of DSA. Depending on the titres of antibodies patients undergo varying numbers of PP sessions (higher titres, more sessions of PP) followed with the infusion of IVIg. The low-dose IVIg with PP, protocol was modified to include anti-thymocyte globulin for induction along with the addition of rituximab and splenectomy in an attempt to decrease high acute rejection rates.
– High-dose IVIg-based protocols (2 g/kg)
2- Bortezomib (BTZ) is a proteasome inhibitor (PI) that induces endoplasmic reticulum stress, NFkB inhibition and apoptosis in normal and transformed plasma cells
3- Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation. It has been shown to be efficacious in the prevention AMR in renal transplant recipients who had a positive crossmatch against their living donor.
4- Interleukin (IL)-6 is a pleiotropic cytokine that has powerful stimulatory effects on B cells and plasma cells and is responsible, in conjunction with other cytokines, for normal antibody production. It has also been recognized as an important mediator of allograft rejection
5- Tocilizumab (TCZ) a humanized monoclonal antibody directed at the IL-6 receptor has also been studied as a potential desensitization agent.
6- IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS) that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization.
7- Daratumumab is an IgG1k human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts but still under experiments.
Reduce/eliminate DSA, thereby preventing hyperacute rejection and allowing a successful transplantation.
In a study at US, recipients of kidney transplants from incompatible live donors had a higher survival rate than either the group who remained on the waiting list or received a transplant from a deceased donor, or, the group who remained on the waiting list but did not receive a transplant. While the study in UK didn’t show any difference. However; Comparing these two studies is difficult due to many of considerations. So still the overall benefits from desensitization need more studies.
– the risk of development of invasive infections with encapsulated organisms during eculizumab therapy due to which certain vaccinations are pre requisite. Desensitization increases the risk of infection in general
– malignancies
long-term risks from desensitization still needs more thorough and long term follow up studies.
While desensitization treatments increase the cost of transplant, the overall economic impact needs to be considered in light of longer survival and a reduced need for hemodialysis.
The different techniques of desensitization:
-Plasmapheresis:
removes antibodies from the circulation.
Intravenous immunoglobulin (IVIg)
Has been shown to inhibit T- and B-cell proliferation.
-Rituximab
The authors concluded that PP/low-dose IVIG and rituximab demonstrated more success in abrogating positive crossmatch and lower acute rejection rates, but no regimen was completely effective in preventing AMR.
—Bortezomib (BTZ) :
is a proteasome inhibitor (PI) that induces endoplasmic reticulum stress, NFjB inhibition
more study need for there safety and efficacy .
Eculizumab
is a humanized monoclonal antibody , It has been shown to be efficacious in the prevention AMR in renal transplant recipients ,It is unfortunately quite expensive , Another consideration is the risk of development of invasive infections with encapsulated organisms .
Tocilizumab (TCZ) :
a humanized monoclonal antibody directed at the IL-6 receptor has also been studied as a potential desensitization agent. A phase I/II pilot study was performed with TCZ and IVIg to reduce and eliminate anti-HLA antibodies as well as test its safety and efficacy in desensitization.
-IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS):
Cleaves all four human subclasses of IgG has recently been used as an agent for desensitization, different study all crossmatches became negative post-IdeS and the patients underwent successful transplantation.
Benefits of desensitization:
A multi-center analysis on the survival ,the results across 22 centers in the US with 1025 recipients . Their outcomes were matched with controls who remained on the waiting list or received a transplant from a deceased donor (waiting list or transplant control group) and controls who remained on the waiting list but did not receive a transplant (waiting list only control group). Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year.
Long-term risks of desensitization:
Risk for malignancy.
Infection related mortality.
Cost-effectiveness of desensitization:
The cost of desensitization transplant regimen 40 percent more than transplantation of non sensitized patient but still lower than those stay on hemodialysis .
Plasmapheresis:
Removes antibodies from circulation with subsequent decrease in all plasma proteins including clotting factors
Can’t be used alone as has no impact on antibody production by plasma cells
Antibodies rebound shortly due to re-equilibration between intravascular and interstitial compartments.
Side effects include, coagulopathy, hypocalcemia, thrombocytopenia sepsis and catheter relayed infections.
IVIG:
Low dose IVIG and plasmapheresis: was associated with high incidence of acute AMR
High dose IVIG: The efficacy of IVIG alone is not well determined and was shown to be inferior to plasmapheresis and low dose IVIG
Plasmapheresis, low dose IVIG and rituximab:
more successful in rendering positive crossmatch negative with lower acute rejection rates.
Bortezomib (BTZ):
Proteasome inhibitor, It is suggested that BTZ may deplete antibody secreting long lived plasma cells and affect DSA production, but it couldn’t change cPRA in sensitized recipients.
Eculizumab:
Monoclonal antibody, blocks cleavage of C5 and prevent terminal complement activation.
It was efficient in prevention of AMR in recipients with positive crossmatch against their live donor.
Quite expensive and is associated with risk of infection with encapsulated organism
Tocilizumab (TCZ):
Humanized monoclonal antibody directed at IL-6 receptor
Large control studies are needed to determine its efficacy.
IgG degrading enzyme derived from streptococcus pyogenes (IdeS):
Prevent IgG mediated antibody dependent cellular cytotoxicity and complement mediated cytotoxicity
2 studies showed that it could reduce or eliminate DSA and permit HLA incompatible transplant in highly sensitized patients.
Daratumumab:
Monoclonal antibody, still tested in nonhuman primate .
A multi-center analysis showed that patients who had HLA incompatible transplant had higher survival rates than patients who remained on dialysis and than those who remained on waiting list and received deceased donor transplant
Another analysis showed no difference in survival between patients who had HLA incompatible transplant and patients who remained on waiting list.
Determination of long term risks is not possible as most studies are short termed
A nationwide cohort analysis showed lower survival rate in incompatible transplants compared to standard transplant, the most common cause was infection related mortality
Desensitization attempts were more significant risk factor for infection than ABO and HLA incompatibility.
Further studies are needed to determine long term risks.
Desensitization significantly increase the cost of transplantation, however the longer survival and reduced need for hemodialysis should be considered
Incompatible living donor kidney transplant is associated with greater mean cost of care and longer mean survival.
III. Desensitization strategies: is it worth it?
Discuss the following:
Various techniques of desensitisation
Introduction:
Transplant options for highly sensitized patients:
1. Waiting for a compatible deceased donor (may take years without a suitable donor ever being found)
2. Living donor transplant if the immunological barrier can be successfully dealt with.
3. Enrolling in KPD program
4. Undergo a desensitization procedure.
Techniques of Desensitization
A. Plasmapheresis (PP):
– Removes antibodies from the circulation.
– All plasma proteins are also reduced
– Antibodies can rebound to pretreatment levels
– Does not prevent antibody production by plasma cells &(not suitable as a sole therapy)
– Adverse effects:
i. Coagulopathy
ii. Hypocalcemia
iii. Thrombocytopenia
iv. Hypotension
v. Catheter-related infection & sepsis.
B. Intravenous immunoglobulin (IVIg) :
– Derived from the gamma globulin fraction of plasma from pooled donors
– Inhibits T- & B-cell proliferation, cytokine production & inhibit complement activation
– IVIg-based desensitization approaches:
(i) Combined with alternate day PP at a low dose (100 mg/kg); or at high dose (1–2 g/kg).
(ii) Modified low-dose IVIg with PP protocol to include ATG for induction + rituximab & splenectomy to reduce high rejection rates.
C. Other agents used in desensitization:
1. Anti-CD 20 monoclonal antibodies
– Rituximab depletes B cells & minimize the memory response.
– Reduce the PRA & increase the rate of transplantation
– Reduce FCMX MCS.
– 50% develop early AMR(<30 days posttransplant)
– Obinutuzumab, a 3rd generation anti-CD20, has recently been studied in desensitization. It is more potent in depleating B cells.
2. Bortezomib is a reversible proteasome inhibitor.
It depletes plasma cells causing modest antibody
reductions.
Carfilzomib, an irreversible proteasome inhibitor, has
similar but transient effects.
3. Complement Inhibitors
Eculizumab is a terminal complement inhibitor(anti
C5). It is very costly & carries the risk of invasive
infections.
4.Tocilizumab, an IL-6 receptor blocker humanized
monoclonal antibody, has been studied as a potential desensitization agent.
5.Imlifidase, an IgG-degrading enzyme derived from
Streptococcus pyogenes (IdeS) that cleaves all 4 human
subclasses of IgG has recently been used for de-
sensitization
6.Daratumumab, an ant-CD 38 monoclonal antibody has
been tested in non human primates.
Challenges with the described desensitization agents:
– Poor quality of evidence comparing one agent to another.
– No single strategy that can universally allow transplantation in the face of significant levels of DSAs or a positive crossmatch.
– Unacceptable rates of AMR are reported.
– A challenging question is which is better for sensitized patients? To wait on dialysis or undergo desensitization.
Benefits of desensitization:
1. Increases sensitized patients access to transplantation by decreasing cPRA & the number of unacceptable antigens for listing.
2. Patients with a cPRA of > 99.9% have the greatest need for desensitization.
3. Patients with a cPRA < 98% with an incompatible living donor or those on the waiting list for several years may also benefit from desensitization.
4. Decreases DSA prior transplantation in patients with positive XM to reduce the risk of immediate graft loss from hyperacute rejection.
Long-term risks of desensitization:
Difficult to determine because most of the studies that looked into this issue were short term.
Overall immunosuppression raises concerns of infections & malignancies.
Reduced survival, mostly related to infections, also reported.
Cost-effectiveness of desensitization:
There is increased cost imposed by desensitization treatments, however considering longer survival & reduced need for dialysis makes it cost effective.
The different techniques of desensitisation
# Desensitization protocols have typically combined an approach of removing circulating DSA with plasmapheresis (PP) combined with agents that decrease antibody production, or ones that block their actions.
# Plasmapheresis :
– Removes antibodies from the circulation, this removal is only short lived with antibodies rebounding to pretreatment levels
– PP does not affect ongoing antibody production by plasma cells .
– poor treatment choice for desensitization if used alone .
# Intravenous immunoglobulin (IVIg)
-Inhibit T and B cell proliferation, cytokine production, maturation of dendritic cells, induce B cell apoptosis and inhibit complement activation
– It is use in combination with PP in crossmatch incompatible living donor
transplant .
– IVIG can be divided into two :
* combined with alternate day PP at a low dose (100 mg/kg)
* used at a high dose (2 g/kg).
– Low dose IVIg and PP protocols have been used for patients with living donors and high levels of DSA.
* Using low dose IVIg with PP, AMR has been reported to be as high as 36% with 100% 1 year graft survival
* The low dose IVIg with PP protocol was modified to include ATG, rituximab and splenectomy to decrease high acute rejection rates.
* A report from the Mayo clinic concluded that PP/low-dose IVIG and rituximab are more success in lower acute rejection rates, but no regimen was completely effective in preventing AMR.
# Bortezomib (BTZ) :
– is a proteasome inhibitor that induces endoplasmic reticulum stress, NFjB inhibition and apoptosis in normal and transformed plasma cells and might deplete antibody secreting long lived plasma cells and have an impact on DSA production.
– studies showed use of many sessions of BTZ, non developed a negative cross match and the cPRA was unchanged in all patients.
# Eculizumab:
– is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation.
– It has been shown to be efficacious in the prevention AMR in recipients who had a positive crossmatch against their living donor.
-Study showed benefit for eculizumab compared with standard of care (SOC) in preventing acute AMR in senitized recipients.
– It expensive and has risk ofdevelopment of invasive infections with encapsulated organisms so vaccinations are pre requisite.
# Tocilizumab (TCZ) :
-A humanized monoclonal antibody directed at the IL-6 receptor has also been studied as a potential desensitization agent.
# IgG-degrading enzyme:
– Derived from Streptococcus pyogenes (IdeS) that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization.
– In study IdeS reduced or eliminated DSAs and permitted HLAincompatible transplantation in 24 of 25 patients. AMR
occurred in 10 patients at 2 weeks to 5 months after transplantation.
# Daratumumab :
– Is an IgG1j human mAb that binds to
CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts.
– There is no desensitization strategy that can universally allow transplantation in the presence of significant levels of anti-HLA antibody to the donor or a positive crossmatch.
# Benefits of desensitization:
– Despite the challenging that facing highly sensitized patients it is better for going to desensitization than waiting on dialysis , it given the longer expected survival and improved quality of life.
– Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year, 3 years, 5 years and 8 years.
#Long-term risks of desensitization
-Infection: bacterial, viral, fungal or serious infections
– malignancies
# Cost-effectiveness of desensitization
While desensitization treatments increase the cost of transplant, the overall economic impact needs to be considered in light of longer survival and a reduced need for haemodialysis.
The aim of any desensitization protocol is to achieve a successful transplantation by preventing hyperacute rejection. This involves preventing formation and action of antibodies as well as removing the formed antibodies from circulation. Various methods used for desensitization include:
1) Plasmapheresis alone: Non specific removal of antibodies, which is short lived (due to rebound) and hence not successful.
2) Intravenous immunoglobulin (IVIG): IVIG can be used in either low dose or high does.
a) Low dose IVIG (100 mg/kg) with Plasmapheresis: It has been shown to have AMR rates of 36% with 100% graft survival at 1 year.
b) Low dose IVIG with plasmapheresis and ATG, rituximab and splenectomy: It has been associated with AMR in 43% and 39% at 15 months and 22 months with graft survival of approximately 80% at 15 months.
c) High dose (2 g/kg) IVIG alone: It is used in cadaveric transplant program, associated with slight decrease in PRA levels and increased transplantation rates 2 years post therapy. AMR rates were 31% with high 2 year patient and graft survival.
d) High dose IVIG with rituximab: It is associated with 50% acute rejection and 30% AMR while the 2 year patient and graft survival is 95% and 84% respectively.
Low dose IVIG and plasmapheresis with or without rituximab has shown results superior to use of high dose IVIG alone.
3) Bortezomib: It is a proteasome inhibitor causing apoptosis of plasma cells. Its use saw transplant of 43% of sensitized patients with 12.5% developing de novo DSAs and 18.8% acute rejection.
4) Eculizumab: It is an antibody blocking cleavage of C5. If used in addition to IVIG and plasmapheresis, has shown risk of AMR in range of 7.7% to 11.8% as compared to 21.6% to 41.2% seen with IVIG and plasmapheresis, but with an increased risk of invasive infections.
5) Tocilizumab: It is an antibody against IL-2 receptor which, when used with IVIG in patients unresponsive to IVIG and rituximab, showed good results post-transplant with no AMR at 6 months and good graft function at 1 year post-transplant.
6) IgG degrading enzyme derived from Streptococcus pyogenes (IdeS): It causes proteolysis at Fc region of IgG. Its use has been shown to be associated with approximately 40% AMR which were treated. Long term effects including infections and malignancies need to be evaluated.
7) Daratumumab: It is a CD38 inhibitor and has been used in non-human primates showing marked reduction in antibody levels which was short-lived, hence associated with severe rejections.
Desensitization helps a highly sensitized patient, who is otherwise not getting a living or cadaveric donor and is expected to remain on wait-list for a long time, to get a kidney transplant. A kidney transplant has been shown to be associated with better quality of life, as well as better survival rates with respect to patients remaining on wait-list.
The most important long-term concerns with desensitization include infections and malignancies. In comparison to non-desensitized patients, use of IVIG, plasmapheresis and rituximab desensitization has similar infection rates while eculizumab use increases the infection rates by 50%. Reduced patient survival due to increased infections has been observed in a large study.
Desensitization increases the cost of care by 42%, more so in a CDC positive patient (by 58%) than a flow cytometry crossmatch positive patient (38%). There is an increased mean cost of care in comparison to patients remaining on dialysis.
The different techniques of desensitization:
plasmapheresis, IVIG (low dose 100 mg/kg combined with plasmapheresis or high dose alone 2 g/kg, Rituximab, Bortezomib, Eculizumab, Tocilizumab, IgG-degrading enzyme)
plasmapheresis removes preformed antibodies but a rebound is seen later as it does not affect ongoing production of antibodies
IVIG: inhibits proliferation of T and B cells as well as inhibition of dendritic cells and complement activation.
Bortezomib. affects plasma cells responsible for antibody production
eculizumab inhibits complement
Tocilizumab inhibits IL-6 which is a powerful B and T cell stimulator
Benifits of desensitization:
shortening of waiting on waiting lists
give the chance for patients who are of low chance due to high sensitization
Long-term risks of desensitization
increased incidence of infection and malignancy due to high dose immunosuppression
Cost-effectiveness of desensitization :
The cost is doubled in comparison to the acceptable or compatible donor (as per year)
The different techniques of desensitisation :
1- palsmapharesis :
2- IVIG :
a- inhibition of T-cell and B-cell proliferation.
b- decreasing cytokine production.
c- inducing B-cell apoptosis.
d- inhibition of maturation of dentritic cells.
e- inhibition of complement activation.
3- Rituximab:
4- ATG :
5- Borteozomab :
6- Eculizumab :
7- Tocilizumab :
8- IgG-degrading enzyme :
9- Paratumumab :
Benefits of desensitization :
Long-term risks of desensitization :
1- more susceptibility to infections and flare up of latent viral infections as CMV, EBV,BK polyoma virus, JC virus, Parvovirus-19,…
2- more incidence of malignancies.
Cost-effectiveness of desensitization :
The different techniques of desensitisation
Plasma Exchange
IVIg high and low dosis
Rituximab
Bortezomib
Eculizumab
IgG-degradating enzyme derived from Streptococcus pyogenes (IdeS)
Tocilizumab
Daratumumab
The combination of these protocols must be individualized depending on the immunological status of the patient and the peculiarities of the graft and local protocols and the availability of institutional costs.
Classically, the combination of rituximab, IVIg and plasma exchange is currently the most used and is more consistent in the literature.
Benefits of desensitization
Need to decrease DSA in patients with high rates of antibodies to antigens in organs available for donation. Patients are usually on the waiting list for a long period, low quality of life, high risk of hemodialysis catheter infections, unnecessary invasive manipulation, high cost, and poor survival.
Long-term risks of desensitization
The possibility of risks of infection and neoplasms in the long term is considered. Although rituximab and plasma exchange are related to infections, immunoglobulin tends to compensate for the humoral response, especially against viruses. Eculizumab is closely related to serious infections by encapsulated bacteria, for this reason vaccination and quinolone prophylaxis are necessary to minimize this risk. De novo lesions in the renal graft by costimulation by B and T lymphocytes tend to appear after the first year of transplantation and should be considered in case of worsening renal function.
Cost-effectiveness of desensitization
Despite the higher initial cost of desensitizing the patient with high-cost medications, two important facts should be kept in mind. The first is that the cost of remaining on hemodialysis waiting for an organ that may become available is much higher in the long term. The second is the quality of life gain associated with prolonged survival.
Desensitization strategies: is –it worth it?
1-Techniques of desensitization:
Desensitization is simply depends on removal of performed DSA pre-transplant by PEX and to prevent /or reduce the formation of other antibodies.
=Plasmapheresis is depending on removal of antibodies from circulation and re-bounding of antibodies occur again from interstitial and others from plasma cells, side effects mainly from removal of all plasma proteins.
=Intravenous immunoglobulin (IVIg):two protocol low and high based IVIg with PEX.
A-Low-dose IVIg and PP protocols (100 mg/kg).
B-High-dose IVIg and PP protocols (1-2gm/kg) .
=IVIg + PP protocols +Rituximab.
=Bortezomib (BTZ): deplete antibody-secreting long-lived plasma cells and have an impact on DSA production.
=Eculizumab: prevent terminal complement activation by blocking cleavage of C5, has a good role in preventing AMR in highly sensitized patients but still so costly and associated with high risk if encapsulated organism infection.
=Tocilizumab (TCZ) and IVIg.
=IgG-degrading enzyme derived from Streptococcus pyogenes (Ides).
=Daratumumab is an IgG1j human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasma blasts.
2-Benefits of desensitization.
Recipients of kidney transplants from incompatible live donors had a higher survival rate than either who remained on the waiting list or received a transplant from a deceased donor.
3-Long-term risks of desensitization
Infection and malignancy is considered the most common long-term risks of desensitization but still need more studies with long term follow up.
4-Cost-effectiveness of desensitization:
Desensitization protocols increase cost of transplant procedure but still we should keep in mind the longer survival and reducing duration of hemodialysis.
Techniques of desensitization:
Generally desensitization procedure involve removal of the DSAs from the serum of receipts who are highly sensitized with cPRA of more than 80%.As highly sensitized patients have high risk of AMR, early graft loss and higher chance of being removed from or dying on a waiting list.
Desensitization is one of the option to make transplantation possible.Basically by reducing or eliminating DSAs ,hyperacute rejection risk minimized ,allowing for successful transplantation. Different protocols were endeavoured to overcome this immunologic barrier. Each with different outcomes and disadvantages.
Plasmapheresis PP:
Removing DSAs from circulation. It’s non specific for antibodies removal, all plasma proteins are removed including clotting factors.
The removal of DSAs is short lived with DSAs rebounding to pre treatment level following re_equlibration between intravascular and interstitial compartments.
It dose not affect ongoing DSAs production by plasma cells hence its poor choice for desensitization as sole therapy.
It’s side effects include coagulopathy,hypocalcemia, thrombocytopenia,hypotension and catheter related infection.
Therefore IVIg was added to PP.
Intravenous immunoglobuline IVIg derived from gamma globular fraction of plasma from pooled donors.
Its mode of action include:
1) Inhibit T and B cell proliferation
2) Inhibit cytokine production.
3)Inhibit complement activation
4) Inhibit maturation of dendritic cells.
5) Induce B_cells apposite.
The protocol for combination of IVIg and PP divided into 2 approaches
a) alternate day PP (no. Of sessions depend on titer of DSAs ) combined with low dose IVIg( 100 mg/kg).
b) PP alternating days with high dose IVIg (1_2 gm/kg).
Low dose IVIg with PP:
AMR , has been reported to be as high as 36%, with 100 % one year graft survival.
This protocol was modified to improve the high risk of AMR ,with the inclusion of ATG for induction,along with Rituximab and splenectomy. Despite that modification, AMR was still high with 43% and graft survival of 78% at 15 months. Same incidence risk was reported with a median follow up of 22 months.
One single center analysis compared 8 years survival in 211 desensitized patients with this protocol and underwent living donor transplant. Survival was compared to two other groups of patients (Dialysis only group ) and (Dialysis or HLA matched transplantation group). The result of this study provided evidence that this desensitization protocol could help overcome incompatibility barriers in live donor transplantation with a better graft and patient survival.
Being single center study ,it’s result can’t be generalized.
High dose IVIg 1_2 gm/kg with PP:
AMR was seen in 31% and 7% lost the allograft secondary to rejection.
Induction protocol with Daclizumab, ATG or Alemtuzumab dose not affect the AMR incidence risk.
High dose IVIg, PP and Rituximab:
Due to high rate of acute AMR ,Rituximab ,as a B_lymphocytes depleting agents ,targeting CD20 ,was added to the desensitization regimen.
In conclusion
The AMR was high regardless of which PP/low dose IVIg or high dose IVIg was applied or which type of induction agent was used(Daclizumab,ATG or Alemtuzumab).
The addition of Rituximab or splenectomy did not appear to decrease the incidence of AMR.
Bortizomib based desensitization:
Bortizomib as it might deplete antibody secreting long lived plasma cells and have an impact on DSAs production. Results are inconclusive.
Eculizumab based desensitization protocol:
It’s monoclonal antibody that block cleavage of complement C5 and prevent terminal complement activation. It’s effective in preventing AMR in highly sensitized patients. It’s main issues are ,highly expensive and associated with risk of invasive encapsulated organism.
Tocilizumab( IL_6 inhibitor) based desensitization protocol: As IL6 has powerful stimulators effect on B lymphocytes and Plasma cells. Tocilizumab was advocated to be used in highly sensitized patients. Larger controlled trial needed to verify its potency in this field.
IgG_degrading enzym derived from streptococcus prognosis (IdeS) dependent desensitization:
It cleaves all four subclasses of IgG,,since Fc region ofIgG is critical for interaction with Fc receptor and Complement binding,proteolytic activity at this site prevent the occurrence of IgG dependent cellular toxicity and complement mediated cytotoxicity. Thereby preventing AMR.,Those patients who respond initially experienced rebound of DSAs and AMR..
As it’s noticed ,several protocols for desensitization are available ,Several issues linked to desensitization raised;
1)the quality of evidence comparing one to another is poor.
2)There is no desensitization protocol that permit transplantation in the presence of DSAs or positive cross match.
3)Despite combining the different therapies in several protocols has abrogated the response of high level of preformed DSAs.the higher rate of AMR posed a real challenge to desensitization programs.
These debatable issues raised the question of whether desensitization is superior to waiting on Dialysis.
Benefit of desensitization:
One multi _center study conducted in USA to explore the long term graft and survival rate ,concluded superior result in desensitization group in comparison to HLA matched and waiting on HD patients.A result that was verified by a UK study which showed comparable survival rate.larger cohort controlled studies are needed to answer this question.
Long term complications of desensitization:
Patients survival was reduced in transplanted patient after desensitization, with most common cause of death was infection as per Korean transplant registry data.Sim8larly other study revealed higher infection rate with administration of Eculizumab post transplant.On the other hand ,comparable risk of infection was found in desensitized and in HLA matched recipients.More studies are required to arrive at stronger conclusion.
The other drawback of desensitization transplantation Is the high economic cost ,
Cost effectiveness of desensitization:
In patients with rare HLA typs, uncommon HLA antigens or very high sensitization level (cPRA of more than 95%),when no match from kidney exchange programs(like KPD) are forthcoming after a period of time,desensitization hold be considered given the longer expected survival in comparison to Dialysis and better quality of life.
The different techniques of desensitization:
Aim of desensitization:
1. Removing circulating DSA with plasmapheresis.
2. Reduce Abs production
3. Inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation.
1. Plasmapheresis(PP): removes antibodies from the circulation.
-This technique is not specific to the removal of alloantibodies and therefore all plasma proteins are reduced including clotting factors.
– PP does not affect ongoing antibody production by plasma cells. Its side effects include coagulopathy, hypocalcemia, thrombocytopenia, hypotension, catheter-related infection, and sepsis.
2. Intravenous immunoglobulin (IVIg) derived from the gamma globulin fraction of plasma from pooled donors has been shown to inhibit T- and B-cell proliferation, cytokine production, and maturation of dendritic cells induce B-cell apoptosis, and inhibit complement activation.
– IVIg-based desensitization can be divided into two general approaches: combined with alternate day PP at a low dose (100 mg/kg), or used at a high dose (1–2 g/kg) .
-Low-dose IVIg and PP protocols have been used for ESRD patients with living donors and high levels of DSA. attempt to decrease high acute rejection rates.
– PP/low-dose IVIG and rituximab are more successful in abrogating positive crossmatch and lower acute rejection rates.
3. Bortezomib (BTZ) is a proteasome inhibitor (PI) that induces endoplasmic reticulum stress, NFkB inhibition, and apoptosis in normal and transformed plasma cells.
4. Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation.
5. Tocilizumab (TCZ) a humanized monoclonal antibody directed at the IL-6 receptor has also been studied as a potential desensitization agent.
6. IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS) that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization.
6. Daratumumab is an IgG1j human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts.
There is no desensitization strategy that can universally allow transplantation in the presence of significant levels of anti-HLA antibody to the donor or a positive crossmatch.
Benefits of desensitization
-Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year compared to patients or recipients who received a transplant from a deceased donor.
Long-term risks of desensitization
– Desensitization therapies are associated with infections and malignancies.
-Patient survival rate was reduced in patients who underwent incompatible transplants (ABO, HLA, ABO+HLA) compared to standard transplants. The most common cause of death was infection-related.
Economic assessment of desensitization
-Desensitization therapies significantly increase the cost of the transplant procedure and the medical complexity of renal transplant
-Incompatible living donor transplant was associated with a 42% increase in the
cost of care than compatible living donor transplant.
DESENTIZATION STRATIGES
1-reduce and eliminate DSA.
2-decreasing antibody production.
3-blocking action of antibodies.
DESENTIZATION PRTOCOLS
2.Intravenous immunoglobulin (IVIg) ,
3.Low-dose IVIg and PP protocols ,
4.High-dose IVIg-based protocols ,
5.Rituximab Chimeric monoclonal AB, act on B cell depletion but not
plasma cells, used in combination with plasmapheresis, IVIG,
6.Bortezomib (BTZ) is a proteasome inhibitor (PI ,
7.Eculizumab ,
8.Interleukin (IL)-6 ,
9.IgG-degrading enzyme derived from Streptococcus pyo- genes (IdeS) ,
10.Daratumumab ,
BENFITS OF DESENTIZATION
LONG TERM RISK OF DESENTIZAION
Cost-effectiveness of desensitization
The different techniques of desensitization
1- Remove the antibodies from the circulation by plasmapheresis or immunoadsorption (IA).
2- Inhibition of antibodies production
3- Block further formation of ABS by inhibition of the memory B, plasma cells.
1-Plasmapheresis, used to remove the antibodies from the circulation with the risk of eliminating protein binding clotting factors lead to coagulopathy with increase risk of bleeding, hypocalcemia and infection, with this technique there is a risk of antibodies rebound and cannot prevent the production of ABs from plasma cells so it’s of transient benefits and should be used as part of combination desensitization protocol not alone.
2-Intravenous immunoglobulin, prepared from plasma fraction of pooled donors, it acts as immunomodulating agent through inhibition of both T and B proliferation, reduced cytokines production, induce B cells apoptosis and complement inhibition. Can be used alone or in combination with PP for ABOI desensitization protocol.IVIG, high dose 2gmlkg or low dose 100mg lkg alternating with PP and rituximab 375mg / m2.
3-Rituximab Chimeric monoclonal AB, act on B cell depletion but not plasma cells, used in combination with plasmapheresis, IVIG, its associated with risk of infections.
4- Bortezomib (BTZ) is a proteasome inhibitor (plasma cells depleting agent)
Promising agent different doses density and induction therapy, associated with lower rate of AR ( 18%), and lower denovo AB production( 12.5%) , used in combination with PP, IVIG .
5-Eculuzemab humanized monoclonal AB act on C5 complement inhibition, its use for treatment of AMR based on evidence from small studies its use limited due to the cost , and also risk of meningococcal infection with encapsulated microorganism so need vaccination two weeks prior to its use and antibacterial prophylaxis.
6- 1L 6 inhibitor tocilizumab(TCZ), IL6 Is
pleotropic cytokine with stimulatory effect on both B and plasma cells and interact with other cytokines to produce more antibodies so tocilizumab is humanized monoclonal antibody that act as 1l-6 receptor inhibitor so it help in reduce and inhibit the production of HLA antibodies , its use for desensitization limited to pilot studies with promising results to prevent AMR in combination with IVIG , need more large studies to confirm its potency .
7-(IdeS) IgG-degrading enzyme derived from Streptococcus pyogenes, act on FC receptors of IgG-and stop the IgG mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity
Its promising agent as tested in two large centers in desensitization protocol for highly HLA sensitized patients with successful depletion of DSA but still the risk of DSA rebound and AMR was reported in good numbers of recipients, Ides used with different induction protocols, hoarse ATG from European center, and alemtuzumab in US center with rituximab and IVIG, all received homogenous triple maintenance therapy.
8-daratumumab it’s an IgG 1k monoclonal AB, that bind and inhibit the cd38 expressing cells including plasma and plasmoblasts still under investigation from animal study .
The most common protocals used including the combination of PP alternating with low dose IVIG , rituximab
Benefits of desensitization
according to the evidnece from multicenter experiences-based analysis the benefit of desensitization in HLA incompatible donors not yet determined, some centers reported good early graft and patient survival with 1-3 years after desensitization while other they did not show any difference in graft survival compared to matched sensitized control group, this diversity in the results due to the heterogenicity of these studies by using different definition of desensitization , different methodologyand different population so we need more studies to confirm its potency, but overall still can be used with limitation and accept the risk of complications including AMR ,serious infections like BV , cmv malignancy including PTLD and skin tumors .
Cost-effectiveness of desensitization:
desensitization protocals associated with high cost.
Techniques of desensitization
These include:
Plasmaphresis
It involves removing Circulating DSA from circulation. The effect is usually short term and there can be rebound and should usually be combined with IVIG
Rituximab
It causes B cell depletion thus decreasing DSA formation.
IVIG
This blocks the effect of preformed DSA and also inhibits T& B cell proliferation , compliment activation and cytokine release.
Bortezomib– Inhibits antibody producing B cells
Eclulizumab- Quite effective but can have serios complications like infection. Vaccination is mandatory before start of treatment
Tocilizumab-anti IL6 antibodies used along with IVIG
Dartatumumab-
Ides– Enzyme derived from strept pyogenes and prevents IgG dependent cytotoxicity. It removes all DSA but can be immunogenic and there is risk of rebound rise in DSA
Protocols of desensitization
· High dose IVIG- 2gm/kg
· High dose IVIG- 2gm/kg +Rituximab
· Plasmaphresis+ low dose IVIG
· Plasmaphresis+ low dose IVIG +Rituximab
· Plasmaphresis+ low dose IVIG +Rituximab + Splenectomy
It can be concluded that plasmaphresis should be included in all desensitization protocol . All protocols without plasmaphresis have failed to decrease PRA. IVIG alone is not recommended . Adding Rituximab to plasmaphresis and IVIG is questionable. Splenectomy does not confer significant advantage. The most common protocol involves combination of Plasmaphresis , low dose IVIG and Rituximab. Plasamphresis is done on alternate days and can vary from 5 to more sessions and each session followed by IVIG at 100 mg/kg followed by Rituximab 375 mg m2 after 1 week
Benefits of Desensitization
Options in highly sensitized patients include, Long term Dialysis, kidney paired donation or wait for compatible donor as with improvement of KAS waiting time has decreased.
Desensitisation make transplantation possible in incompatible donors with those with high PRA even >80% .
Risks of Desensitization.
Higher risk of acute rejection as desensitization removes DSA but memory cell are not removed.
Higher risk of infections
Cost effectiveness
Because of high risk of acute rejection more cost is incurred on monitoring , protocol biopsies and costly treatment. Transplantation in positive CDC crossmatch patients is more expensive than positive FCXM .
Future Directions
Improvement of kidney allocation system for deceased donors.
Paired kidney donation and exchange
DSAs remain a major risk for successful transplantation for very highly sensitized recipients
For living donor paired exchange programme had improved chances for sensitized patients
Desensitization despite allowed transplantation in highly sensitized patients but results are still inferior to compatible transplant. Desensitization therapies target removing DSA prior to transplantation and block their production or action .
●Desensitization treatments:
*Plasmapheresis : it removes antibodies from the circulation it is not specific for Ab only and offers only short term solution and doesn’t affect Ab production so its not effective alone.
*Intravenous immunoglobulin (IVIg)
Inhibit T-and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation .
IVIg-based desensitization can be divided into two general approaches: combined with alternate day PP at a low dose (100 mg/kg); or used at a high dose (1–2 g/kg) .
*Combined Low-dose IVIg and PP protocols have been used for desensitization
AMR has been reported to be as high as 36% with 100% 1-year graft survival
* The low-dose IVIg with PP, protocol was added to anti-thymocyte globulin for induction with addition of rituximab and splenectomy in an attempt to decrease high acute rejection rates results showed acute AMR rate was 43% with a 78% graft survival at 15 months.
*High-dose IVIg-based protocols 2 g/kg was also tried for desensitization with little effect on cPRA ,better chances for transplantation and higher acut rejection rates .
*Examination of AMR rates using different antibody induction regimens (Zenapax or Thymoglobulin) in patients with desensitized with IVIG (2 g/kg) showed no difference.
*rituximab with high-dose IVIg (2 g/kg) :patients 30% of patients experiencing AMR in early post-transplant period.
*Bortezomib (BTZ) is a proteasome inhibitor (PI) that induces endoplasmic reticulum stress, apoptosis in normal and transformed plasma cells it depletes antibody-secreting long-lived plasma cells.
In a study aimed to determine the safety and efficacy of 32 doses of BTZ in 10 highly sensitized kidney transplant candidates with alloantibodies against their living donor, no patient developed a negative crossmatch against their original intended donor, and the calculated panel reactive was unchanged in all patients.
*Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation.its result in preventing AMR in sensitized patients results are promising but its very expensive and It increased the risk of development of invasive infections with encapsulated organisms .
* Tocilizumab (TCZ) a humanized monoclonal antibody directed at the IL-6 receptor ( recognized as an important mediator of allograft rejection) has also been studied as a potential desensitization agent. TCZ and IVIg were used to reduce and eliminate anti-HLA antibodies with good resullts in desensitization and AMR was seen on protocol biopsies performed at 6 months.
This combination might be promising but more studies are needed.
*IgG-degrading enzyme derived from Streptococcus pyo genes (IdeS) ;
It cleaves all four human subclasses of IgG . Since the Fc region of IgG is critical for interaction with Fc receptors and complement binding, proteolytic activity on IgG molecules at this site prevents the occurrence of IgG-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity, two processes that are critical for AMR.
*Daratumumab is an IgG1k human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts it was tried on animal ,reduction in DSA was not maintained and rapid rebound of antibodies developed with profound rejection.
●Various techniques of desensitisation ?
1Low dose of intravenous immunoglobulin + plasma exchange.
2 Low dose of intravenous immunoglobulin + plasma exchange+ rituximab with or without splenectomy .
3 High dose of intravenous immunoglobulin+ rituximab.
3 Low dose of intravenous immunoglobulin + plasma exchange after ATG induction.
4 daclizumab +ATG or alemtuzumab .
5 Low dose of intravenous immunoglobulin + plasma exchange+Bortezomib.
●Benefits of desensitization
Desensitization offered more chances for sensitized patient to be transplanted so improved patient’s survival
Recipients of kidney transplants from incompatible live donors had a higher survival rate than patients on the waiting list at 1 year, 3 years, 5 years and 8 years.
Long-term risks of desensitization :most published studies are short-term.
1 it is associated with Higher incidence of infection and malignancy as other immunosuppression comparison of infectious complications between kidney transplant recipients desensitized with Rituximab and IVIg and nondesensitized patients showed no difference in bacterial, viral, fungal or serious infections over an 18-month follow-up period
Patient survival rate was reduced in patients who underwent incompatible transplants (ABO, HLA, ABO+HLA) compared to standard transplants.
Cost-effectiveness of desensitization
Desensitization therapies significantly increase the cost of the transplant procedure. Incompatible living donor transplant was associated with a 42% increase in the cost of care in National cohort study. incremental cost-effectiveness of desensitization was estimated to be $80 486 per quality-adjusted life year. In comparison, compatible living donor transplant was estimated to cost $39 939 per quality-adjusted life year
Plasma pheresis
This technique removes antibodies temporally along other plasma proteins as clotting factors , causing side effects as coagulopathy, hypocalcemia, thrombocytopenia, hypotension and catheter-related infection and sepsis.
IVIG
Acts by inhibiting T- and B-cell proliferation, cytokine production, maturation of dendritic cells and inhibit complement activation .
Mayo clinic study published that PP/low-dose IVIG and rituximab combination gave lower rates of AMR compared to other regimens.
Mean while no specific regimen can be standerdised.
Bortezomib (BTZ)
A proteosome inhibitor act by depleting antibody-secreting plasma cells affecting DSA production,
It did not show any decline in c PRA levels
Eculizumab
is a humanized monoclonal antibody that blocks cleavage of C5 and prevents terminal complement activation
It prevented AMR in renal transplant recipients who had a positive crossmatch against their living donor.
It’s main side effect is the liability of infection with encapsulated organisms and being an expensive drug as well.
Tocilizumab (TCZ)
a humanized monoclonal antibody against IL-6 receptor. TCZ with IVIg seemed to have beneficial effects on desensitization.
IdeS
IgG-degrading enzyme derived from Streptococcus pyogenes that cleaves all four human subclasses of IgG preventing IgG-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity, thereby preventing AMR.
It reduced or eliminated DSAs allowing HLA incompatible transplantation .
Daratumumab
an IgG1j human mAb acts by inhibiting the development of CD 38 expressing cells as plasma cells and plasma blasts.
It reduced DSA levels compared to untreated controls but rebound increase in Ab levels occurred with rejection.
o low dose (100 mg/kg)on alternate day with PP which was applied for cases having living donors and high levels of DSA.
o anti-thymocyte globulin with low dose IVIG , PP ,rituximab and splenectomy .
o IVIG ,with PP with rituximab
o a high dose IVIG (1–2 g/kg) lead to high AMR rates
o High dose IVIG with rituximab yet the results was not acceptable.
-better long term survival rates
-better quality of life with less waiting list time burden.
-Over all economic wise can be cost effective ,decreasing the financial dialysis burden
More studies are needed to assess it .
· But it includes infection as viral infections as Cytomegalovirus (CMV), Epstein–Barr virus, parvovirus B-19 and BK polyomavirus and other immunosuppression related complications including malignancy ,progressive multifocal leukoencephalopathy.
· AMR rate is high in desensitised cases.
· It is an expensive method.
Incompatible living donor transplant was associated with a 42% increase in the cost of care.
The cost was highest in patients with positive cytotoxic crossmatch compared with those with flow positive crossmatch .
While desensitization treatments increase the cost of transplant, the overall economic impact needs to be considered regarding the longer survival and reduced need for haemodialysis.
Renal transplantation is the best treatment for patients with ESRD. DSAs are major obstacle to access to transplantation for many transplant patients. Sensitized patients have the option of enrolling in a kidney paired donation programme or undergoing a desensitization procedure.
Desensitization therapies target:
Removing preformed DSA
Decrease antibody production, or ones that block their actions.
Desensitization treatments
Plasmapheresis removes antibodies from the circulation. This technique removes all plasma proteins including clotting factors. However, this removal is only short-lived with antibodies rebounding to pretreatment levels following re-equilibration between intravascular and interstitial compartments.
IVIg has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation .Low-dose IVIg have been used complementary to PP protocols for ESRD patients with living donors and high levels of DSA. IVIg-based desensitization can be divided into two general approaches: combined with alternate day PP at a low dose (100 mg/kg); or used at a high dose (1–2 g/kg).
Rituximab in combination with high-dose IVIg (2 g/kg) or PP
Bortezomib is a proteasome inhibitor that induces endoplasmic reticulum stress, NFjB inhibition and apoptosis in normal and transformed plasma cells.
Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation. The efficacy of eculizumab was demonstrated few studies, when added to conventional desensitization protocol. It was shown it was associated with lower risk of AMR. risk of development of invasive infections with encapsulated organisms during eculizumab therapy. Eculizumab 21,000 $ per dose.
Tocilizumab a humanized monoclonal antibody directed at the IL-6 receptor, cytokine that has powerful stimulatory effects on B cells and plasma cells, has also been studied as a potential desensitization agent. TCZ with IVIg appears to be an additional agent with potential in desensitization.
IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS) that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization. IdeS prevents the occurrence of IgG-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity.
Daratumumab is an IgG1k human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts. However, the reduction was not maintained and rapid rebound of antibodies developed with profound rejection.
Various protocols of desensitization
a- Plasmapheresis + low dose IVIG
b- High dose IVIG (2 gm/kg)
c- High dose IVIG (2 gm/kg ) + Rituximab
d- Plasmapheresis + low dose IVIG + Rituximab
e- Plasmapheresis + low dose IVIG + Rituximab + splenectomy
f- Plasmapheresis + low dose IVIG + Bortezomib
g- Alemtezumab + low dose IVIG+ Ides
h- Low dose IVIG+ Tocilizumab
Benefits of desensitization
Recipients of kidney transplants from incompatible live donors had a higher survival rate than patients on the waiting list at 1 year, 3 years, 5 years and 8 years.
Long-term risks of desensitization
Desensitization improves the short term graft and patient survival but associated with:
1- Increased risk of acute rejection 3 fold higher than in non-sensitized patients ·
2- Higher incidence of infection risk
3- Increased risk of malignancy, in particular skin and hematologic malignancies.
Cost-effectiveness of desensitization
Desensitization therapies significantly increase the cost of the transplant procedure. Incompatible living donor transplant was associated with a 42% increase in the cost of care in National cohort study. Over 10 years, incompatible living donor kidney transplant was associated with a greater mean cost of care ($440 234 vs. $292 117) and longer mean survival.
Different techniques of desensitization:
Various techniques of desensitization:
There was a conflict about the benefit of desensitization. In USA studies proved that desensitization of positive cross match & incompatible donor had better survival than patient remain on waiting list while UK result was the opposite ( no survival benefit).
The long term risk of desensitization can’t be predicted because all the studies were short term study.
Using of desensitization protocol was associated with increased cost in around 40%. This increase in cost should be considered with longer survival. The cost effectiveness of incompatible living donor transplant around 80486$/ quality adjusted life year while in compatible living donor around 39939$/ year.
Different techniques of desensitisation?
The goal of desensitisation is remove circulating DSA and inhibition production of antibodies and blocking action of antibodies.
1. Plasma exchange to remove circulating DSA but may remove plasma protein and it’s side effects coagulopathy, leukopenia hypocalcemia and hypotension
2. intravenous immunoglobulin for inhibition T and B cell proliferation/ reduce cytokines production and maturation of dentric cell / induce B cell apotosis and inhibition of complement activation.
3. Anti thymoglobulin antibodies
4. Rituximab is monoclonal antibody against CD 20
5. splenectomy plus rituximab
6. Bortezomib is proteasome inhibitors that induce endoplasmic reticulum NfkB inhibition and apoptosis
7. Eculizumab C5 inhibitors
8. Interleukin (IL-6) pleiotropic cytokine that has powerful stimulating effects on B cell & plasma cell
9. Tocilizumab humanized monoclonal antibody directed at IL6 receptor
10. IgG degradation enzymes derived from streptococcus pyrogens.
Various techniques of desensitisation ?
1. Low dose of intravenous immunoglobulin plus plasma exchange plus rituximab
2. High dose of intravenous immunoglobulin plus rituximab
3. Low dose of intravenous immunoglobulin plus plasma exchange plus ATG
4. Splenectomy plus rituximab
5. daclizumab plus ATG or alemtuzumab .
Benefits of desensitisation:
2 studies done on outcome of survival graft in incompatible donor transplant shows different results and different definition of desensitisation and matching method for patients waiting transplant.
one study shows the outcome of patients receiving incompatible donor has higher survival rate than patients on waiting list.
Other study shows no difference in survival was noticed between patients who underwent HLA incompatible transplant in comparison to patients on waiting list.
Long term risk:
desensitisation patients underwent transplant have risk of serious infection and malignancy and desensitisation protocol has short term and production of DSA may appear post transplant with long term of graft leading to failure of graft despite using high dose of immunosuppressive drug.
Patients survival rate reduced who underwent ABO / HLA incompatible.
Cost effectiveness:
desensitisation treatment and cost care very high in comparison to compatible patients.
The different techniques of desensitization;
1-Removal of circulating DSA
2- Decrease antibody production
3- Block antibody actions
Various techniques of desensitization;
1-Plasmapheresis; Removes antibodies from the circulation. Its side effects include coagulopathy , hypocalcemia, thrombocytopenia, hypotension and catheter-related infection and sepsis.
2-Intravenous immunoglobulin (IVIg); inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation . IVIg-based desensitization can be divided into two general approaches:
1-combined with alternate day PP at a low dose (100 mg/kg)
2- used at a high dose (1–2 g/kg) [20,21]
3-Bortezomib (BTZ) is a proteasome inhibitor (PI) that induces endoplasmic reticulum stress, NFjB inhibition and apoptosis in normal and transformed plasma cells . PI BTZ might deplete antibody-secreting long-lived plasma cells and have an impact on DSA production.
4-Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation. It is increased the risk of development of invasive infections with encapsulated organisms .
5- Interleukin (IL)-6 is a pleiotropic cytokine that has powerful stimulatory effects on B cells and plasma cells and is responsible, in conjunction with other cytokines, for normal antibody production. It has also been recognized as an important mediator of allograft rejection.
– Tocilizumab (TCZ) a humanized monoclonal antibody directed at the IL-6 receptor has also been studied as a potential desensitization agent. A phase I/II pilot study was performed with TCZ and IVIg to reduce and eliminate anti-HLA antibodies as well as test its safety and efficacy in desensitization.
6- IgG-degrading enzyme derived from Streptococcus pyo genes (IdeS) ;
that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization . Since the Fc region of IgG is critical for interaction with Fc receptors and complement binding, proteolytic activity on IgG molecules at this site prevents the occurrence of IgG-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity, two processes that are critical for AMR.
7- Daratumumab is an IgG1k human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts.
Various protocols of desensitization ;
a- High dose IVIG (2 gm/kg)
b- High dose IVIG (2 gm/kg ) + Rituximab
c- Plasmapheresis + low dose IVIG
d- Plasmapheresis + low dose IVIG+ Rituximab
e- Plasmapheresis + low dose IVIG+ Rituximab + splenectomy
Benefits of desensitization;
Desensitization can increase access to both living and deceased donor transplants and can be used individually or in combination with KPD.
Long-term risks of desensitization;
1-Desensitization therapies add to overall immunosuppression raising the obvious concerns of infection and other immunosuppression related complications including malignancies.
2-Patient survival rate was reduced in patients who underwent incompatible transplants (ABO, HLA, ABO+HLA) compared to standard transplants.
Cost-effectiveness of desensitization;
The incremental cost-effectiveness of desensitization was estimated to be $80 486 per quality-adjusted life year. In comparison, compatible living donor transplant was estimated to cost $39 939 per quality adjusted life year.
1-The different techniques of desensitization
The goal of desensitization is to reduce or eliminate DSA to prevent hyperacute rejection. Desensitization protocols combine antibody elimination by PE and decrease antibody production or block their action.
2-Various techniques of desensitization
Plasmapheresis has short term effects and removes not only circulating DSA but also all plasma proteins including clotting factors, with post treatment rebound if used alone.
Intravenous immunoglobulin (IVIg): inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation. Two protocols have been studied so far :low dose IVIG (100mg/kg) with alternate day PLEX or high dose(1-2g/kg)combined with alternate day PP . Administration of IVIG was associated with a modest decrease in reactivity to both class I and II HLA antigens so need to be used in combination with other modalities.
Rituximab: monoclonal antibody against CD20 : ABMR still occur in 29% of the patients if used in combination with high dose IVIG , with patient and graft survival of 95% & 84% respectively at 02 years.
Other agents used includes Bortezomib(proteasome inhibitor-no role in desensitization ), Eculizumab (a humanized monoclonal antibody against C5-is expensive, may show some benefit but have risk of meningococcal infection and also needs vaccination prior to transplant ), Tocilizumab (a humanized monoclonal antibody against IL-6 receptor -under investigation but may have potential role), and IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS) (Prevent IgG dependent (cellular cytotoxicity and complement mediated toxicity, has promising results but need more studies)and Daratumumab (IgG1j –a human monoclonal antibody that binds to CD 38 and inhibits the development of plasma cells and plasmablasts-reduce DSA level but causes rebound rise of antibodies).
Various protocols of desensitization
a- High dose IVIG (2 gm/kg)
b- High dose IVIG (2 gm/kg ) + Rituximab
c- Plasmapheresis + low dose IVIG
d- Plasmapheresis + low dose IVIG+ Rituximab
e- Plasmapheresis + low dose IVIG+ Rituximab + splenectomy
3-Benefits of desensitization
Transplantation in highly sensitized patients is very difficult and challenging. Desensitization removes preformed DSA and allow to proceed with transplant and prevent hyperacute rejection and enhances transplantability of highly sensitized patient on the waiting list of deceased kidney transplantation and provide him better QOL than to stay on dialysis.
.4-Long-term risks of desensitization
Desensitization recipients has high risk of rejection episodes ,infection rates and other immunosuppression related complications including malignancies. Also had reduced graft and patient survival ) compared to standard transplant patients.
5-Cost-effectiveness of desensitization
Desensitization therapies significantly increase the expenses of the transplant procedure, accounting for about 42% increase in its according to one study. But still the overall economic impact needs to be considered in light of longer survival and a reduced need for hemodialysis.
Alternatives to desensitization: kidney paired donation:
Kidney allocation system for deceased donor. And Paired kidney donation and exchange between living donors should be encouraged to improve outcomes and prevent graft failure.
Desensitization therapies target removing and/or reducing donor-specific antibodies (DSA) prior to transplantation, thereby preventing hyperacute rejection and allowing a successful transplantation
.
Desensitization protocols have typically combined an approach of removing circulating DSA with plasmapheresis (PP), combined with agents that decrease antibody production, or ones that block their actions.
Plasmapheresis removes antibodies from the circulation. This technique is not specific for the removal of alloantibodies and this removal is only short-lived with antibodies rebounding to pre-treatment levels following re-equilibration between intravascular and interstitial compartments. More importantly, PP does not affect ongoing antibody production by plasma cells and, hence, is a poor treatment choice for desensitization as sole therapy. Its side effects include coagulopathy, hypocalcemia, thrombocytopenia, hypotension and catheter-related infection and sepsis.
Intravenous immunoglobulin (IVIg) has been shown to inhibit T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation. IVIg-based desensitization can be divided into two general approaches: combined with alternate day PP at a low dose (100 mg/kg); or used at a high dose (1–2 g/kg). Despite the modification in the dose, the acute AMR rate is still high. Luminex single-antigen testing was performed before and after IVIg. Administration of IVIg was associated with a modest decrease in reactivity to both class I and II HLA antigens but did not significantly alter mean cPRA.
The effects of high-dose IVIG (2 g/ kg) and Rituximab were examined in a prospective study on desensitizing transplant candidates with a cPRA >50% waiting for a deceased donor kidney for more than 5 years. It showed no significant reduction in patients’ class I and II cPRA levels, nor any change in the mean number of unacceptable antigens or their mean fluorescence intensity values.
The addition of rituximab or splenectomy did not appear to decrease the acute AMR rate.
Bortezomib (BTZ): is a proteasome inhibitor (PI) that induces endoplasmic reticulum stress, NFjB inhibition and apoptosis in normal and transformed plasma cells. In different studies of patients who used many sessions of BTZ, non-developed a negative cross-match against their original intended donor, and the calculated panel reactive was unchanged in all patients.
Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation. It has been shown to be efficacious in the prevention AMR in renal transplant recipients who had a positive crossmatch against their living donor with a significant reduction in the rates of AMR. However, it’s of high cost, with an average wholesale price of $21 000 per dose. Another consideration is the risk of the development of invasive infections with encapsulated organisms during eculizumab therapy due to which certain vaccinations are prerequisites.
Tocilizumab (TCZ) a humanized monoclonal antibody directed at the IL-6 receptor has also been studied as a potential desensitization agent. Looks promising agent in reducing AMR, however, larger controlled studies are essential to better study its efficacy.
IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS) that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization. Out of the 25 patients, 22 had DSA present before transplantation. IdeS reduced or eliminated DSAs and permitted HLA incompatible transplantation in 24 of 25 patients. AMR occurred in 10 patients from 2 weeks to 5 months after transplantation; all of these patients had a response to treatment.
Daratumumab is an IgG1j human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts. Its use is still experimental. Animals treated with daratumumab had significantly reduced DSA levels compared to untreated controls (57.9% vs. 13%). However, the reduction was not maintained and a rapid rebound of antibodies developed with profound rejection.
· Benefits of desensitization
Recipients of kidney transplants from incompatible live donors had higher survival, though results are controversial between different analyses.
· Long-term risks of desensitization
Desensitization therapies lead to an increase in the rate of infection and other immunosuppression related complications including malignancies.
The patient survival rate was reduced in patients who underwent incompatible transplants (ABO, HLA, ABO+HLA) compared to standard transplants.
· Cost-effectiveness of desensitization
In addition to increasing the medical complexity of renal transplants, desensitization therapies significantly increase the cost of the transplant procedure. In Axelrod et al. study Incompatible living donor transplant was associated with a 42% increase in the cost of care ($151 024 vs. $106 636 P < .001). Medicare reimbursement was also increased, with a mean payment (excluding the cost of organ acquisition) of $92 150 for incompatible vs. $58 084 for compatible transplants. However, While desensitization treatments increase the cost of the transplant, the overall economic impact needs to be considered in light of longer survival and a reduced need for haemodialysis
Alternative to desensitization is kidney paired donation which can provide access to organs where the immunological barrier can be avoided. KPD is associated with better outcomes and lower costs.
Ø Available desensitization agents:
o Plasmapheresis: remove all antibodies, but unfortunately
§ Short lasting effect and rebound DSA after treatment due to redistribution between intravascular compartment and interstitial spaces, so it can not be used alone.
§ Not prevent new DSA formation from plasma cells.
§ Adverse effects: coagulopathy, hypocalcemia, complications of central line as infection and thrombosis.
o IVIG: neutralizes DSA, prevent T and B cell maturation and decrease cytokines production.
§ Either low dose (100 mg/kg) or large dose (2 gm/kg).
§ Usually follow PEX therapy on alternate days.
§ Combined PEX and low dose IvIg is better than high dose IvIg alone.
o Rituximab: chimeric molecule against CD 20, deplete B cells (precursor of antibody producing plasma cells)
o Bortezomib:
§ Inhibit anti body producing plasma cells.
§ Failed to turn XM negative and decrease cPRA
§ Need further studies.
o Eculizimab:
§ May be effective, but very expensive and can lead to serious infections by encapsulated organism (vaccination prior to transplant is mandatory).
o Anti IL-6 r antibodies (tocilizumab): just add on therapy with IvIg and still under investigations.
o IdeS:
§ an enzyme derived from strept pyogens that can cleave all 4 subtypes of human IgG.
§ Prevent IgG dependent (cellular cytotoxicity and complement mediated toxicity).
§ Can remove all DSA and turn +ve XM to -ve.
§ However, it is immunogenic that antibodies formed against it
§ Also associated with rebound DSA with AMR, fortunately responded to standard of care therapy as (PEX and IvIg).
Ø Various protocols of desensitization
1- Plasmapheresis + low dose IVIG
2- Plasmapheresis + low dose IVIG+ Rituximab
3- High dose IVIG (2 gm/kg) alone.
4- High dose IVIG (2 gm/kg) + Rituximab
5- Plasmapheresis + low dose IVIG+ Rituximab + splenectomy
Ø The most commonly used protocol is combined PE, low dose IVIG and Rituximab (5 sessions of plasmapheresis on alternate days (more sessions can be done according to titer of DSA), followed by low dose of IVIG 100 mg/kg after each session and 1 dose of Rituximab 375 mg/m2 1 week later).
Ø Benefits of desensitization
§ Transplantation in the context of positive crossmatch and high level of detected DSA and cPRA > 80% is very challenging and can be done by:
§ In living donor: kidney paired donation system for exchange of donors between couples.
§ Deceased donor: no time for KPD, so only available option is desensitization to proceed to transplantation. Other options, unlimited waiting for another deceased donor or keep on dialysis.
§ Sensitization enhance transplantability of highly sensitized host on the waiting list of deceased kidney transplantation and provide him better QOL than to stay on dialysis.
§ Desensitization remove preformed DSA and turn XM to be negative to allow transplant and prevent hyperacute rejection.
Ø Long-term risks of desensitization
§ Acute rejection can still occur 3 times higher in desensitized recipients than non sensitized regardless the regimen used for desensitization and induction therapy. This is coasty and associated with worse long term graft survival. This can be explained by formation of memory cells
§ Risk of infections and malignancy after those immune depleting regimens can not be neglected.
Ø Cost-effectiveness of desensitization
§ The cost of desensitization protocols + cost of treatment of inevitable close monitoring as protocol biopsy and DSA monitoring + cost of treatment of expected acute rejection in case of HLA -incompatible transplantation represent a major burden.
§ This cost may overweigh short term benefit of trasplantability of some patients with very high risk of rejection ( impossible transplant without desensitization)
§ So , desensitization protocol should be used only for those who has been on waiting list for long time and no suitable deceased donor.
§ The direction must be toward improvement of:
o Kidney allocation system for deceased donor.
o Paired kidney donation and exchange between living donors.
Renal transplantation is the best option for ESRD on regular dialysis to decrease comorbidities and for better quality of life.
HLA mismatch is the biggest barrier against renal transplantation, also sensitized patient to HLA antigens following pregnancy, blood transfusion or previous transplant usually have higher calculated panel reactive antibody and may reach 100%, which means decrease chance to meet compatible matched donor , and also highly sensitized patient have more chance to develop antibody mediated rejection and decrease graft survival and ends by graft loss.
Desensitization protocol in spite of being expensive but should be done to desensitize the patient or remove DSA and block its production:
Plasmapheresis PP : not used as single treatment as it removed circulating antibodies and not specific to alloantibodies but also it removes plasma proteins including clotting factors , and also has no effect on ongoing antibody production by plasma cells so rebound can be done early, so not used alone.
Side effects including infection, bleeding disorders
Intravenous immunoglobulin (IVIg) it inhibits T- and B-cell proliferation, cytokine production, maturation of dendritic cells, induce B-cell apoptosis and inhibit complement activation. Can be used combined with alternate day PP at a low dose (100 mg/kg), or used at a high dose (1–2 g/kg)
Low-dose IVIg and PP protocols used for the patients with living donors and high levels of DSA. higher titre of DSA, more sessions of PP, followed with the infusion of IVIg. Here, AMR incidence is 36% with 100% 1-year graft survival.
In spite of a lot of trials (use ATG as induction, addition of rituximab to desensitization protocol, and splenectomy) to decrease incidence of AMR, the incidence of AMR remains high as 43% with 78% graft survival at 15 months.
Use of high dose IVIg has variable results in variable studies.
Bortezomib (BTZ) is a proteasome inhibitor (PI) that induces endoplasmic reticulum stress, NFjB inhibition and apoptosis in normal and transformed plasma cells. treatment with the PI BTZ might deplete antibody-secreting long-lived plasma cells and have an impact on DSA production.
Eculizumab is a humanized monoclonal antibody that blocks cleavage of the human complement component C5 and prevents terminal complement activation. It has been shown to be efficacious in the prevention AMR in renal transplant recipients who had a positive crossmatch against their living donor.
Tocilizumab (TCZ) a humanized monoclonal antibody directed at the IL-6 receptor has also been studied as a potential desensitization agent. IL-6 is a pleiotropic cytokine that has powerful stimulatory effects on B cells and plasma cells and is responsible, in conjunction with other cytokines, for normal antibody production. It has also been recognized as an important mediator of allograft rejection.
IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS) that cleaves all four human subclasses of IgG has recently been used as an agent for desensitization.
Daratumumab is an IgG1 human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts.
Desensitization protocol is expensive and has long term complications added to complications of immunosuppression drugs , also there is no standard protocol can decrease DSA and decrease incidence of AMR.
Kidney exchange donor program KPD (kidney paired donation) is the best option for living donation, can solve many problems of the recipients.
The different techniques of desensitization
3 main lines are available for desensitization
· Plasmapharesis which remove circulating DSA , it provide short term removal of antibodies, with post treatment rebound if used alone.
· Rituximab which decrease the production of DSA by producing B cell depletion
· IVIG which block the effect of preformed DSA and cause inhibition of T cell, B cell proliferation, cytokine release, complement activation and promote B cell apoptosis
Other agents used includes Bortezomib (no rule), Eculizumab (potentioal benefit, expensive, risk of meningiococcal infection), Tocilizumab (may have potential rule-needs more studies), Daratumumab (rebound rise of antibodies) and IdeS (promising, need more studies)
Various protocols of desensitization
1- High dose IVIG (2 gm/kg)
2- High dose IVIG (2 gm/kg ) + Rituximab
3- Plasmapheresis + low dose IVIG
4- Plasmapheresis + low dose IVIG+ Rituximab
5- Plasmapheresis + low dose IVIG+ Rituximab + splenectomy
Conclusion obtained from studies
· Plasmapheresis should be included in any regimen used for desensitization since all regimens that did not contain plasmapheresis fail to decrease PRA and obtain negative cross match
· Addition of rituximab to plasmapharesis and IVIG is debatable
· Splenectomy offer no advantage in desensitization protocols
· Use of high dose IVIG alone is not recommended
– The most commonly used protocol is combined PE, low dose IVIG and Rituximab. 5 sessions of plasmapheresis are done on alternate days (more sessions can be done according to titre of DSA), each session is followed by low dose of IVIG 100 mg/kg and 1 week later give 1 dose of Riuximab 375 mg/m2.
Benefits of desensitization
Highly sensitized transplant candidate who cannot find suitable donor has one of the following possibilities:
1- Keeping the patient on hemodialysis which is associated with higher mortality
2- Try to find compatible living kidney donor, it may be difficult but because of KPD (local or preferred national) any recipient with a living donor even if ABO or HLA incompatible can exchange donor with another pairs
3- Wait for compatible deceased donor and this will take very long time, but because of improvement of the kidney allocation system (KAS), wait list was reduced from > 19 years to around 3 years
4- Desensitization to render incompatible donor possible for transplantation
Desensitization offer a good transplant opportunity and survival advatage for highly sensitized recipient with cPRA> 80% who has very low likehood to get a transplant (living or deceased) due to positive cross match
The goal of desensitization is to remove preformed DSA that cause positive cross match with the doner and are associated with hyper acute rejection with immediate loss of the graft upon transplantation
The main indication of desensitization nowadays is a recipient with no living donor and highly sensitized so cannot find deceased offer and expected to be waitlisted for long time
Long-term risks of desensitization
· Desensitization was found to improve short term graft and patient survival, but rate of acute rejection is more than 3 fold higher than in non sensitized patients regardless of the regimen used for desensitization and induction and this may affect long term graft survival
· Higher incidence of acute rejection may be explained by the effect of desensitization which remove or decrease production of DSA but will not remove memory cells which are capable of producing strong rejection later on.
· The most important concern when using desensitization strategies is infection risk, some found increase in the risk of infection but other failed to find this finding
Cost-effectiveness of desensitization
· Desensitization was found to improve short term graft and patient survival, but rate of acute rejection is high adding more cost due to aggressive monitoring, protocol biopsies and cost of treatment
· Desensitization is expensive, the cost of transplanting incompatible donors with positive CDC cross match is the highest, followed by those with positive FCM and negative CDC then patients kept on hemodialysis and lastly compatible kidney transplantation which offers the least cost
Desensitization in Kidney Transplant: A Risky (but Necessary?) Endeavor for Those With Limited Options
· The development of good allocation system and national kidney paired donation facilitates deceased and living kidney transplantation and decrease the need for desensitization.
· The main indication of desensitization nowadays is a recipient with no living donor and highly sensitized so cannot find deceased offer and expected to be waitlisted for long time
· Desensitization is associated with higher acute rejection and infection rate, and is expensive
· So the author recommends avoidance of HLA incompatible transplantation whenever possible due to cost and risks associated with this strategy.
The goal of desensitization is to reduce or eliminate DSA to prevent hyperacute rejection. Desensitization protocols combine antibody elimination by PE and decrease antibody production or block their action.
Comparing the two studies are difficult as they have different definition of sensitization, different matching methods, different population, different waiting time, and different socioeconomic factors.
Most published studies are short term studies, so it is difficult to determine the long term effect of desensitization. there is a concern about infection and malignancy risks. In a study that evaluated the risk of CMV & BK virus infection in patients desensitized with IVIG+ PE+ Rituximab, the risk of these infections was similar to that observed in standard transplant recipients. larger studies are needed to arrive at a stronger conclusion.
Desensitization therapies significantly increase the cost of transplantation.
Incompatible living donor transplant was associated with a 42% increase in the cost of care according to a cohort. The overall economic impact needs to be considered in light of longer survival and a reduced need for haemodialysis. An incompatible living donor kidney transplant was associated with a greater cost of care ($440 234) and longer mean survival. In comparison, a compatible living donor transplant was estimated to cost $39 939 per quality-adjusted life-year.
Plasmapheresis
removes antibodies from the circulation
not specific for the removal of alloantibodies
all plasma proteins are reduced including clotting factors. removal is only short-lived
PP does not affect ongoing antibody production by plasma cells
side effects
coagulopathy
hypocalcemia
thrombocytopenia
hypotension
catheter-related infection
sepsis.
Intravenous immunoglobulin (IVIg)
inhibit T- and B-cell proliferation
cytokine production
maturation of dendritic cells
induce B-cell apoptosis
inhibit complement activation
can be divided into two general approaches:
combined with alternate day PP
at a low dose (100 mg/kg)
patients undergo varying numbers of PP sessions (higher titres, more sessions of PP) followed with the infusion of IVIg.
Using low-dose IVIg with PP, AMR has been reported to be as high as 36%.
The low-dose IVIg with PP, protocol was modified to include anti-thymocyte globulin for induction along with the addition of rituximab and splenectomy.
Despite the modification, acute AMR rate was 43%.
at a high dose (1–2 g/kg)
use in both living and deceased donors
IVIg (2 g/kg) was given to cross- match-positive recipients.
In addition various induction agents like thymoglobulin, alemtuzumab used
As AMR rates remained high despite pretreatment intervention rituximab was added to high-dose IVIg (2 g/kg) based regimen.
studies question the ability of IVIg alone to meaningfully decrease sensitization status.
Mayo clinic authors in their single centre study concluded that PP/low-dose IVIG and rituximab demonstrated more success in abrogating positive crossmatch and lower acute rejection rates, but no regimen was completely effective in preventing AMR.
Other agents used-
Bortezomib
Forty-four patients received 52 desensitization courses. Only 19 out of 44 patients (43.2%) could be transplanted low acute rejection rate (18.8%)
12.5% of subjects had de novo DSA formation
Eculizumab
One hundred and two patients underwent desensitization. Post-transplant, 51 patients received standard of care (SOC) and 51 received eculizumab. Treatment failure rates were 11.8% and 21.6% for the eculizumab and SOC.
Quite expensive
risk of develop- ment of invasive infections with encapsulated organisms.
Tocilizumab
Tocilizumab with IVIg appears to be an additional agent with potential in desensitization.
IgG-degrading enzyme derived from Streptococcus pyo- genes (IdeS)
Since the Fc region of IgG is critical for inter- action with Fc receptors and complement binding, proteolytic activity on IgG molecules at this site pre- vents the occurrence of IgG-mediated antibody-depen- dent cellular cytotoxicity and complement-mediated cytotoxicity, two processes that are critical for AMR.
Daratumumab
IgG1 human mAb that binds to CD 38 and inhibits the development of CD 38 expressing cells including plasma cells and plasmablasts.
Studied in primates
Benefits of desensitization
A multi-centre analysis on the survival benefit of kidney transplants from HLA-incompatible live donors exam- ined the results across 22 centres in the US with 1025 recipients.
Their outcomes were matched with controls who remained on the waiting list or received a transplant from a deceased donor (waiting list or transplant control group) and controls who remained on the waiting list but did not receive a transplant.
Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year (95.0% vs. 94.0% for the waiting list or transplant control group and 89.6% for the waiting list-only control group)
3 years (91.7% vs. 83.6% and 72.7%, respectively)
5 years (86.0% vs. 74.4% and 59.2%)
8 years (76.5% vs. 62.9% and 43.9%
Analysis of the UK adult transplant waiting list –
compared the patient survival of crossmatch- positive living donor HLA-incompatible kidney transplant with that of similarly sensitized patients awaiting a compatible organ . Two hundred and thirteen patients who underwent HLA-incompatible transplant were matched in a 1:4 ratio with similarly sensitized patients listed for a transplant across the same time period.
No difference in survival was noted between patients who underwent a HLA-incompatible transplant compared with the listed only group, or listed or transplant group.
Long-term risks of desensitization
Infection
Malignancies
Cost-effectiveness of desensitization
Incompatible living donor transplant was associated with a 42% increase in the cost of care.