ABO incompatibility was considered as an absolute contraindication to transplantation. The shortage in donated organ and development in the transplant management pre and post the procedure, pushed toward acceptance of this risky process after certain and special techniques being accomplished to minimize the risk of rejection. Graft survival rate in ABOi transplantation was found to be comparable to that in compatible transplantation.
Blood group Antigens and Antibodies
· The ABO antigen system consists of oligosaccharides.
· They are predominantly expressed on red blood cells and are also found on endothelial cells, tubuli, and glomeruli making the ABO antigen system important for kidney transplantation.
· Blood group A2 recipients have a low expression of blood group antigen molecules (30–50%) on the surface of erythrocytes, which is believed to be responsible for the lower immunogenicity of organs from blood group A2 donors.
· Naturally occurring anti-A/B antibodies are predominantly of the IgM class but especially in blood group O individuals they also consist of IgG and IgA class
Desensitization for ABOi kidney transplantation
Currently proposed strategies share some common principles, together with a powerful maintenance immunosuppression:
1. (1) Extracorporeal therapy for depletion of Anti-A/B antibody.
2. (2) Modulation of the recipient’s immune system by the use of intravenous immunoglobulins (IVIgs)
3. (3) Reduction of the B lymphocyte pool by splenectomy, or more recently by the anti-CD20 antibody rituximab.
4. Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the graft endothelium.
Antibody depletion by extracorporal treatment
No significant differences were found in clinical studies that compared the impact of different IA strategies on clinical outcomes, including anti-A/B antibody reduction, survival, kidney function, rejection episodes, or complications Antibody removal strategies may be divided into:
· Complete removal of plasma proteins via PP.
· Removal of specific fraction of plasma protein via membrane separation or via more specific method as unselective or selective IA.
· Combination of membrane separation and unselective IA.
Intravenous Immunoglobulins
· It helps prevent the anti-A/B antibody rebound in the early phase after transplantation.
· It reduces infectious complications by substituting depleted immunoglobulins.
· As a note of caution; may increase anti-A/B antibody titers upon administration. B-Cell Depletion by Splenectomy or Rituximab
· Splenectomy reduces the B-lymphocyte pool. Associated with surgical risk and high risk of infection.
· Anti-B cell therapy as Rituximab reduces lymphocyte pool.
Inhibition of Complement Activation
· The use of Eculizumab was successful in treating anti-A/B antibody rebound. But other study declared that the results on the use of eculizumab after ABOi kidney transplantation are inconclusive.
Desensitization protocols and Survival after ABOi living donor kidney transplantation:
In comparison to ABOc transplantation;
· the rates for antibody- and T-cell-mediated rejections were anot significantly different.
· Similar death-censored graft survival as being showed by study from UK.
· Patient survival in ABOi transplant recipients was reduced due to infectious complications, mostly Pneumocystis jirovecii pneumonia. Complications and Barriers of ABOi transplantation:
· Accommodation versus Rejection; accommodation appears to be a frequent phenomenon after ABOi kidney transplantations and is often associated with C4d deposi- tion in peritubular capillaries of allograft biopsies.
· Infection; A higher frequency of viral infection ssuch as CMV,HSV,VZV,and BKvirus, as well as P. jirovecii pneumonia, wound, and severe urinary tract infections have been described . The rate of BK virus nephropathy was about three times higher in ABOi patients compared to patients with HLA antibodies.
· Malignancy; No increased cancer risk when comparing ABOi kidney transplant recipients to matched ABOc controls.
· Higher risk of early hemorrhage.
Alyaa Ali
2 years ago
For long time, the ABO-incompatible (ABOi) kidney transplantation was considered a contraindication to successful kidney transplantation.
The solution for the increasing number of ESRD patients with more time in waiting list is to seek for strategies to overcome the ABO antibody barrier.
Nowadays, after development of de-sensitization protocols , the transplantation against ABO barrier can be done and it showed a comparable graft survival with ABOc- transplantation. Blood group antigens and antibodies
ABO antigen system crucial for kidney transplantation,as its antigens are expressed on red blood cells and are also found on endothelial cells, tubuli, and glomeruli.
Anti-A/B antibodies are predominantly of the IgM class but in blood group O individuals they also consist of IgG and IgA class. Desensitization for ABOi kidney transplantation
There is no generally accepted desensitization guidelines
Antibody depletion at the time of transplantation which can be divided into methods that completely remove plasma proteins such as PP, methods that remove only a specific fraction of the plasma proteins including the immunoglobulins (such as double filtration ), and more specifc methods such as unselective or selective IA.
Intravenous Immunoglobulins centers before ABOi kidney transplantation to prevent the anti-A/B antibody rebound in the early phase a#er transplantation.
B-Cell Depletion,Before the introduction of pharmacological anti-B cell therapies,splenectomy was an integral component for the reduction of the B lymphocyte pool prior to ABOi kidney transplantation. Due to the surgical risk and increased risk of sepsis, splenectomy was gradually substituted by the anti-CD20 antibody rituximab.
Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the graft endothelium as inhibition of Complement Activation with using eculizumab, but results on the use of eculizumab after ABOi kidney transplantation are inconclusive.
Results from the CTS
Study 3-year outcomes of 1,420 ABOi kidney transplant recipients who were transplanted at 101 different centers between 2005 and 2012 showed that the overall graft, death-censored graft, and patient survival were not statistically significant different between ABOi recepients and their matched group of ABOc kidney transplant recipients,but early patient survival was reduced in ABOi kidney transplant recipients due to a higher rate of early infection-associated death versus matched controls. Complications of ABOi kidney transplantation Accommodation versus Rejection
About 2 weeks after successful transplantation, accommodation is established and even high anti-A/B antibody exposure does not harm the kidney transplant. Local up-regulation of complement regulatory proteins, like CD45, CD55, and CD59, as a consequence of anti-A/B antibody-dependent inactivation of ERK1/2 signaling pathway are discussed as one possible mechanism. Infections
A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus,as well as P. jirovecii pneumonia, wound, and severe urinary tract infections have been detected i n ABOi kidney transplantation versus ABOc kidney transplantation. Malignancy studies show no an increased risk of malignancy in ABOi compared to ABOc patients
MICHAEL Farag
2 years ago
ABO-Incompatible Kidney Transplantation Introduction ABO-incompatible (ABOi) kidney transplantation has long been considered a contraindication to successful kidney transplantation but due to the accumulation of the waiting list, many studies evolved in previous decades about ABOi tx as still transplantation is he best modality of renal replacement therapy for the patients with end stage renal disease. Therefore, desensitization protocols used to try to overcome this challenge, the aim of desensitization protocols is the reduction and maintenance of anti-A/B antibodies (isoagglutinins) during the “first 2 weeks after transplantation below a threshold that is considered to be safe (e.g., <1:32 in tube technique). Even when anti-A/B antibodies recur at high levels they will not harm the kidney transplant, a phenomenon that is called accommodation. In recent years, graft survival rates after ABOi kidney transplantation nearly equaled those afterABO-compatible (ABOc) procedures. BLOOD GROUP ANTIGENS AND ANTIBODIES Compared to blood group A1 and blood group B individuals, blood group A2 recipients have a low expression of blood group antigen molecules (30–50%) on the surface of erythrocytes, which is believed to be responsible for the lower immunogenicity of organs from blood group A2 donors. ABOi kidney transplantation with A2 organs has been accomplished with standard immunosuppressive therapy without any additional measures. DESENSITIZATION FOR ABOi KIDNEY TRANSPLANTATION These include together with a powerful maintenance immunosuppression one or more of the following: (1) Anti-A/B antibody depletion at the time of transplantation using PP, double-filtration PP/membrane filtration, or selective or unselective immunoadsorption (IA) (2) Modulation of the recipient’s immune system by the use of intravenous immunoglobulins (IVIgs) (3) Reduction of the B lymphocyte pool by splenectomy, or more recently by the anti-CD20 antibody rituximab (4) Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the graft endothelium. A)Antibody Depletion by Extracorporal Treatment Antibody removal strategies may be divided into methods that completely remove plasma proteins such as PP, methods that remove only a specific fraction of the plasma proteins including the immunoglobulins (such as membrane separation), and more specific methods such as unselective or selective immunoadsoption; IA B) Intravenous Immunoglobulins It is used to reduce anti A/B abs in first 2 weeks post transplant and also to reduce the potential infection complications of PP , As a note of caution, IVIg preparations contain IgG antibodies directed against A/B antigens and can effectively increase anti-A/B antibody titers upon administration. C) B-Cell Depletion by Splenectomy or Rituximab Before the introduction of pharmacological anti-B cell therapies, splenectomy was an integral component for the reduction of the B lymphocyte pool prior to ABOi kidney transplantation. Due to the surgical risk and increased risk of sepsis, splenectomy was gradually substituted by the anti-CD20 antibody rituximab D) Inhibition of Complement Activation New concept using eculizumab but still the studies are inconclusive. COMPLICATIONS AND HURDLES OF ABOi KIDNEY TRANSPLANTATION In contrast to transplantation in the HLA-sensitized patient, accommodation appears to be a frequent phenomenon after ABOi kidney transplantations and is often associated with C4d deposition in peritubular capillaries of allograft biopsies. An accommodation phenotype may be achieved by the controlled anti-A/B antibody exposure to antigens in the early phase after kidney transplantation. About 2 weeks after successful transplantation, accommodation is established and even high anti-A/B antibody exposure does not harm the kidney transplant. Local upregulation of complement regulatory proteins, like CD45, CD55, and CD59, as a consequence of anti-A/B antibody-dependent inactivation of ERK1/2 signaling pathway are discussed as one possible mechanism. Infection and Malignancy and other complications Studies have shown that there is higher risk of infection especially viral infection in ABOi tx more than ABOc tx while no increase in the malignancy in both groups .
In ABOi there is higher risk of
– Bleeding: which was attributed to the unspecific binding of coagulation factors during repeated IA and there is correlation between the number of pretransplant apheresis treatments and the peri- and posttransplant bleeding risk
– an increased rate of surgical complications after ABOi kidney transplantation, which were attributed to early intensified immunosuppression with mycophenolic acid and removal of coagulation factors by apheresis
Mohamed Essmat
3 years ago
Blood group antigens are present on the RBCS and on the endothelial cells and they include A, B, AB, O .
Individuals with blood group O has no antibodies so they are universal donors, While with AB are universal recipients.
The first 2 weeks are the most important in measuring the antibodies levels .
Titre > 1/256 is considered high by most centres while acceptable level pre transplantation vary between 1/4 to 1/32.
Desensitization protocols include Rituximab , PTx , IVIG , induction by ATG or Simulect according to the risk
There is increased risk of ABMR in the first 2 weeks of transplantation.
Diagnosis is based on the presence of histological features of ABMR and the presence of antibodies ( C4d can be present in biopsy with no features of ABMR ) .
saja Mohammed
3 years ago
Summary: introduction:
ABO antigens structure of oligosaccharide protein which mainly expressed in RBC, endothelial cells, epithelial cells, tubules and glomerulus which is very important in kidney transplantation
ABOI kidney transplant earlier considered as an absolute contraindication for kidney transplant and associated with hyper-acute rejection due to anti A/B antibodies but with the introduction of desensitization protocol since last 25 years the access to ABOi transplant increased with similar outcome to ABO c kidney transplant it helps in expanding the pool of the donors and shortening the waiting list with better survival compared to waiting on dialysis blood group A2 found in about 20% of the white population and less antigenic expression in RBCS so less immunogenic compare to A1 group, so ABOi Kidney transplant from A2 blood group requiring only standard IS without desensitization while anti A/B antibodies including IgM and IgG, immunoglobulin and their pathogenic importance in known in sold organ transplantation with more antigenic density and expression in RBCS.
Desensitization protocols evolving over time not yet standardized and each center have their own protocols based on local experience and available resources, and most of the evidence based on observational trails no RCT yet available
By principle of desensitization protocol aims for antibodies removal to the acceptable value at the date of transplantation also avoid further production of ABS by using immunomodulating agent like IVIG with B cell depleting agents earlier surgical elective splenectomy and recently replace by antiCD20 RITUXIMAB to allow the transplantation and avoid rebound in the first two weeks post-transplant and allowed for graft accommodation after that combination therapy preferable including plasmapheresis 3-5 sessions 10-14 days prior to transplant the therapeutic plasmapheresis each session can remove 30% of IgM abs and 20% of IgG anti B/A abs
IA kind of more selective removal of anti IgM, IgG abs more available in Europe
All kinds of therapeutic plasmapheresis aim for antibodies removal, nonselective or selective all does not show any impact on the graft survival and all associated with the risk of AB rebound post-transplant and AMR so need close monitoring of the ABS titer early post-transplant for the first few weeks. IVIG low dose or high dose used in combination with plasmapheresis to prevent the ABS rebound also replace the Igs removed during plasmapheresis and reduce the rate of infections
B cell depleting agents:
Splenectomy which nowadays replaced by medical therapy with rituximab as its associated with more surgical and infection complication, even rituximab anti CD20, act as B cells depleting agent associated with higher rate of infection and some centers remove it from desensitization protocols or using lower doses of 100-200mg /M2 instead of 375g/m2
CTSs shows higher rate of death censored graft loss death in ABOI KTX without rituximab.
Inhibition of Complement Activation
Eculizumab anti c5 complement monoclonal ABS used for prevention of complement mediated ABMR and one pilot study show s inconclusive results, in addition its use limited due to the high cost .the ABO I kidney transplant graft and patient survival was similar to the control groups of ABOc KTX based on the available evidence from different observational studies from different centers in Europe and Japan which most shows similar graft and death censored graft loss in one year and 3 years and even 9 years in one study , but in some studies shows that the graft survival can be affected earlier post-transplant due to increased rate of infections including BKV nephropathy , bacterial infections like PJP and MDR bacteremia due to intense immunosuppression with desensitization protocol especially with rituximab use .
ABOI kidney transplant did not increased the rate of malignancy based on the available evidence Accommodation versus Rejection:
Accommodation commonly occurs in ABOi KTX sensitized recipients which characterized by C4D staining but without evidence of acute graft injury.
Batool Butt
3 years ago
ABO incompatibility was considered an absolute contraindication to kidney transplantation until 1982 when successful desensitization done together with intensified immunosuppression.
The ABO antigens are expressed not only on RBCs but also on endothelial, tubular, and glomerular cells. Density of antigens on erythrocytes differ between different blood groups and patients with blood group A2 makes up 20% of blood group A in Caucasian individuals have lower immunogenicity compared to blood group A1 or B, so kidney from A2 donor can be transplanted with standard immunosuppressive therapy without any additional measures. To overcome shortage of donors, strategies to manage ABOi living transplantation has been developed.
Different desensitization protocols are used aiming to reduce anti-A/B antibodies below a threshold that is considered to be safe (e.g., <1:8) especially during the first 2 weeks post transplantation
Desensitization for ABOi kidney transplantation consist of one or more of following:
(1)Anti-A/B antibody depletion at the time of transplantation using PP, double-filtration PP/membrane filtration, or selective or unselective immunoadsorption (IA) .IA could be selective and non –selective.
Non selective IA is more effective in removing A/B IgG than selective IA but unselective IA is less effective in removing A/B IgM
(2) Modulation of the recipient’s immune system by the use of intravenous immunoglobulins (IVIgs)
(3) Reduction of the B lymphocyte pool by splenectomy, or more recently by the anti-CD20 antibody rituximab.
(4)Inhibition of Complement Activation :The use of eculizumab as an inhibitor to membrane attacking complex is controversial DESENSITIZATION PROTOCOLS AND SURVIVAL AFTER ABOi LIVING DONOR KIDNEY TRANSPLANTATION
The cumulative incidence of graft loss during the first year after transplantation was 5.9% in ABOi as compared to only 2.9% in ABO compatible transplantations. Early recognition and prompt action is crucial for graft survival for ABOi kidney transplantation. A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound, and severe urinary tract infections and higher bleeding risk have been described. CONCLUSION:
In conclusion, ABOi kidney transplant significantly expand the living donor pool by 30%.However,ABOi transplantation carried a higher risk of early rejection, infection, and infection-associated death. Therefore, ABO compatible transplantation should be done whenever possible
Wee Leng Gan
3 years ago
ABO-Incompatible Kidney Transplantation.
Desensitizing strategies and early recognition of complications are the keys for successful for ABO-incompatible (ABOi) kidney transplantation. Effective desensitization protocols ensure the reduction and maintenance of anti-A/B antibodies within the recommended range of <1:32 in tube technique during the first 2 weeks after transplantation. The outcome of ABOi kidney transplant almost the same as ABO compatible kidney transplant even with the presentation of accommodation phenomenon.
Desensitization protocol include Anti-A/B antibody depletion by plasmapheresis or immunoadsorption (IA) , IVIG, B cell depletion by splenectomy or Rituximab, and preventive measures for complement activation. Splenectomy less commonly practice due to its surgical risk and future risk of sepsis as compare to Rituximab. Ex-vivo infusion of endo-beta-galactosidase is currently under clinical trial to serve as newer agent to reduce the blood group antigen levels in the allograft.
Early recognition and prompt action is crucial for graft survival for ABOi kidney transplantation. Possible complications include infection from CMV, HSV, VZV, and BK virus, P. jirovecii pneumonia, surgical wound infection, and severe urinary tract infection. There is a report stated that BK virus nephropathy was about three times higher in ABOi recipients. On the other hand, bleeding risk is high in a cohort of pediatric ABOi kidney transplant recipients due to the unspecific binding of coagulation factors during repeated IA. Malignancy risk remain controversial in ABOi kidney transplant.
In conclusion, ABOi kidney transplant significantly expand the living donor pool. However, we should be caution for the mortality risk due early rejections and infections secondary to intensified immunosuppressant. Thus, whenever possible, ABO compatible kidney should be the first choice in kidney transplantation.
Jamila Elamouri
3 years ago
ABO-Incompatible Kidney Transplantation
As the ESRD population increases, there is an increase in organ shortage resulting in waiting times for deceased donor kidney transplants exceeding 5 years in some countries. Transplantation across ABO antibody barriers is one possibility to reduce the waiting time. Kidney transplantation across ABO antibody barrier from a living donor can increase the number of kidney transplants by up to 30%. 90% of the patients with an ABOi living donor may be effectively desensitized and transplanted with the currently existing protocols.
Desensitization aimed to decrease and maintain the anti-A/B antibodies (isoagglutinin) below a threshold that is considered to be safe (> 1:32) during the first 2 weeks after transplantation. after that period, even when anti-A/B antibodies rebound to a high level, they will not harm the kidney transplant, a phenomenon called accommodation. The graft survival rate after ABOi kidney transplantation is nearly the same as that of ABOc transplantation. Blood Group Antigens and Antibodies
The ABO antigens are expressed on RBCs and also on endothelial, tubular, and glomerular cells. different blood groups have different antigen densities on erythrocytes. Blood group A2 makes up 20% of blood group A in Caucasian individuals, it has low blood group antigen expression (30—50%)on the surface of the erythrocytes therefore, it is of lower immunogenicity as compared to group A1 and B. Kidney from A2 donor has been transplanted with standard immunosuppressive therapy without any additional measures.
The anti-A/B antibodies are formed during infancy upon contact with gut bacteria. They are mainly of IgM class, but in group O especially, they also formed of IgG and IgA class. The role of different subclasses in organ transplantation remains to be clarified. Desensitization for ABOi kidney Transplantation
Although there are no standard desensitization protocols for ABOi transplantation, all currently designed strategies share some common principles.
In addition to powerful maintenance immunosuppression, the desensitization strategy includes one or more of the following:
1- Anti-A/B antibody depletion by PP, double-membrane filtration PP, or selective or unselective IA at the time of transplantation.
2- IVIG
3- B-cells depletion by splenectomy (historical), or by rituximab recently.
4- Prevention of the harmful effect of complement activation as consequence to binding of the anti-A/B antibody to graft endothelium.
Antibody depletion by extracorporeal treatment.
These are divided into:
1- Methods that completely remove plasma proteins (PP).
2- Methods that remove a specific fraction of plasma proteins including immunoglobulins (membrane separation)
3- Methods that are more specific such as unselective or selective IA.
There were no significant differences in clinical studies that compared the impact of different IA strategies on the clinical outcomes. Intravenous Immunoglobulins (IVIG)
IVIG is given to prevent the anti-A/B antibody rebound in the early period post-transplantation. as well, to reduce the infectious complications by replacing the removed immunoglobulin. B-cell depletion by splenectomy or Rituximab
Historically, splenectomy was done to reduce the B lymphocyte pool prior to ABOi kidney transplantation. due to surgical risk and increased infectious complications, splenectomy was replaced by the anti-CD20 antibody rituximab. Results from the CTS
Overall, graft, death-censored graft, and patient survival were not statistically significantly different between the groups (ABOc and ABOi). Early patient survival was reduced in ABOi kidney transplant recipients due to a higher rate of early infection-associated complications.
Complications and hurdles of ABOi kidney transplantation: Accommodation versus Rejection
Accommodation is a condition in which the graft biopsies show C4d deposition with no other signs of rejection in the presence of normal graft function. It occurs in the early period after kidney transplantation. it may be achieved by controlled exposure of the anti-A/B antibody to antigens. After 2 weeks of kidney transplantation, even a high level of anti-A/B antibody exposure will not harm the graft due to the accommodation. Infection and Malignancy
There is a higher frequency of viral infections, as well as P. jirovecii pneumonia, wound infection and severe urinary tract infection. Although, there are conflicting results in the literature. This results in increased death in ABOi kidney transplant recipients. In a study by Sharif et al., the rate of BK virus nephropathy was about three times higher in ABOi patients compared with HLA antibodies. US Renal Data System registry found a higher risk of early hemorrhage in ABOi recipients when compared to ABOc recipients. This complication attributed to apheresis treatment. In addition, lymphoceles were reported significantly higher in ABOi recipients than in ABOc controls. Future perspectives:
Reduction of blood group antigen levels in the allograft by ex vivo infusion of endo-beta-galactosidase is a promising new strategy.
PKD is another way to overcome ABO antibody barrier, although, blood group O patients are still difficult to transplant and they accumulate on the waiting list. conclusion
ABOi kidney transplantation become possible recently. It increased the living donor pool by 30%. Transplantation of ABO-incompatible, however, carried a higher risk of early rejection, infection, and infection-associated death. Therefore, ABO compatible transplantation should be done whenever possible.
Introduction
ABO incompatibility was considered absolute contraindication to kidney transplantation until 1982 until successful desensitization together with intensified immunosuppression.
Desensitization:
The aim of desensitization protocols is the reduction and maintenance of anti-A/B antibodies during the first 2 weeks post transplantation below threshold to be considered safe. Antibody Depletion :
Plasma Exchange or Imunoadsorption.
Intravenous Immunoglobulin
IVIG acting by decrease proliferation of B, T cells , inhibit CD8 , inhibit complement activation .
it is given to prevent the anti-A/B antibody rebound in the early period post-transplantation. as well, to reduce the infectious complications by replacing the removed immunoglobulin.
B-Cell Depletion by Splenectomy or Rituximab
Splenectomy which is obsolete and now replaced by Rituximab (anti CD20)
Inhibition of Complement Activation
Inhibition of complement activation by eculizumab, however, the use of eculizumab after ABOi kidney transplantation is inconclusive.
DESENSITIZATION PROTOCOLS AND SURVIVAL AFTER ABOi LIVING DONOR KIDNEY TRANSPLANTATION
Most patients were desensitized by PP and low-dose IVIG.
The cumulative incidence of graft loss during the first year after transplantation was 5.9% in ABOi as compared to only 2.9% in ABOc transplantations.
Patient survival in ABOi transplant recipients was reduced due to infectious complications, mostly Pneumocystis jirovecii pneumonia and BK virus . Complications Accommodation versus Rejection: Infection and Malignancy: A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, higher incidence of BK virus .
Esmat MD
3 years ago
ABO-incompatible kidney transplantation has been considered a contraindication for transplantation for a long time. Because of organ shortage, new strategies emerge for overcoming ABO antibodies barrier. With utilizing these strategies including apheresis and B-cell depleting therapies, accompanied by intensive immunosuppression, kidney transplantation survival in ABO incompatible transplants is comparable with ABO compatible patients.
By overcoming ABO barrier, the number of living donor kidney transplantation can increase by up to 30%, and about 90% of recipients with ABOi living donor may successfully be transplanted.
The aim of these therapies is to decline ABO antibodies below a threshold level (less than 1:32 in tube technique) at the time of ABOi kidney transplantation and within two weeks after kidney transplantation. It is approved that because of the phenomenon of accommodation even rebound in ABO antibodies are not associated with harm consequences in kidney transplantation. Although intensive immunosuppressive therapy may be related to increased risk of infections consist of BK virus replication and BK virus nephropathy, and colonization with multi-drug resistant bacteria.
Blood group antigens and antibodies
In addition to RBCs, ABO antigens are expressed on endothelial cells, tubules and glomeruli, thus they are important in kidney transplantation. Density of antigens on erythrocytes differ between different blood groups and patients with blood group A2 have lower antigen density on erythrocytes compared to blood group A1 or B. consequently, ABOi kidney transplant with A2 organ has been managed with standard immunosuppressive therapy. Anti AB antibodies are primarily of IgM class, but blood group O also consists of IgA and IgG classes.
Desensitization for ABOi KT
Other than powerful maintenance immunosuppression, desensitization for ABOi kidney transplantation consist of one or more of following:
(1) Anti-A/B antibody depletion at the time of transplantation using PP, double-filtration PP/membrane filtration, or selective or unselective immunoadsorption (IA)
(2) Modulation of the recipient’s immune system by the use of intravenous immunoglobulins (IVIgs)
(3) Reduction of the B lymphocyte pool by splenectomy, or more recently by the anti-CD20 antibody rituximab
(4) Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the graft endothelium.
Antibody depletion by extracorporeal treatment
Antibody removing strategies consist of PP, membrane separation, and unselective and selective IA.
Unselective IA is more effective in removal of anti AB IgG antibodies and less effective in removal of anti AB IgM antibodies compared to selective immunoadsorption.
Combination of unselective IA and membrane separation can effectively remove IgM, IgG and C1q complement components.
Intravenous immunoglobulins
IVIG is administered for prevention of anti AB antibody rebound early after kidney transplantation and reduce the probability of infictiins. Although it can increase anti AB antibody titers upon administration.
B-cell depletion by splenectomy or Rituximab
Prior to development of anti B cell therapies, splenectomy was considered for reduction of B cell pool. Splenectomy is mainly replaced by Rituximab. In recent studies B cell depletion therapy is eliminated from desensitization protocols, although it can be associated with higher risk of graft loss.
Inhibition of complement activation
Eculizumab has been utilized for inhibition of complement activation on endothelium in ABOi KT, but the results were inconclusive.
Desensitization protocols and survival after ABOi living donor kidney transplantation.
The results of ABOi KT including graft survival were comparable with ABOc KT in different studies by utilizing various desensitization protocols.
A recent meta-analysis of 101 different centers, comparing ABOi with ABOc KT, Overall graft, death-censored graft, and patient survival were not statistically significant different between the groups. Early patient survival was reduced in ABOi kidney transplant recipients due to a higher rate of early infection-associated death. Anti B-cell therapy was associated with better death-censored graft survival in the setting of ABO incompatibility.
Complications and hurdles of ABOi kidney transplantation
Accommodation versus Rejection
Accommodation in the setting of ABO incompatibility is related to C4d deposition in peritubular capillaries. An accom modation phenotype may be achieved by the controlled anti AB Antibodies to antigens interaction in the early phase kidney transplantation (About 2 weeks after successful transplantation). Local upregulation of complement regulatory proteins, such as CD45, CD55, and CD59 are proposed as a possible mechanism.
Infection, malignancy and bleeding risk
A higher incidence of viral infections such as CMV, HSV, VZV, and BK virus as well as P. jirovecii pneumonia, wound, and severe urinary tract infections have been reported, especially an increased risk for early severe infection and increased risk of infection associated death.
It is not reported increased risk of malignancy in ABOi compared to ABOc kidney transplantations.
Higher bleeding risk that was reported in ABOi kidney transplantation may be attributed to unspecific binding of coagulation factors during repeated IA. In addition, an increased rate of surgical complications such as lymphoceles were also reported, which may be due to early intensified immunosuppression.
Future perspective
Another emerging strategy is reduction of blood group antigen levels in the allograft by ex vivoinfusion of endo-beta-galactosidase. Another approach to overcome ABO antibody barrier is involving in kidney exchange programs.
Nasrin Esfandiar
3 years ago
With increasing organ shortage and increasing number of patients with ESKD, ABOi-KT become a solution. It was contraindication for KT, but recently there are increasing number of successful ABOi-KT which can increase living donors. This is done by desensitization protocols to reduce isoagglutinins during TX and first 2 weeks post-TX. After this time rebound of isoagglutinins would not be problematic, because of accommodation:
ABO Ags are present on endothelial cells, tubules and glomeruli beside RBCs, making them an important Ag during KT. A2 recipients (20 %) have lower expression of Abo Ags. So ABOi-KT in A2 organs could be done by standard immune suppression. By contact with bowel bacteria, most people have anti-A / B Abs early in the infancy. So desensitization and a powerful maintenance immunosuppression are mandatory to overcome ABO Ags. These strategies include:
1) PP, DFPP, IA for depletion of Abs.
2) Using IVIG in recipient.
3) B cell reduction by splenectomy in the past and Rituximab nowadays.
4) Complement inhibitors
IA is the most successful method of removing anti -A / B Abs.
Outcome of ABOi-KT was acceptable in 20 years’ cohort in Japan. Patient and graft survival were 98 and 96 % for the First year and 91 and 83 % after 9 years (1427 patients were analyzed). In the US outcome of 738 ABOi-KTs were published that showed 5.9 % incidence of graft loss. Recently in Europe ABOi-KT among 43 patients had overall patient and graft survival of 93 and 91 % during 4.5 years. Another in the Germany and the UK showed similar results. Since 2006 in Heidelberg using a desensitization protocol of unselective IAs and additional PP the day before TX, graft survival was significantly lower in these patients comparing standard risk group. Two patients died, due to infection. In another recently published study among 1420 ABOi-KTs, showed a need for anti-B cell therapy in ABOi-KT. After two weeks accommodations is established and kidney is safe in spite of high titers of anti-A / B Abs.
Higher risk of infections such as CMV, BKV, HSV and VZV resulted in one additional patient death in loo ABOi-KT during the first year.
There was no increasing rate of malignancy among these patient. A higher rate of bleeding episodes was seen in three patients due to binding of coagulation factors during IA. Another complication was an increased rate of surgical complications such as lymphocele. So, whenever possible, ABO compatible KTs are preferred.
Zahid Nabi
3 years ago
Summary
The ABO antigen system consists of oligosaccharides that are predominantly expressed on red blood cells and are also found on endothelial cells, tubuli, and glomeruli making the ABO antigen system important for kidney transplantation.
ABOi kidney transplantation with A2 organs has been accomplished with standard immunosuppressive therapy without any additional measures because of their low immunogenicity
During the last 25 years, increasing organ shortage enforced the development of strategies to overcome the ABO antibody barrier.
In the meantime, ABOi kidney transplantation has become a routine procedure with death-censored graft survival rates comparable to the rates in compatible transplantations.
Desensitization is usually achieved by
Apheresis
B cell-depleting therapies that are accompanied by powerful immunosuppression.
Anti-A/B antibodies are aimed to be below a certain threshold at the time of ABOi kidney transplantation and during the first 2 weeks after surgery.
Thereafter, even a rebound of anti-A/B antibodies does not appear to harm the kidney transplant, a phenomenon that is called accommodation, but is poorly understood.
There is still concern, however, that infectious complications such as viral disease, Pneumocystis jirovecii pneumonia, and severe urinary tract infections are increased after ABOi transplantations.
Recent data from the Collaborative Transplant Study show that during the first year after kidney transplantation, one additional patient death from an infectious complication occurs in 100 ABOi kidney transplant recipients.
Filipe prohaska Batista
3 years ago
Introduction
Major ABO incompatibility has been considered a contraindication to kidney transplantation until 1982, when desensitization protocols is the reduction and maintenance of anti-A/B antibodies (isoagglutinin) during the first 2 weeks post-transplantation below to be considered safe.
Blood group A2 donors are of lower immunogenicity than other groups.
Desensitization
High maintenance immunosuppression together with the use of these strategies including anti-A/B antibody depletion at the time of transplantation using Plasma Exchange or immunoadsorption, modulation of the recipient’s immune system by the use of intravenous immunoglobulin, reduction of the B lymphocyte pool by anti-CD20 antibody rituximab.
Antibody Depletion by Extracorporeal Treatment
Plasma Exchange or Imunoadsorption.
Intravenous Immunoglobulin
Deduce infectious complications by substituting depleted immunoglobulins, and apoptosis induced by IgG
B-Cell Depletion by Splenectomy or Rituximab
Rituximab is the gold standard nowadays instead of splenectomy
Inhibition of Complement Activation
Inhibition of complement activation by eculizumab, however, the use of eculizumab after ABOi kidney transplantation is inconclusive.
DESENSITIZATION PROTOCOLS AND SURVIVAL AFTER ABOi LIVING DONOR KIDNEY TRANSPLANTATION
Patient and graft survival rates were excellent. Most patients were desensitized by PP and low-dose IVIG. The cumulative incidence of graft loss during the first year after transplantation was 5.9% in ABOi as compared to only 2.9% in ABOc transplantations. Splenectomy was replaced by the anti CD20 antibody rituximab.
Patient survival in ABOi transplant recipients was reduced due to infectious complications, mostly Pneumocystis jirovecii pneumonia. Kidney recipients were a higher incidence of BK virus replication and BK virus nephropathy (SV 40 positive in biopsy). A higher prevalence of colonization with multidrug-resistant bacteria was also noted. RESULTS
Overall graft, death-censored graft, and patient survival were not statistically significantly different.
Early patient survival was reduced in ABOi kidney transplant recipients due to a higher rate of early infection-associated death.
Complications Accommodation versus Rejection: accommodation appears to be a frequent phenomenon after ABOi kidney transplantations and is often associated with C4d deposition in peritubular capillaries of allograft biopsies. Two weeks after successful transplantation, accommodation is established and even high anti-A/B antibody exposure does not harm the kidney transplant by local up-regulation of complement regulatory proteins, like CD45, CD55, and CD59, as a consequence of anti-A/B antibody-dependent inactivation of ERK1/2 signaling pathway are possible mechanisms. Infection and Malignancy: A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound, and severe urinary tract infections, have been demonstrated to result in approximately one additional patient death in 100 ABOi kidney transplant recipients during the first year after surgery. A higher incidence of BK virus replication and BK virus-associated nephropathy was also observed. Bentall et al. hypothesized that different blood group antigens may influence binding of viral pathogen receptors to sialic acid on renal tubular cells. While for malignancy, Hall et al. found no increased cancer risk when comparing 318 ABOi kidney transplant recipients to matched ABOc controls. Additional Observations
US Renal Data System registry found a two times higher risk of early hemorrhage in 119 ABOi kidney transplant recipients when compared to ABOc controls. A significant correlation between the number of pre-transplant apheresis treatments and the peri- and post-transplant bleeding risk.
Conclusion
Reduces waiting list
Transplantation in the presence of ABO incompatibility places the patient at a higher risk of early rejection, infection, and infection-associated death. So, whenever possible, ABOc procedures should be preferred.
Mahmud Islam
3 years ago
Till 1982 with the sturdy of Alexander et al., ABOi was considered a contraindication. The earlier protocols, including splenectomy, plasmapheresis, donor thrombocyte infusion etc, led to success. the 1-year survival was around 75%. after the spread of ABOİ transplantation overall in the world. Although compatibility is better, the shortage of organs led to the utilisation of desensitisation protocols to transplant against ABO compatibility.
the aim of desensitisation is the reduction and maintenance of anti A/B antibodies during the first two weeks below the safe threshold (<1:32 in tube technique, for example)
The elevation of the antibodies later seems to be of no harm due to accommodation, a phenomenon not well explained.
ABO blood groups differ in their immunogenicity and presentation on glomerular and tubular endothelşm as well as RBCs. Blood group A is nearly 20% of the blood group a and less expressed. Transplantation of A2 group was accomplished by standard immunosuppression.
Desensitization against ABO compatibility aims can be summarized as: ant-A/B antibodies depletion by plasmapheresis, modulation of recipients immune system by IVIG, reduction of B lymphocytes by either splenectomy or more recently by depletion with Rituximab.
Antibodies removal can be partial or complete specific immunoglobulin removal can be performed with adsorption and membrane separation. Studies showed same results for these different techniques.
Many centres give IVIG with aim of modulation and reducing infection. Of note, IVIG may increase the titers of anti A/B antibodies.
After the introduction of rituximab, splenectomy is not integral in desensitisation protocols. Many centres even do not give Rituximab if the antibody titers are lower below 1/32.
The role of eculizumab was not studied well because the study was terminated due to poor enrollment.
The earlier protocols used splenectomy but then was replaced with Rituximab. The ABOi Tx increased. A report from Japan regarding patients from 2001to 2010 showed 96% success and excellent survival in the first year. Another study from the US using PP and low dose IVIG showed graft loss of around %5,9 compared to 2.6 %in ABOc group.
Accommodation seen in ABO-incompatible transplants shows no harm after the second week even in presence of high titers.
To conclude, ABOi kidney transplantation became routine in recent years (in many countries) but this will put the patient at high risk of infection etc. So, ABO compatibility should be preferred whenever possible.
Last edited 3 years ago by Mahmud Islam
Ahmed Omran
3 years ago
Antigens are present on surface of RBCs, renal tubules, glomeruli, and endothelial cells.
Antibodies of A/B are essentially of IgM class and in group O mostly of IgG and IgA. Desensitization in case of ABOI-KT: – Antibody depletion :
1-PE
2-Immunoadosorption: could be selective and non -selective
non selective IA is more effective in removing A/B IgG than selective IA
but unselective IA is less effective in removing A/B IgM B- IVIG:
prevent A/B rebound following KT with additional benefit of decreasing the risk of infections C-Splenectomy or RTX :
Splenectomy was replaced by an antiCD20 AB (Rituximab) to avoid surgical risk and risk of infections. Inhibition of Complement Activation :
The use of eculizumab as an inhibitor to membrane attacking complex is controversial. Kidney allograft outcome in ABOi kidney transplantation with using different desensitization protocols:
Double filtration PP with Rituximab is associated with patients and graft survival 98% and 96 % in the first year; respectively.
Desensitization with PP and low dose IVIG is associated with graft loss 5.9 % in the first year and overall graft loss in ABOi KT patients and graft survival of 4.5 years was 93 and 91 % during follow-up.
There is higher risk of infection increasing risk of death in the first year of ABOi transplantation compared with ABOc transplantation. Complications: Accommodation is more likely to occur in ABOi transplantation than HLA sensitized patients despite higher exposure to the kidney to A/B antibodies; not causing harm to the kidney by C4d deposition in peritubular capillaries of kidney allograft. Infections: increase risk of BK virus in ABOi transplantation 3 times in comparison with HLA sensitized patients in addition to higher risk of viral infections of CMV, HSV, and VZV in addition to . jirovecii pneumonia.
There is no higher risk of malignancy in ABOi than ABOc KT. Conclusion:
ABOi kidney transplantation has advantage of expanding the pool of living donors but increases the risk of rejection, infection, and death due to increasing infection rates.
Introduction
ABO incompatibility was considered absolute contraindication to kidney transplantation until 1982 until successful desensitization together with intensified immunosuppression.
Desensitization: The aim of desensitization protocols is the reduction and maintenance of anti-A/B antibodies during the first 2 weeks post transplantation below threshold to be considered safe. Antibody Depletion :
Plasma Exchange or Imunoadsorption.
Intravenous Immunoglobulin IVIG acting by decrease proliferation of B, T cells , inhibit CD8 , inhibit complement activation . it is given to prevent the anti-A/B antibody rebound in the early period post-transplantation. as well, to reduce the infectious complications by replacing the removed immunoglobulin.
B-Cell Depletion by Splenectomy or Rituximab
Splenectomy which is obsolete and now replaced by Rituximab (anti CD20)
Inhibition of Complement Activation
Inhibition of complement activation by eculizumab, however, the use of eculizumab after ABOi kidney transplantation is inconclusive.
DESENSITIZATION PROTOCOLS AND SURVIVAL AFTER ABOi LIVING DONOR KIDNEY TRANSPLANTATION
Most patients were desensitized by PP and low-dose IVIG.
The cumulative incidence of graft loss during the first year after transplantation was 5.9% in ABOi as compared to only 2.9% in ABOc transplantations.
Patient survival in ABOi transplant recipients was reduced due to infectious complications, mostly Pneumocystis jirovecii pneumonia and BK virus . Complications Accommodation versus Rejection: Infection and Malignancy: A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, higher incidence of BK virus .
Mohammed Sobair
3 years ago
ABoi transplant was contraindicated, till the breakthrough made by Alexandre et al. from
Belgium where successful transplantation was done. Successful desensitization was
achieved by repeated plasmapheresis (PP), splenectomy, donor thrombocyte
transfusion, and infusion of A or B trisaccharide, together with intensive
immunosuppression. One-year graft survival in this study was a remarkable 75%
.
This led to a wider utilization of ABoi, first in Japan then USA and latter in Europe.
It improved the chances of transplant for high-risk patient and increased. The pool of
donors.
BLOOD GROUP ANTIGENS AND ANTIBODIES:
Are oligosacride antigen.
Blood group A2 less antigenic, so less transplant rejection.
DESENSITIZATION FOR ABoi KIDNEY TRANSPLANTATION:
Anybody Depletion by Extra corporal Treatment:
Antibody removal strategies may be divided into methods:
that completely remove plasma proteins such as PP.
methods that remove only a specific fraction of the plasma proteins including the
immunoglobulins (such as membrane separation),
and more specific methods such as unselective or selective IA.
Intravenous Immunoglobulins:
given by many centers before ABOi kidney transplantation to prevent the anti-A/B
antibody rebound in the early phase after transplantation.
B. Cell Depletion by Splenectomy or Rituximab.
Before the introduction of pharmacological anti-B cell therapies, splenectomy was an
integral component for the reduction of the B lymphocyte pool.
to the surgical risk and increased risk of sepsis, splenectomy was gradually substituted
by the anti-CD20 antibody rituximab.
More recently, several groups completely abandoned anti-B cell therapies from their
protocols.
Patient and graft survival in this cohort was 100% after a median of 26 months after transplantation.
observed in the Collaborative Transplant Study (CTS) a higher rate of death-censored
graft loss in ABOi kidney transplant.
Inhibition of Complement Activation:
Can reduce incidence of allograft rejection if added to the standard protocol but studies
are not conclusive.
Desensitization PROTOCOLS AND SURVIVAL AFTER ABOi LIVING DONOR KIDNEY
TRANSPLANTATION:
Patient and graft survival rates were an excellent. Graft loss more in first two weeks
posttransplant.
RESULTS FROM THE CTS:
We recently published 3-year outcomes of 1,420 ABOi kidney transplant recipients who
were transplanted at 101 deferent centers between 2005 and 2012 .
Overall graft and death-censored graft and patient survival were not statistically Signiant
different between the groups. Patients were compared to a matched group of ABOc
kidney transplant recipients and to all ABOc kidney transplant recipients from centers.
Early patient survival was reduced in ABOi kidney transplant recipients due to a higher
rate of early infection-associated death.
Complication:
A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as
P. jirovecii pneumonia, wound, and severe urinary tract infections have been described.
A higher bleeding risk. High surgical risk.
FUTURE PERSPECTIVES:
A new strategy that may come into clinics in the future is the reduction of blood group
antigen levels in the allograft by ex vivo infusion of endo-beta-galactosidase.
Conclusion:
In recent years, ABOi kidney transplantation has become a routine procedure. By this
approach, about 30% of living donors who were refused in the past can now donate their
kidneys and thereby significantly expand the living donor pool.
Transplantation in the presence of major ABO incompatibility, however, places the
patient at a somewhat higher risk of early rejection, infection, and infection-associated
death.
Therefore, whenever possible, ABOc procedures should be preferred.
Ahmed Abd El Razek
3 years ago
INTRODUCTION
Major ABO incompatibility has been considered a contraindication to kidney transplantation till 1982, with the “first large study on ABOi kidney transplantation by Alexandre et al. after successful desensitization was achieved together with intensified immunosuppression one-year graft survival in this study was a remarkable 75%.
The aim of desensitization protocols is the reduction and maintenance of anti-A/B antibodies (isoagglutinins) during the first 2 weeks post transplantation below threshold to be considered safe.
Even after anti-A/B antibodies recur at high levels they will not harm the graft, a phenomenon that is called accommodation.
BLOOD GROUP ANTIGENS AND ANTIBODIES
Blood group A2 donors are of lower immunogenicity than other groups.
DESENSITIZATION FOR ABOi KIDNEY TRANSPLANTATION
A powerful maintenance immunosuppression together with the use of these strategies including anti-A/B antibody depletion at the time of transplantation using PP or immunoadsorption, modulation of the recipient’s immune system by the use of intravenous immunoglobulin, reduction of the B lymphocyte pool by anti-CD20 antibody rituximab.
Antibody Depletion by Extracorporeal Treatment
Antibody removal strategies methods that completely remove plasma proteins such as PP or immunoadsorption. No significant differences were found in clinical studies that compared the impact of different IA strategies on clinical outcomes, including anti-A/B antibody reduction, survival, kidney function, rejection episodes, or complications.
Intravenous Immunoglobulin
To prevent the anti-A/B antibody rebound in the early phase after transplantation. IVIG infusion is believed to reduce infectious complications by substituting depleted immunoglobulins.
B-Cell Depletion by Splenectomy or Rituximab
Due to the surgical risk and increased risk of sepsis, splenectomy was gradually substituted by the anti-CD20 antibody rituximab. The use of standard immunosuppressive therapy without rituximab when the patient had reached an anti-A/B antibody titer of less than 1:32.
Inhibition of Complement Activation
Inhibition of complement activation upon binding of antibodies to the allograft endothelium by inhibiting the assembly of the membrane attack complex by eculizumab so severe antibody-mediated rejection during anti-A/B antibody rebound can be successfully treated. However the use of eculizumab after ABOi kidney transplantation are inconclusive. DESENSITIZATION PROTOCOLS AND SURVIVAL AFTER ABOi LIVING DONOR KIDNEY TRANSPLANTATION
Patient and graft survival rates were excellent. Most patients were desensitized by PP and low dose IVIG. The cumulative incidence of graft loss during the first year after transplantation was 5.9% in ABOi as compared to only 2.9% in ABOc transplantations. Splenectomy was replaced by the anti CD20 antibody rituximab.
Patient survival in ABOi transplant recipients was reduced due to infectious complications, mostly Pneumocystis jirovecii pneumonia. Kidney recipients were a higher incidence of BK virus replication and BK virus nephropathy (SV 40 positive in biopsy). A higher prevalence of colonization with multidrug-resistant bacteria was also noted.
RESULTS
Overall graft, death-censored graft, and patient survival were not statistically significant different.
Early patient survival was reduced in ABOi kidney transplant recipients due to a higher rate of early infection-associated death.
COMPLICATIONS AND HURDLES OF ABOi KIDNEY TRANSPLANTATION Accommodation versus Rejection: accommodation appears to be a frequent phenomenon after ABOi kidney transplantations and is often associated with C4d deposition in peritubular capillaries of allograft biopsies. Two weeks after successful transplantation, accommodation is established and even high anti-A/B antibody exposure does not harm the kidney transplant by local up regulation of complement regulatory proteins, like CD45, CD55, and CD59, as a consequence of anti-A/B antibody-dependent inactivation of ERK1/2 signaling pathway are possible mechanisms.
Infection and Malignancy: A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound, and severe urinary tract infections have been demonstrated resulting in approximately one additional patient death in 100 ABOi kidney transplant recipients during the first year after surgery. Higher incidence of BK virus replication and BK virus-associated nephropathy was also observed. Bentall et al. hypothesized that different blood group antigens may influence binding of viral pathogen receptors to sialic acid on renal tubular cells. While for malignancy, Hall et al. found no increased cancer risk when comparing 318 ABOi kidney transplant recipients to matched ABOc controls.
Additional Observations
US Renal Data System registry found a two times higher risk of early hemorrhage in 119 ABOi kidney transplant recipients when compared to ABOc controls. A significant correlation between the number of pre-transplant apheresis treatments and the peri- and post-transplant bleeding risk. FUTURE PERSPECTIVES
The reduction of blood group antigen levels in the allograft by ex vivo infusion of endo-beta-galactosidase may be a new strategy in the future. Kidney exchange programs are good options as well. CONCLUSION
Desensitization for ABOi kidney transplantation was the only way to transplant these patients within a reasonable period of time.
Transplantation in the presence of ABO incompatibility places the patient at a higher risk of early rejection, infection, and infection-associated death. So, whenever possible, ABOc procedures should be preferred.
Shereen Yousef
3 years ago
ABO incompatibility was considered a contraindication to transplantation but advances in immunosuppssion and desensitization protocols led to more ABOi kidney transplantations, even today, kidney transplantation is best performed in the absence of (major) ABOi but the increasing number of patients on dialysis and organ shortage directed many centres to ABOi -KT.
Different desensitization protocols are used aiming to reduce isoagglutinins and keep it at low levels below a threshold that is considered to be safe (e.g., <1:32 in tube technique) especially during the first 2 weeks post transplantation
after that accommodation Occure and even rebound rise in antibodies won't affect the graft it was found that survival rates of ABOi kidney transplantation nearly equal to ABOc transplant.
▪︎BLOOD GROUP ANTIGENS AND ANTIBODIES
ABO antigen expressed on red blood cells , endothelial cells, tubuli, and glomeruli.
antigen density on erythrocytes differs accordingto bl.group .
blood group A1 and B individuals have high antigen expression on erythrocytes and can elicit strong immuneresponse,while individuals with blood group A2 showes a low expression of the blood group antigen So it has lower immunogenicity and transplantation with A2 organs can be done without intensified immunosuppression.
▪︎DESENSITIZATION FOR ABOi KIDNEY TRANSPLANTATION
There is no standard protocol for desensitization for ABOI-KT
But there are common principles :
Generally a powerful maintenance immu-nosuppression is needed with one or more of the following:
*Anti-A/B antibody depletion at the time of transplantation using PP, double- filtration PP/membrane filtration, or selective or unselective immunoadsorption (IA)
PP is the preferred antibody removal strategy in the US, membrane separation is popular in Japan. Unselective and selective IAs are used in Europe.
*use of intravenous immunoglobulins (IVIgs) aiming to modulate the recipient’s immune system,prevent rebound AB rise early after transplantation also may reduce infectious complications by substituting depleted immunoglobulins.
*splenectomy, or more recently by the anti-CD20 antibody rituximab to Reduce B cells and decrease antibody production some groups has recently performed ABOI-KT without rituximab when antibody titer of less than 1:32 with Patient and graft survival was 100% after a median of 26months. Two antibody-mediated rejection episodes were successfully reversed. But CTS observes a higher rate of death-censored graft loss when rituximab wasn't used.
*Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the graft endothelium but still
results on the use of eculizumab after ABOi kidney transplantation are inconclusive.
Most of studies on ABOi kidney transplantation with different desensitization protocols showed good long term graft and patient survival for up to 9 years without significant difference than ABOC transplantation.
▪︎COMPLICATIONS AND HURDLES OF ABOi KIDNEY TRANSPLANTATION
*Accomodation versus Rejection
accommodation is a phenomenon that occurs within the first 2 weeks after ABOi kidney transplantations with C4d deposition in peritubular capillaries of allograft.
Might be due to the controlled anti-A/B antibody exposure to antigens in the early phase after transplantation and further rise in antibodies will not harm the graft .
The exact mechanism is not clear but Local upregulation of complement regulatory proteins, like CD45, CD55, and CD59 is one possible mechanism .
▪︎Infection and Malignancy
patient survival in ABOi transplant recipients was reduced due to infectious complications, mostly Pneumocystis jirovecii pneumonia.
In some cases there were higher incidence of BK virus replication and BK virus nephropathy and a higher prevalence of colonization with multidrug-resistant bacteria .
higher frequency of viral infections such as CMV, HSV, VZV, wound, and severe urinary tract infections were also noted.
Hall et al. found no increased cancer risk when comparing 318 ABOi kidney transplant recipients to matched ABOc controls.
▪︎Other complications included ,risk of hemorrhage, surgical complications.
▪︎In conclusion
ABOI-KT is widly used today provides more donors to reduce waiting list but stil transplantation in the presence of major ABO incompatibility, places the patient at a somewhat higher risk of early rejection, infection, and infection-associated death.
CARLOS TADEU LEONIDIO
3 years ago
Summarise this article
BLOOD GROUP ANTIGENS AND ANTIBODIES
The ABO antigen system consists of oligosaccharides that are predominantly expressed on red blood cells and are also found on endothelial cells, tubuli, and glomeruli making the ABO antigen system important for kidney transplantation. Patients with different blood groups differ with respect to their antigen density on erythrocytes and consequently immunogenicity of organs and immunosuppressive therapy.
DESENSITIZTION FOR ABOi KIDNEY TRANSPLATATION
All currently proposed strategies share some common principles. These include together with a powerful maintenance immunosuppression one or more of the following:
(1)Anti-A/B antibody depletion at the time of transplantation using PP, double-infiltration PP/membrane “filtration, or selective or unselective immunoadsorption (IA)
(2)Modulation of the recipient’s immune system by the use of intravenous immunoglobulins (IVIgs)
(3)Reduction of the B lymphocyte pool by splenectomy, or more recently by the anti-CD20 antibody rituximab
(4) Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the graft endothelium
Antibody depletion by extracorporal treatment
Antibody removal strategies may be divided into:
A-Methods that completely remove plasma proteins such as PP;
B-Methods that remove only a specific fraction of the plasma proteins including the immunoglobulins (such as membrane separation);
C- Specific methods such as unselective or selective IA – no significant diferences were found in clinical studies that compared the impact of diferent IA strategies on clinical outcomes, including anti-A/B antibody reduction, survival, kidney function, rejection episodes, or complications;
Intravenous Imunoglobulins
Intravenous immunoglobulins are given by many centers before ABOi kidney transplantation to prevent the anti-A/B antibody rebound in the early phase after transplantation. In addition, IVIg infusion is believed to reduce infectious complications by substituting depleted immunoglobulins. As a note of caution, IVIg preparations contain IgG antibodies directed against A/B antigens and can efectively increase anti-A/B antibody titers upon administration.
B-Cell Depletion by Splenetomy or Rituximab
Before the introduction of pharmacological anti-B cell therapies, splenectomy was an integral component for the reduction of the B lymphocyte pool prior to ABOi kidney transplantation. Due to the surgical risk and increased risk of sepsis, splenectomy was gradually substituted by the anti-CD20 antibody rituximab. More recently, several groups completely abandoned anti-B cell therapies from their protocols when the patient had reached an anti-A/B antibody titer of less than 1:32 (tube method).
Inhibition of Complement Activation
An emerging new concept in the transplantation across ABO antibody barriers is the inhibition of complement activation upon binding of antibodies to the allograft endothelium. Severe antibody-mediated rejection in this patient during anti-A/B antibody rebound was successfully treated by inhibiting the assembly of the membrane attack complex by eculizumab.
DESENSITIZATION PROTOCOLS AND SURVIVAL AFTER ABOi LIVING DONOR KIDNEY TRANSPLANTATION
In Japan, desensitized by double-filtration PP, and splenectomy was more recently replaced by the anti-CD20 antibody rituximab. For the most recent area from 2001 to 2010, patient and graft survival rates for the 1,427 analyzed patients were an excellent 98 and 96% for the first year, and 91 and 83% after 9 years, respectively.
In US, most patients were desensitized by PP and low-dose IVIg. The cumulative incidence of graft loss during the first year after transplantation was 5.9% in ABOi as compared to only 2.9% in ABOc transplantations and occurred mainly during the first 2 weeks after surgery due to rejection.
A study from the UK showed similar death-censored graft survival in 62 patients 3 years after ABOi kidney transplantation when compared to ABOc controls. However, patient survival in ABOi transplant recipients was reduced due to infectious complications, mostly Pneumocystis jirovecii pneumonia.
RESULTS FROM CTS
Patients were compared to a matched group of ABOc kidney transplant recipients and to all ABOc kidney transplant recipients from centers that performed at least have ABOi procedures. Overall graft, death-censored graft, and patient survival were not statistically significant diffferent between the groups. Early patient survival was reduced in ABOi kidney transplant recipients due to a higher rate of early infection-associated death (P = 0.037 versus matched controls and P < 0.001 versus center controls). Specifically, one additional death per 100 patients occurred in the first year after ABOi kidney transplantation from an infectious complication.
COMPLICATIONS AND HURDLES OF ABOi KIDNEY TRANSPLANTATION
Accomodation versus Rejection
An accommodation phenotype may be achieved by the controlled anti-A/B antibody exposure to antigens in the early phase after kidney transplantation. About 2 weeks after successful transplantation, accommodation is established and even high anti-A/B antibody exposure does not harm the kidney transplant.
Infection and Malignancy
There are conflicting results on infectious complications after ABOi kidney transplantation in the literature. A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound, and severe urinary tract infections have been described.
Hall et al. found no increased cancer risk when comparing 318 ABOi kidney transplant recipients to matched ABOc controls. The analysis of 1,420 ABOi transplantations from the CTS study also did not show an increased risk of malignancy in ABOi compared to ABOc patients.
Additional Observation
A study from the US Renal Data System registry found a two times higher risk of early hemorrhage in 119 ABOi kidney transplant recipients when compared to ABOc controls (adjusted HR, 1.96, P < 0.05). This assumption is supported by the findings of de Weerd et al. who found a significant correlation between the number of pre-transplant apheresis treatments and the peri- and posttransplant bleeding risk.
CONCLUSION
In recent years, ABOi kidney transplantation has become a routine procedure. By this approach, about 30% of living donors who were refused in the past can now donate their kidneys and thereby significantly expand the living donor pool. Transplantation in the presence of major ABO incompatibility, however, places the patient at a somewhat higher risk of early rejection, infection, and infection-associated death. Therefore, whenever possible, ABOc procedures should be preferred
Mohamed Ghanem
3 years ago
Blood group antigens and antibodies:
Antigens are present n the surface of RBCs, renal tubules, glomeruli, and endothelial cells.
Antibodies of A/B are mainly of IgM class but in group O mostly of IgG and IgA. Desensitization for ABOi kidney transplantation : A- Antibody depletion :
1-Plasmapheresis: removal of plasma containing immunoglobulins
2-Immunoadosorption: may be selective and unselective
Unselective IA is more effective in removing A/B IgG than selective IA
however unselective IA is less effective in removing A/B IgM B- Intravenous Immunoglobulin:
prevent A/B rebound after kidney transplantation with added benefit as it decreases the risk of infections C-Splenectomy or Rituximab :
Splenectomy was substituted by an antiCD20 antibody (Rituximab) due to surgical risk and increased risk of infections.
With trials for Rituximab withdrawal when the titer of A/B antibodies < 1/32 (tube method) Inhibition of Complement Activation :
The use of eculizumab as an inhibitor to membrane attacking complex wasn’t inconclusive. Kidney allograft outcome in ABOi kidney transplantation according to different desensitization protocols:
Double filtration PP + Rituximab: Patients and graft survivals were 98% and 96 % in the first year.
desensitization with PP with low dose IVIG: graft loss was only 5.9 % in the first year
of overall graft loss in ABOi renal transplantation patients and graft survival of 4.5 years was 93 and 91 % during follow-up.
A higher rate of infection increases the risk of death in the first year of ABOi transplantation in comparison to ABOc transplantation.
Complications: Accommodation is more likely to occur in ABOi transplantation than HLA sensitized patients despite higher exposure to the kidney to A/B antibodies, these don’t cause harm to the kidney
with C4d deposition in peritubular capillaries of kidney allograft.
Infections: increase risk of BK virus in ABOi transplantation three times more HLA sensitized patients
with more risk of viral infections of CMV, HSV, and VZV in addition to . jirovecii pneumonia. Malignancy: there is no increase in the risk of malignancy in ABOi compared to ABOc transplantation. Conclusion:
ABOi kidney transplantation has expanded the pool of living donors however increases the risk of rejection, infection, and death related to increasing infection rates.
Reem Younis
3 years ago
-The number of kidney transplantations from living donors can be increased by up to 30% when patients are transplanted across the ABO antibody barrier.
-With currently existing protocols, as many as 90% of patients with an ABOi living donor may effectively be desensitized and transplanted.
-The aim of desensitization protocols is the reduction and maintenance of anti-A/B antibodies (isoagglutinins) during the first 2weeks after transplantation below a threshold that is considered to be safe (e.g., <1:32 in tube technique).
-Thereafter, even when anti-A/B antibodies recur at high levels they will not harm the kidney transplant, a phenomenon that is called accommodation.
– In recent years, graft survival rates after ABOi kidney transplantation nearly equaled those after ABO-compatible (ABOc) procedures.
– -Compared to blood group A1 and blood group B individuals, blood group A2 recipients, who make up 20% of all Caucasian individuals with blood group A, have a low expression of blood group antigen molecules (30–50%) on the
the surface of erythrocytes, which is believed to be responsible for the lower immunogenicity of organs from blood group A2 donors.
– ABOi kidney transplantation with A2 organs has been accomplished with standard immunosuppressive therapy without any additional measures .
-Anti-A/B antibodies are formed upon contact with gut bacteria during early infancy.
-Naturally occurring anti-A/B antibodies are predominantly of the IgM class but especially in blood group O individuals they also consist of IgG and IgA class .
-All currently proposed strategies share some common principles include together with a powerful maintenance immunosuppression one or more of the following:
(1) Anti-A/B antibody depletion at the time of transplantation using PP, double-filtration PP/membrane filtration, or selective or unselective immunoadsorption (IA)
(2) Modulation of the recipient’s immune system by the use of intravenous immunoglobulins (IVIgs)
(3) Reduction of the B lymphocyte pool by splenectomy, or more recently the anti-CD20 antibody rituximab
(4) Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the graft endothelium.
-Antibody removal strategies may be divided into methods that completely remove plasma proteins such as PP, methods that remove only a specific fraction of the plasma proteins including the immunoglobulins (such as membrane separation), and more specific methods such as unselective or selective IA.
-Intravenous immunoglobulins are given by many centers before ABOi kidney transplantation to prevent the anti-A/B antibody rebound in the early phase after transplantation.
– IVIg infusion is believed to reduce infectious complications by substituting depleted immunoglobulins.
-IVIg preparations contain IgG antibodies directed against A/B antigens and can effectively increase anti-A/B antibody titers upon administration .
-Due to the surgical risk and increased risk of sepsis, splenectomy was gradually substituted by the anti-CD20 antibody rituximab.
-More recently, several groups completely abandoned anti-B cell therapies from their protocols.
-Patient survival in ABOi transplant recipients was reduced due to infectious complications, mostly Pneumocystis jirovecii pneumonia.
-Important differences between ABOi and standard risk kidney recipients were a higher incidence of BK virus replication and a higher prevalence of colonization with multidrug-resistant bacteria .
-In contrast to transplantation in the HLA-sensitized patient, accommodation appears to be a frequent phenomenon after ABOi kidney transplantations and is often associated with C4d deposition in peritubular capillaries of allograft biopsies.
-About 2weeks after successful transplantation, accommodation is established and even high anti-A/B antibody exposure does not harm the kidney transplant.
-A study from the US Renal Data System registry found a two times
higher risk of early hemorrhage in 119 ABOi kidney transplant recipients when compared to ABOc controls .
-An increased rate of surgical complications after ABOi kidney transplantation, which were attributed to early intensified immunosuppression with mycophenolic acid and removal of coagulation factors by apheresis.
-Significantly higher number of lymphoceles in ABOi patients than in ABOc controls that required surgical revisions .
nawaf yehia
3 years ago
As a result of increasing shortage in live kidney donors and increasing waiting list in both time and No. of patients ; transplantation against ABO barrier has been evolving with promising results
Theoretically, the number of kidney transplantations from living donors can be increased by up to 30% when patients are transplanted across the ABO antibody barrier with good desensitization and Ab depletion .
The aim of desensitization protocols is the reduction and maintenance of anti-A/B antibodies (isoagglutinins) during the first 2 weeks after transplantation below a threshold that is considered to be safe (e.g., <1:32 in tube technique). Thereafter, even when anti-A/B antibodies recur at high levels they will not harm the kidney transplant, a phenomenon that is called accommodation
anti-A/B antibodiesare formed upon contact with gut bacteria during early infancy.Naturally occurring anti-A/B antibodies are predominantly of the IgM class but especially in blood group O individuals they also consist of IgG and IgA class
DESENSITIZATION FOR ABOi KIDNEY TRANSPLANTATION
Despite the absence of a generally accepted desensitization protocol for the transplantation across the ABO antibody barrier,all currently proposed strategies share some common principles
these include together with a powerful maintenance immunosuppression one or more of the following:
(1) Anti-A/B antibody depletion at the time of transplantation using one of the aphresis methods
(2) Modulation of the recipient’s immune system by the use of (IVIgs) which has many immunologic effects besides replacing Ig depleted by aphresis and thereby reduces infections .
(3) Reduction of the B lymphocyte pool by the anti-CD20 antibody rituximab
(4) Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the endothelium by using anti C5 Eculizumab , although results of its use in ABOi KT are inconclusive
SURVIVAL AFTER ABOi KT :
Althogh several studies show that ABOi KT has comparable results to ABOc KT , however , However, patient survival in ABOi transplant recipients was reduced due to infectious complications, mostly Pneumocystis jirovecii pneumonia.Other important differences between ABOi and standard risk kidney recipients were a higher incidence of BK virus replication (>104!copies/mL plasma, 21 versus 6%, P!=!0.04) and BK virus
nephropathy (SV 40 positive in biopsy, 12 versus 0%, P!=!0.01) and a higher prevalence of colonization with multidrug-resistant bacteria (15 versus 1%, P!=!0.02).
regarding the theoratically higher risk of malignancies in ABOi KT , studies have shown no increased cancer risk as compared to ABOc KT
A study from the US Renal Data System registry found a two times higher risk of early hemorrhage in 119 ABOi kidney transplant recipients when compared to ABOc controls which was attributed to the unspecific binding of coagulation factors during repeated IA where a signifcant correlation between the number of pretransplant apheresis treatments and the peri- and posttransplant bleeding risk
CONCLUSION
In recent years, ABOi kidney transplantation has become a routine procedure. By this approach, about 30% of living donors who were refused in the past can now donate their kidneys and thereby significantly expand the living donor pool.
Transplantation in the presence of major ABO incompatibility, however, places the
patient at a somewhat higher risk of early rejection, infection, and infection-associated death. $erefore, whenever possible, ABOc procedures should be preferred.
Weam Elnazer
3 years ago
Increasing the number of living donors through ABO-incompatible kidney transplantation has lately become more common, because of new effective desensitization methods and increased graft survival.
Antigens and antibodies specific to blood groups
RBCs, endothelial cells, tubules, and glomeruli are all known to express the ABO antigen system.
Organs from blood type A2 donors are less immunogenic than organs from other blood groups because of the limited expression of blood group antigen on the surface of red blood cells (RBCs).
Anti-A/B antibodies are well-known for their pathogenic potential, although the relative contributions of different immunoglobulin isotypes and subclasses are not well understood in this context.
Desensitization for kidney transplantation in patients with ABO-incompatible (ABOi) blood types
There is no singular desensitization procedure that has been developed.
Extracorporeal therapy for the elimination of antibodies:
Plasmapheresis is used to fully remove all plasma proteins, whereas membrane separation is used to remove a particular percentage of plasma proteins, such as immunoglobulins.
IA can be either non-selective or selective.
IVIG is used to modulate the immune system. IVIG is utilized to prevent anti-A/B antibody rebound in the early post-transplant period.
Substitute immunoglobulins that lower the risk of infection associated with plasmapheresis are available.
Antibody removal by plasmapheresis or immunoadsorption (IA) is a concept of desensitization that is more selective and specific than plasma exchange. It is preferred for HLA I and ABOI transplantation because it removes anti-A and anti-B antibodies with an average reduction rate of 3-4 fold and is associated with fewer infectious or bleeding side effects than plasma exchange, but it is more expensive.
Immunomodulating agent IVIG is a complementary treatment after plasmapheresis that replaces removed antibodies while also performing other important functions such as complement inhibition, FC receptor binding, inhibiting B and T cell proliferation, CD8 T cell inhibition, and inducing B cell apoptosis, among other things.
Although there is no standardized dosage, there are many side effects, including infusion-related allergic reactions, increased risk of thromboembolic events, and acute kidney injury (AKI). Its use in combination with plasmapheresis is the preferred and widely used protocol, with or without Rituximab, and it is the preferred and widely used protocol with or without Rituximab.
The anti-CD20 antibody is used to remove B cells from the body. Rituximab has taken the role of surgical splenectomy, and while rituximab is administered in a variety of dosages and frequencies depending on local centre guidelines, the current tendency is to provide low-dose rituximab 14 days before surgery.
Infection and malignancy are two of the risks associated with desensitization treatment.
In spite of the fact that extensive immunosuppression raises the risk of malignancy in HLA incompatible transplantation, the risk of cancer was not observed to be greater when ABOi-KT recipients were compared to ABOc controls. In the aftermath of ABOi-KT, there is a lot of disagreement on whether or not there will be an infectious complication.
According to the findings, a higher prevalence of viral infection (CMVSHVVZV and BK virus) as well as P. jiroveci pneumonia were seen, as well as wound infection and severe UTI.
mai shawky
3 years ago
· New advances in immunosuppression made the outcomes of ABO I kidney transplantation near that of ABO c ones..
· It increased the pool of living donor by up to 30% and hence shortened the waiting time list.
· Available desensitization protocols served to decrease or remove the anti A and anti B isoagglutinin to prevent hyper acute rejection and AMR which moistly occurs in 1st 4 weeks post transplant. After which, accommodation can occur and risk can be declined.
· Pretransplant isoagglutinin titer of <1:32 can be considered safe.
Desensitization protocols:
· No consensus about ideal protocol, it depends on available expertise and facilities.
· It includes antibody removal either non selectively by PEX or selectively by IA to minimize loss of coagulation proteins and other IgG which can increase risk of infection.
· B cell depletion by rituximab and antibody neutralization with IVIG.
· Powerful tacrolimus based triple maintenance immunosuppression greatly improved outcomes.
· Medical splenectomy by Rituximab has replaced surgical splenectomy with minimization of surgical risk.
Different available protocols:
· Japan (double-filtration PP, and splenectomy was more recently replaced by rituximab) with good outcome.
· US patients desensitized by PP and low dose IVIg. With coparable outcome to ABO c kidney transplant.
· European protocol (desensitization by selective IA + Rituximab) with good outcomes.
· Heidelberg using (unselective IA +one PP session one day before surgery + Rituximab ) led to successful desensitization of 12 patients after a median of six IA treatments, After a median postoperative follow-up of 22 months.
Accommodation means :C4d deposition in peritubular capillaries of allograft biopsies without pathological injuries which occur mainly after 2 weeks from transplantation despite of high anti-A/B antibody exposure.
Complications of large cumulative dose of immunosupressives:
· Viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound sepsis, severe UTI.
· Malignancy
In conclusion, it can be considered the last resort in those who failed to get ABO c offer through PKD.
Theepa Mariamutu
3 years ago
ABO-Incompatible Kidney Transplantation.
Graft survival rates after ABOi kidney transplantation comparable to those ABOc.
ABOi KT increased the number of kidney transplantations from living donors by up to 30% and able to shorten the waiting time for KT
Through current protocols about 90% of patients with an ABOi LKT may effectively be desensitized.
The role of desensitization protocols is reduction and maintenance of anti-A/B antibodies at low level (isoagglutinin) during the first 2 weeks after transplantation (<1:32) to allow accommodation occur.
BLOOD GROUP ANTIGENS AND ANTIBODIES
These oligosaccharides are expressed on the surface of a variety of different cell types, including RBCs, endothelial cells, and kidney parenchymal cells.
Antigenic expression of A2 is quantitatively and qualitatively less than that of A1, immunogenic risk based on antigen expression alone is A1>B>A2.
DESENSITIZATION FOR ABOi KIDNEY TRANSPLANTATION:
Protocol of desensitization based on centre experiences so there are many different protocols but generally they depends on antibody removal by PEX or IA with anti-CD20 as B cell depletion and IVIG with powerful triple tacrolimus based immunosuppression.
Antibody Depletion by Extracorporeal Treatment:
There are 3 methods:
PP completely remove plasma proteins
membrane separation-Remove only a specific fraction of the plasma proteins including the immunoglobulins
unselective or selective IA -More specific methods
Unselective IA is more effective than selective anti-A/B antibody columns in removing anti-A/B IgG than IgM.
Intravenous Immunoglobulins.
The role is to prevent the anti-A/B antibody rebound in the early phase after transplantation decrease rate of infection but sometimes it is associated with IgG against A/B antigens also.
B-Cell Depletion by Splenectomy or Rituximab.
Anti-CD 20 now is considered medical splenectomy and used in most protocols.
There is emerging protocols that did not use rituximab in patient with an anti-A/B antibody titre of less than 1:32 and showed good graft survival.
DESENSITIZATION PROTOCOLS AND SURVIVAL AFTER ABOi LKT
Study from Japan used (double-filtration PP, and splenectomy was more recently replaced by the anti-CD20 antibody rituximab) showed patient and graft survival rates 98 and 96% for the first year, and 91 and 83% after 9 years.
Study in US patients were desensitized by PP and low dose IVIg. the incidence of graft loss during the first year after transplantation was 5.9% in ABOi as compared to only 2.9% in ABOc.
European protocol (recipient desensitization by selective IA + Rituximab) patient and graft survival after a mean follow-up of 4.5 years was 93 and 91%, respectively.
Heidelberg desensitization protocol using (unselective IA +one PP session one day before surgery + Rituximab) led to successful desensitization of 12 patients after a median of six IA treatments, after a median postoperative follow-up of 22 months, graft survival in ABOi kidney transplant recipients was insignificantly lower compared to standard risk recipients.
CTS:
Death-censored graft and patient survival were not statistically significant different between the groups.
Early patient survival was reduced in ABOi kidney transplant recipients due to a higher rate of early infection-associated death.
ISSUES OF ABOi KIDNEY TRANSPLANTATION
Accommodation versus Rejection:
C4d deposition in peritubular capillaries of allograft biopsies without pathological injuries which occur mainly after 2 weeks from transplantation despite of high anti-A/B antibody exposure .
Infection and Malignancy
There is higher incidence of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound, and severe urinary tract infections.
Cumulative incidence of death due to infection in recipients of an ABOi living donor graft is higher than matched controls receiving an ABOc living donor graft.
Some studies shown increasing in bleeding tendency and surgical complications in ABOi group than ABOc GROUP.
Summary:
ABO-Incompatible Kidney Transplantation is considered now one of the important option to decrease time in waiting list for KTX.
It has its merits and demerits, and we should dealing with it in combination with other PKD and KAS for improving graft and patient survival.
Huda Al-Taee
3 years ago
Summarise this article
Introduction:
ABO incompatibility has been considered a contraindication to kidney transplantation.
In 1982, the first large study on ABOi kidney transplantation come from Belgium and led to a wider utilization of ABOi kidney transplantations.
Blood group antigens and antibodies:
ABO antigen system consists of oligosaccharides that are predominantly expressed on red blood cells and are also found on endothelial cells, tubules, and glomeruli making the ABO antigen system important for kidney transplantation.
Patients with different blood groups differ with respect to their antigen density on erythrocytes. Compared to blood group A1 and blood group B individuals, blood group A2 recipients, who make up 20% of all Caucasian individuals with blood group A, have a low expression of blood group antigen molecules (30–50%) on the surface of erythrocytes, which is believed to be responsible for the lower immunogenicity of organs from blood group A2 donors. ABOi kidney transplantation with A2 organs has been accomplished with standard immunosuppressive therapy without any additional measures. Of interest, anti-A/B antibodies reformed upon contact with gut bacteria during early infancy. Naturally occurring anti-A/B antibodies are predominantly of the IgM class but especially in blood group O individuals they also consist of IgG and IgA class. The relative contribution of the different immunoglobulin isotypes and their subclasses to organ rejection remains to be elucidated.
Desensitization for ABOi Tx:
There is no generally accepted protocol for desensitization in ABOi Tx,
They include one or more of the following:
Anti-A/B antibody depletion at the time of transplantation using DFPP, or selective or unselective immunoadsorption.
Modulation of the recipient’s immune system by the use of intravenous immunoglobulins.
Reduction of the B lymphocyte pool by splenectomy, or more recently by the anti-CD20 antibody rituximab.
Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the graft endothelium.
In addition, powerful maintenance IS is required.
Antibody Depletion by Extracorporeal Treatment:
Antibody removal strategies may be divided into:
methods that completely remove plasma proteins such as PP. ( prefered in US)
methods that remove only a specific fraction of the plasma proteins including the immunoglobulins (such as membrane separation). ( used in Japan)
more specific methods such as unselective or selective IA. ( used in Europe)
No significant differences were found in clinical studies that compared the impact of different IA strategies on clinical outcomes, including anti-A/B antibody reduction, survival, kidney function, rejection episodes, or complications
IVIG:
Intravenous immunoglobulins are given by many centers before ABOi kidney transplantation to prevent the anti-A/B antibody rebound in the early phase after transplantation.
In addition, it reduces infectious complications by substituting depleted immunoglobulins, but it contains IgG antibodies directed against A/B antigens and can effectively increase anti-A/B antibody titers upon administration.
B-Cell Depletion by Splenectomy or Rituximab:
splenectomy was used for the reduction of the B lymphocyte pool prior to ABOi kidney transplantation.
Due to the surgical risk and increased risk of sepsis, splenectomy was gradually substituted with the anti-CD20 antibody rituximab.
More recently, several groups completely abandoned anti-B cell therapies from their protocols, patient and graft survival were good and ABMR episodes were successfully reversed, but a high rate of death censored graft loss was observed.
Inhibition of Complement Activation:
An emerging new concept in the ABOi Tx.
It was used in ABOi kidney-pancreas transplantation. Severe antibody-mediated rejection during anti-A/B antibody rebound was successfully treated by inhibiting the assembly of the membrane attack complex by eculizumab.
Still, results on the use of eculizumab after ABOi kidney transplantation are inconclusive.
Desensitization protocols and survival after ABOi LD KTx:
the largest cohort of patients after ABOi kidney transplantation with the longest follow-up of more than 20 years is reported from Japan. Most patients were desensitized by double-filtration PP, and splenectomy was more recently replaced by the anti-CD20 antibody rituximab.
In the US, most patients were desensitized by PP and low-dose IVIg.
In 2003, Sweden published a protocol for ABOi transplantation that is based on recipient desensitization by selective IA using Glycosorb columns, splenectomy was replaced by rituximab. this protocol led to a renaissance of ABOi kidney transplantation in Europe. Good patient and graft survival were obtained by using this protocol and no evidence of ABMR was observed.
Using the Stockholm protocol, they achieved a 10-year patient and death-censored graft survival of 99 and 94%, respectively, which did not differ significantly from recipients of ABOc transplants. also, rates for antibody- and T-cell-mediated rejections were also not significantly different.
A study from the UK showed similar death-censored graft survival when compared to ABOc controls, however, patient survival in ABOi transplant recipients was reduced due to infectious complications, mostly Pneumocystis jirovecii pneumonia.
Complications of ABOi KTx:
Accommodation versus Rejection:
Accommodation appears to be a frequent phenomenon after ABOi kTx and is often associated with C4d deposition in peritubular capillaries of allograft biopsies.
An accommodation phenotype may be achieved by the controlled anti-A/B antibody exposure to antigens in the early phase after kidney transplantation. About 2 weeks after successful transplantation, accommodation is established and even high anti-A/B antibody exposure does not harm the kidney transplant.
Local upregulation of complement regulatory proteins, like CD45, CD55, and CD59, as a consequence of anti-A/B antibody-dependent inactivation of the ERK1/2 signalling pathway, is one possible mechanism.
Infection and Malignancy
There are conflicting results on infectious complications after ABOi kidney transplantation in the literature. A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound, and severe urinary tract infections have been described.
Some showed an increased risk of BK virus infection and nephropathy and they hypothesized that the different blood group antigens may influence the binding of viral pathogen receptors to sialic acid on renal tubular cells.
kumar avijeet
3 years ago
ABOi transplant previously considered a contraindication now is a possibility with 30%increase in tx rate due to dire need of organs.
ABO ag is an oligosaccharide Ag which is present on rbc,glomerulus,tubules, endothelium which reacts with anti-A and B titre that will cause early rejection.So the sole purpose of desensitization is reduction of ab titre to a safe limit of B>A2 in line of immunogenicity.
Here the main culprits are-
1.Antibody(IgG is imp than IgM,because IgM is intravascular hence amenable to removal)
2.B-cell/plasma cell
3.complement
Mode of removal/suppression-
1.ANTIBODY
A.plasmapheresis(nonspecific,albumin,coagulation proteins also removed)
B.double filtration plasmapheresis(more specific,only albumin loss)
C.immuneadsorption(specific IA against anti-A or anti-B)(no loss of albumin)
2.B-CELL
A.splenectomy (not practised now)
B.Rituximab (low to high dose, replaced splenectomy with increase in death censored graft function and prevent rebound of ab titre during initial tx weeks)
3.COMPLEMENT-
A.eculizumab (very expensive)
B.IVIG-modulate the immunity by neutralization of antibody,complement,T-cell inhibition,supplement immunoglobulin deficiency, but increases antibody titre)
4.ATG/BASILIXIMAB induction with triple immunosuppression.
OUTCOME-patient survival is less due to more infections,mdr bacteria colonization,bkvirus nephropathy, but malignancy risk is equal.
ABOi tx graft survival,patient survival ,death censored graft survival is equivalent to ABOc tx but initial survival is less due to increased infections and rejection.
Wael Jebur
3 years ago
ABOi transplantation has over come the shortage of kidney transplantation. Recently it becomes a routine procedure with comparable graft survival to compatable ABO transplantation.The number of kidney transplantation can increase by 30% when patients are transplanted against ABO antibody barrier.
The scope of desensitization protocols in ABOi transplant is the reduction and maintenance of anti A/B antibodies (isoagglutinin) during the first 2 weeks post transplantation below a threshold that considered to be safe which is 1/32 in tube technique .
ABO Antigen system:
Oligosaccharide present on red blood cells,endothelial cells,tubular and glomeruli.
Patients with different blood groups differe with respect to their ABO antigen expression in RBC and different tissues.
A2 HLA antigen:
1)Blood group A2 is making up 20% of total people with blood group A antigen .
2)It has low expression of A2 molecules on surface of RBCs 30 to 50% less.
3) It explains the lower immunogenicity of organs from blood group A2 donors
4) A2 organs transplantation can be accomplished by standard immunosuppressive protocoles without any additional measures
ANTI ABO antibodies:
Anti A/B antibodies are predominantly of the IgM class, in the contrary ,in blood group O,they consist of IgG and IgA.
The relative contribution of different ig classes to solid organ rejection is yet to be elucidated
Desensitization of ABOi kidney transplantation:
Includes one or more of the following;
1)Anti A/B depletion at the time of transplantation.,
These involve PP, double filtration PP,and the IA that is commonly adopted in North Europe protocol .Frequency depend on level of antibodies and usually started 14 days prior to transplantation . Cutoff target antibody titer is less than 32% . Post transplant IA is not routinly indicated, but depend on the antibody rebound and post transplant antibody titer. Accomodati9n is a common phenomina in ABOi transplantation, wherein ,despite the higher rebound with prominent C4d deposition in PTC, no rejection could be detected in this context, this phenomina would be fully mature 2 weeks post ABOi transplantation.
2) Modulation of recipients immune system by the use of IVIG:
High dose IVIG 2gm/kg used to be given one day before the transplantation, It has several roles in transplantation including neutralization of antibodies,inducing apoptosis of B and T lymphocytes,apoptosis of plasma cells.Its usually given after PP or IA to reconstitute the immunoglobine profile of the patients.
3) Depletion of B lymphocytes population . As B lymphocytes react with antigenic stimulation maturing to antibody producing plasma cells.This step was accomplished previously by splenectomy, that was replaced by anti CD 20 antibody Rituximab.
Due to over immune suppression incured by Rituximab and the subsequent immunosuppressive protocols with high potential risk of malignancy and opportunistic infections, Rituximab was omitted from the protocol, especially North Europe protocol. However it’s still considered in other centers. Usually administered in 2 doses 28 and 1 day before transplantation.
4) An emerging new concept in ABOi transplantation is the inhibition of complement activation upon binding of antibodies to endothelial antigens. Anti C5 Eculizumab prevent the formation of membrane attack complex. Used in special cases where othe measures fail to treat the AMR.
5) Immunosuppressive protocol: include anti IL-2 receptor antibodies Basiliximal on day 1 and 4 post transplantation. Tacrolimus ,MMF and prednisone started 14 days prior to transplantation.
In conclusion ABOi transplantation has eme4ged as a salvage procedure to expand the living donor transplantation.however down side include infection, malignancy and early rejection.
I would prefer non ABOi kidney transplant whenever possible.
Abdulrahman Ishag
3 years ago
ABO-Incompatible Kidney Transplantation
With currently existing protocols, as many as 90% of patients with an ABOi living donor may effectively be desensitized and transplanted. The aim of desensitization protocols is the reduction and maintenance of anti-A/B antibodies (isoagglutinins) during the first 2 weeks after transplantation below a threshold that is considered to be safe . Thereafter, even when anti-A/B antibodies recur at high levels they will not harm the kidney transplant, a phenomenon that is called accommodation.
Blood group antigens and antibodies ;
ABO antigens are predominantly expressed on red blood cells and are also found on endothelial cells, tubuli, and glomeruli making the ABO antigen system important for kidney transplantation. Blood group A2 recipients, have a low expression of blood group antigen molecules (30–50%) on the surface of erythrocytes, which is believed to be responsible for the lower immunogenicity of organs from blood group A2 donors.
Desensitization for ABOi kidney transplanation;
These include together with a powerful maintenance immune suppression one or more of the following:
(1) Anti-A/B antibody depletion at the time of transplantation using PP, double-“ltration PP/membrane “ltration, or selective or unselective immunoadsorption (IA).
(2) Modulation of the recipient’s immune system by the use of intravenous immunoglobulins (IVIgs).
(3) Reduction of the B lymphocyte pool by splenectomy, or more recently by the anti-CD20 antibody rituximab.
(4) Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the graft endothelium.
Extracorporal treatment ;
Antibody removal strategies may be divided into;
1-methods that completely remove plasma proteins such as PP.
2- methods that remove only a specific fraction of the plasma proteins including the immunoglobulins .
3-more specific methods such as unselective or selective IA.
They prevent the anti-A/B antibody rebound in the early phase after transplantation. IVIg infusion is believed to reduce infectious complications by substituting depleted immunoglobulins.
B-cell depletion by splenectomy or rituximab;
Due to the surgical risk and increased risk of sepsis, splenectomy was gradually substituted by the anti-CD20 antibody rituximab.
Inhibition of complement activation;
An emerging new concept in the transplantation across ABO antibody barriers is the inhibition of complement activation upon binding of antibodies to the allograft endothelium.
Desensitization protocols and survival after ABOi living donor kidney transplantation;
Patient survival in ABOi transplant recipients was reduced due to infectious complications .Other important differences between ABOi and standard risk kidney recipients were a higher incidence of BK virus replication and BK virus nephropathy and a higher prevalence of colonization with multidrug-resistant bacteria .
Complications of ABOi kidney transplantation;
1- Accomodation ;
Accommodation appears to be a frequent phenomenon after ABOi kidney transplantation and is often associated with C4d deposition in peritubular capillaries of allograft biopsies.
2- Infection and Malignancy ;
There are conflicting results on infectious complications after ABOi kidney transplantation in the literature.
A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound, and severe urinary tract infections have been described .
Studies found no increased cancer risk when comparing ABOi kidney transplant recipients to matched ABOc controls.
Amit Sharma
3 years ago
· Summarise this article
ABO incompatibility was once considered a contraindication for kidney transplant, but not anymore and it can increase the number of living donor kidney transplants by 30%.
The blood group antigens are present on RBCs, endothelial cells, tubules and glomeruli, contributing to their importance in kidney transplantation. The immunogenic strength of the blood group antigens is A1>B>A2.
Desensitization for ABO incompatible transplant includes:
1) Antibody depletion is performed using:
a. Plasmapheresis: It removes plasma proteins
b. Double filtration plasmapheresis (DFPP/ membrane separator): It removes specific fractions of plasma proteins
c. Immunoadsorption (IA):
i. Selective IA: removes specific anti-A or B antibody selectively, but reduce total IgG and IgG against polysaccharide antigens also.
ii. Unselective IA: Better removal of anti-A or B IgG, but poorly remove IgM and IgG3.
It has been seen that membrane separation and unselective IA combination effectively removed IgG, IgM as well as C1q.
2) Immunomodulation using intravenous immunoglobulin (IVIG) decreases rebound and infection risk, but can increase anti A/B antibody titres due to IgG antibodies present in them.
3) B cell depletion involves using either splenectomy (abandoned nowadays due to its surgical and infectious complications) or rituximab (preferred nowadays). Few centers have shown good results without rituximab use. Rituximab non-use has been shown to have increased death censored graft loss.
4) Prevention of complement activation using eculizumab has been tried, but with inconclusive results.
Results of ABO incompatible transplants, in comparison with ABO compatible transplants, show similar patient survival, graft survival as well as death censored graft survival, although with higher rates of early rejection. Early patient survival is reduced due to increased infections causing mortality in ABO incompatible transplants. There is a trend towards better death censored graft survival at 3 years if antiCD20 antibody is used.
Increased incidence of viral infections like CMV, HSV, Varicella zoster virus, BK virus nephropathy and multidrug resistant bacterial infections is seen in ABO incompatible transplants. The risk of malignancy remains similar to that in ABO compatible transplants.
There is 2 times increased risk of haemorrhage due to removal of coagulation factors during antibody depletion, increased risk of surgical complications, lymphocele formation and increased need of surgical revision in ABO incompatible transplants.
Due to these complications, whenever possible, a blood group compatible transplant should be performed. Kidney paired donation programs are an alternative to ABO incompatible transplants, especially with living donor programs.
Sahar elkharraz
3 years ago
In the past ABOI is contraindicated because high risk of rejection at moment of transplant.
Now kidney transplant possible in patients with ABOI due to improving immunological technology in detection of anti A/B antibodies and strategies to removal and maintenance of anti A/B antibodies titres. The survival of graft reach to 98% in first year post transplant and from 90% to 88% within 9 years post transplant.
Anti A/B antibodies are oligosaccharides that expressed on surface of endothelial cell of RBC and varieties of cell in the body especially glomeruli.
These antibodies responsible for hyperacute AMR; different type of blood group has different antigen expressed on the surface of cell. blood group A2 present in 20% of Caucasians population has low immunological reactions in comparison to blood group A1 and blood group B. All blood group has anti A/B antibodies with predominantly IgM class but blood group O has IgM class and Class IgG / IgA.
Strategies of desensitisation depend on
– [ ] Removal of anti A/B antibodies pre and post transplant in first 2 weeks by plasma pharesis or by immunoadsorption
– [ ] Intravenous immunoglobulin help to decrease risk of infection
– [ ] depletion of B cell by splenectomy plus rituximab
Splenectomy recently replaced by anti CD20 (rituximab).
– [ ] inhibition of complement activation by eculizumab
Maintenance by triple immunosuppressive agents MMF and low dose steroid and CIN.
Disadvantages of desensitisation protocol are high risk of fatal infection such as TB CMV BK virus and pneumacystic Jirvici and high risk of malignancy.
Case report study shows patient with ABOi kidney transplant die from sepsis and biopsy results show evidence of AMR and presence of C4d deposition along peritubular arteries.
Many reports shows no significant difference in incidence of malignancy between ABOI and ABOc.
Conclusion:
Kidney transplant the best option in patients with ESRD and patients with ABOi has chance to get transplant with good graft function by detection and reduction level of anti A/B antibodies and using desensitisation protocol.
Mohamed Saad
3 years ago
ABO-Incompatible Kidney Transplantation. INTRODUCTION:
Nowadays, graft survival rates after ABOi kidney transplantation nearly equaled those after ABO-compatible (ABOc) procedures.
When ABO-Incompatible Kidney Transplantation emerged , the number of kidney transplantations from living donors increased by up to 30% and it is an important factor to shortening the waiting time on waiting list.
Specially with currently protocols, as many as 90% of patients with an ABOi living donor may effectively be desensitized.
The role of desensitization protocols is the reduction and maintenance of anti-A/B antibodies (isoagglutinins) during the first 2 weeks after transplantation below a threshold that is considered to be safe (e.g., <1:32).
Deepening on Accommodation phenomena which till now not completely understood as no harmful effect despite of rebound of the anti A/B antibodies. BLOOD GROUP ANTIGENS AND ANTIBODIES
These oligosaccharides are expressed on the surface of a variety of different cell types, including RBCs, endothelial cells and kidney parenchymal cells.
Antigenic expression of A2 is quantitatively and qualitatively less than that of A1, immunogenic risk based on antigen expression alone is A1>B>A2. DESENSITIZATION FOR ABOi KIDNEY TRANSPLANTATION:
Protocol of desensitization based on center experiences so there are many different protocol but generally they depends on antibody removal by PEX or IA with anit-CD20 as B cell depletion and IVIG with powerful triple tacrolimus based immunosuppression. A-Antibody Depletion by Extracorporeal Treatment :
There are 3 methods :
completely remove plasma proteins such as PP .
Remove only a specific fraction of the plasma proteins including the immunoglobulins (such as membrane separation)
More specific methods such as unselective or selective IA.
Unselective IA to be more effective than with selective anti-A/B antibody columns in removing anti-A/B IgG than IgM. B- Intravenous Immunoglobulins.
The role is to prevent the anti-A/B antibody rebound in the early phase after transplantation decrease rate of infection but sometimes it is associated with IgG against A/B antigens also. C-B-Cell Depletion by Splenectomy or Rituximab.
Anti-CD 20 Rituximab now is considered medical splenectomy
For B-cell depletion is used now by rituximab in most protocols.
Also some protocols not used rituximab at all if patient had reached an anti-A/B antibody titer of less than 1:32 with good graft survival. DESENSITIZATION PROTOCOLS AND SURVIVAL AFTER ABOi LIVING DONOR KIDNEY TRANSPLANTATION
Study from Japan used (double-filtration PP, and splenectomy was more recently replaced by the anti-CD20 antibody rituximab) showed patient and graft survival rates 98 and 96% for the first year, and 91 and 83% after 9 years.
Study in US patients were desensitized by PP and low dose IVIg. the incidence of graft loss during the first year after transplantation was 5.9% in ABOi as compared to only 2.9% in ABOc.
European protocol (recipient desensitization by selective IA + Rituximab) patient and graft survival after a mean follow-up of 4.5 years was 93 and 91%, respectively.
Heidelberg desensitization protocol using (unselective IA +one PP session one day before surgery + Rituximab ) led to successful desensitization of 12 patients after a median of six IA treatments, After a median postoperative follow-up of 22 months, graft survival in ABOi kidney transplant recipients was insignificantly lower compared to standard risk recipients. RESULTS FROM THE CTS
Death-censored graft and patient survival were not statistically significant different between the groups.
Early patient survival was reduced in ABOi kidney transplant recipients due to a higher rate of early infection-associated death. COMPLICATIONS AND HURDLES OF ABOi KIDNEY TRANSPLANTATION
Accommodation versus Rejection:
C4d deposition in peritubular capillaries of allograft biopsies without pathological injuries which occur mainly after 2 weeks from transplantation despite of high anti-A/B antibody exposure .
Infection and Malignancy
There is higher incidence of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound, and severe urinary tract infections.
Cumulative incidence of death due to infection in recipients of an ABOi living donor graft is higher than matched controls receiving an ABOc living donor graft.
Some studies shown increasing in bleeding tendency and surgical complications in ABOi group than ABOc GROUP. CONCLUSION:
ABO-Incompatible Kidney Transplantation is considered now one of the important option to decrease time in waiting list for KTX.
It has its merits and demerits and we should dealing with it in combination with other PKD and KAS for improving graft and patient survival.
Alaa eddin salamah
3 years ago
Article II
ABO-Incompatible Kidney Transplantation
major ABO incompatibility has been considered a contraindication to kidney transplantation
theoretically, the number of kidney transplantations from living donors can be increased by up to 30% when patients are transplanted across the ABO antibody barrier
The aim of desensitization protocols is the reduction and maintenance of anti-A/B antibodies (isoagglutinin) during the first 2 weeks after transplantation below a threshold that is considered to be safe (e.g., <1:32 in tube technique). thereafter, even when anti-A/B antibodies recur at high levels they will not harm the kidney transplant, a phenomenon that is called accommodation.
DESENSITIZATION FOR ABOi KIDNEY TRANSPLANTATION
these include together with a powerful maintenance immunosuppression one or more of the following: (1) Anti-A/B antibody depletion at the time of transplantation using PP, double-filtration PP/membrane “filtration, or selective or unselective immunoadsorption (IA) (2) Modulation of the recipient’s immune system by the use of intravenous immunoglobulins (IVIgs) (3) Reduction of the B lymphocyte pool by splenectomy, or more recently by the anti-CD20 antibody rituximab (4) Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the graft endothelium.
Antibody Depletion by Extracorporal Treatment
Antibody removal strategies may be divided into methods that completely remove plasma proteins such as PP, methods that remove only a specific fraction of the plasma proteins including the immunoglobulins (such as membrane separation), and more specific methods such as unselective or selective IA. While PP is the preferred antibody removal strategy in the US, membrane separation is popular in Japan. Unselective and selective IAs are often used in Europe.
Intravenous Immunoglobulins
– to prevent the anti-A/B antibody rebound in the early phase after transplantation
– to reduce infectious complications by substituting depleted immunoglobulins
B-Cell Depletion by Splenectomy or Rituximab
We observed in the Collaborative Transplant Study (CTS) a higher rate of death-censored graft loss in ABOi kidney transplant recipients when rituximab was omitted
Inhibition of Complement Activation
results on the use of eculizumab after ABOi kidney transplantation are inconclusive.
DESENSITIZATION PROTOCOLS AND SURVIVAL AFTER ABOi LIVING DONOR KIDNEY TRANSPLANTATION
Different protocols were suggested for desensitization. Actually, all with great results with the same core treatments.
COMPLICATIONS AND HURDLES OF ABOi KIDNEY TRANSPLANTATION
Accommodation versus Rejection
An accommodation phenotype may be achieved by the controlled anti-A/B antibody exposure to antigens in the early phase after kidney transplantation. About 2 weeks after successful transplantation, accommodation is established and even high anti-A/B antibody exposure does not harm the kidney transplant.
Infection and Malignancy
A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound, and severe urinary tract infections have been described
No increased risk of malignancy in ABOi compared to ABOc patients
Additional Observations
two times higher risk of early hemorrhage in 119 ABOi kidney transplant recipients when compared to ABOc controls
Some authors observed an increased rate of surgical complications after ABOi kidney transplantation, which were attributed to early intensified immunosuppression with mycophenolic acid and removal of coagulation factors by apheresis.
MOHAMMED GAFAR medi913911@gmail.com
3 years ago
ABOi kidney transplantion was an absolute contarindication for kidney transplantion.
Due to organ shortage transplant nephrologist considered ABOi kidney transplantion to increase donor pool.
this can be done by desensetizaing the recipent anti A or B antibodies in their serum to decrease the chance of ABMR.
Desentization of antibodies can be done by many stratiges.
1- Antibody Depletion by Extracorporal Treatment ,pp,or slective IA,or unslective IA 2- Intravenous Immunoglobulins . 3-Cell Depletion by Splenectomy or Rituximab . 4-Inhibition of Complement Activation for example ecluizimab.
After ABOI kidney transplantion, accomodation happens about 2 weeks after succeful transplantion and often asscoiated with c4d deposition.
Higher frequence rate of viral infections happens after ABOi kidney , like cmv ,BK, HSV,HZV.
No data showed increse malignancy rate after ABOi kidney transplant.
ABOc kidney transplantion is perrferd over ABOi kidney transplantion.
Heba Wagdy
3 years ago
ABO incompatible kidney transplantation is recently used to increase the number of living donors, this was helped by new successful desensitization protocols and improved graft survival. Blood group antigens and antibodies ABO antigen system is expressed in RBCs, endothelial cells, tubuli and glomeruli. Organs from blood group A2 donors are less immunogenic due to low expression of blood group antigen on surface of RBCs Pathogenic importance of anti-A/B antibodies is well known but the relative contribution of different immunoglobulin isotypes and subclasses is not well determined. Desensitization for ABO incompatible (ABOi) kidney transplantation No single desensitization protocol is defined Antibody depletion by extracorporeal treatment:
Plasmapheresis completely remove all plasma proteins
membrane separation remove specific fraction of plasma proteins including immunoglobulins.
Unselective or selective IA Modulation of immune system by IVIG:
IVIG used to prevent anti-A/B antibody rebound early post transplant.
Substitute immunoglobulins which reduce the risk of infection due to plasmapheresis. Reduction of B lymphocytes by rituximab or splenectomy:
Splenectomy is replaced by anti-CD20 rituximab.
Several centers recently omitted B cell depletion from its protocol with controversial results regarding graft survival. Inhibition of complement activation:
New strategy in ABOi kidney transplantation but with inconclusive results about its efficacy. Desensitization protocols and survival after ABOi living donor kidney transplantation
Desensitization with double filtration PP and splenectomy which was replaced recently by rituximab was associated with excellent patient and graft survival.
Desensitization with PP and low dose IVIG was associated with higher incidence of graft loss compared to ABOc transplants.
Desensitization with selective IA and splenectomy recently replaced by rituximab was successful with comparable graft and patient survival.
Desensitization with unselective IA without IVIG was associated with insignificantly lower graft survival compared to standard risk transplants and higher prevalence of infectious complications. Complications of ABOi kidney transplantation Accommodation versus rejection:
Accommodation is frequent and may be achieved by controlled anti-A/B antibody exposure in early phase post transplant. Infection and malignancies:
ABOi kidney transplantation is associated with increased risk of early severe infections, higher frequency of viral infection and increased incidence of BK nephropathy.
It was not associated with increased risk of malignancy post transplant. Additional observations:
Higher risk of early bleeding mostly due to PP and unselective IA.
Increased rate of surgical complications mostly due to coagulopathy and intensified immunosuppression. Future perspectives
Reducing blood group antigen levels in allograft.
Kidney paired donation programs.
Ben Lomatayo
3 years ago
Introduction
At the begining in 1955 ABOi KT was contraindicated until 1982 where Alexander et al.published first large cohort on ABOi KT with 1 year survival of 75 % after successful desensitization and aggressive immune-suppression [2,3]. Due to accumulation of large numbers of patients in the waiting list and shortages of the donors organ, ABOi KT became a valid option to increase the living donors pool. This study reviewed the latest data on ABOi KT.
Blood group antigens and antibodies
The ABO system are oligosacharrides expressed mainly on RBS. They are also expressed on kidney cells namely endothelial cells, tubuli, and glomeruli. This makes the kidney important targets to antibodies against ABO system.
The A antigen is divided into sub-type A1 and A2. A2 is less immuno-genic and expressed is ~ 20% of white people [4,5]. ABOi KT with A2 organs was successful with standard immune-suppression without the need for any extra measures [6]
Anti A/B antibodies are developed upon contact with gut bacteria during infancy.They are mainly IgM but blood type O individuals they are of IgG/IgA subclass.
Desensitization for ABOi Kidney Transplantation
1.Antibody depletion by Extra-corporal Treatment
Plasma-phersis (US)
Double filtration phasma-phersis or membrane separation (Japan)
Immuno-adsorption selective or un-slective(Europe)
2.Intravenous Immunoglobulin
Prevent early re-bound
Decrease infections by providing depleted immunoglobulin
3.B cell depletion I.Splenectomy ;
This was historical and it is not done any more due surgical and infectious risks
II.Rituximab ;
This replaced splenectomy
III.Standard immune-suppressive therapy WITHOUT Rituximab ;
New strategy reported by Flint et al.[14]
Patient and graft survival was 100% after a median of 26 months post-transplant
4.Inhibition of Complement Activation e.g. Eculizumab
Reports are controversial ( Biglarnia et al. vs Stegall et al.)
Desensitization protocols and Survival After ABOi-living Donor Kidney Transplantation
Most protocols in Japan involveddouble filtration PP, Rituximab, and splenectomy is no longer performed
In analysis of 1427 patients, patient and graft survival was 98% and 96% for the first year, 91% and 83% after 9 years respectively[17]
Genberg et al. showed patent and graft survival after 4.5 years was 93% and 91% respectively[20]
Stockhlom protocol ; 10 years patient and death-censored graft survival was 99% and 94% respectively[22]
Results from the CTS
1420 ABOi-KT at different center ~101 between 2005 to 2012
ABOi-KT compared to control group of ABOc-KT
Early patient survival was reduced in ABOi-KT(P<0.001) compared with the matched control
This was due to high rates of infection-associated death among ABOi-KT cohort
Complications and Hurdle of ABOi-KT
Accommodation versus Rejection ;
The presence C4d in the ptc without evidence of AMR
Developed after 2 weeks ABOi-KT and the presence of high titre of antiA/B antibodies does’t injure the graft
The mechanism id not clear, may be up-regulation of the local complement regulatory proteins[24]
Infection and Malignancy
ABOi-KT is associated with increased risk of infectious complications[15,23]
Higher rates of BKVAN[23]
No differences in cancer risk between ABOi-KT and ABOc-KT(Hall et al)
Additional Observations
Increased rate of bleeding complications seen in ABOi-KT compared to ABOc-KT [26]
This was due to non-specific binding of coagulation factors on subsequent cycle of AI [30]
Increased rate of surgical complications due to early intensified immune-suppression and removal of coagulation factors
Increased rate of surgical revisions [21]
Higher numbers of lymphocele in ABOi-KT compared to ABOc-KT [21]
Future perspectives
Reduction blood group antigen levels in the allograft by ex-vivo infusion of endo-beta-galactosidase [32]
Avoid ABOi-KT by adopting Kidney Exchange Programs
Conclusion
At the moment ABOi-KT is used routinely in some centers and it has increased the living kidney donors pool by ~30%. Despite this success, ABOi-KT is associated with increasede mortality due high rate of infectious complications. Therefore ABOc-KT should always be the standard practice unless one is foreced to proceed towards the direction of ABOi-KT.
Mohamad Habli
3 years ago
To reduce the waiting time is the transplantation across ABO antibody barriers, there is a lot of options including transplantation with ABOi. Theoretically, the number of kidney transplantations from living donors can be increased by up to 30% when patients are transplanted across the ABO antibody barrier.
The aim of desensitization protocols is the reduction and maintenance of anti-A/B antibodies during the first 2 weeks after transplantation below a threshold that is considered to be safe (e.g., <1:32 in tube technique). thereafter, even when anti-A/B antibodies recur at high levels they will not harm the kidney transplant, a phenomenon that is called accommodation.
Blood group antigens and antibodies
The ABO antigen system consists of oligosaccharides that are predominantly expressed on red blood cells and are also found on endothelial cells, tubuli, and glomeruli.
anti-A/B antibodies are formed upon contact with gut bacteria during early infancy. Naturally occurring anti-A/B antibodies are predominantly of the IgM class. blood group O individuals they also consist of IgG and IgA class.
Desensitization protocols for ABOI kidney transplantation are changing with time and remain center based. yet not standardized, each center have their own protocol based on their experience, facilities, resources and infrastructure.
Plasmaphersis and IA- The concept of desensitization based on antibodies removal by plasmapheresis or immunoadsorption (IA) which is more selective and specific , preferred for HLA I , ABOI transplant with specific removal of anti-A,anti B abs with average reduction rate by 3-4 fold and associated with less infectious or bleeding side effects compared to plasma-exchange but more expensive.
Immunomodulating agent IVIG-is complementary treatment after plasmapheresis to replace removed antibodies along with other important functions as complement inhibition, FC receptors binding, inhibit B and T cells proliferation, CD8 T cell inhibition, with B cells apoptosis.
No standardized dose, high dose, low dose usually given after plasmapheresis many side effects including infusion related allergic reaction, risk of thromboembolic events, AKI, its use in combination with plasmapheresis the preferred and widely used protocol with or without Rituximab.
B cell depletion- B cell depletion using anti-CD20 Rituximab replaced surgical splenectomy, while rituximab with used in different doses and frequency based on local center protocols but trend nowadays to use low dose rituximab usually 14 days before surgery.
Complications of desensitization therapy include Infection and Malignancy
Although aggressive immunosuppression increases the risk of malignancy in HLA incompatible transplantation,cancer risk was not found to be higher compared ABOi -KT to match ABOc controls. After ABOi -KT there are conflict result regarding infectious complication in the literature.
Higher frequency of viral infection (CMV.HSV,VZV and BK virus) as well as P. Jiroveci pneumonia along with wound infection and severe UTI were reported.
Mohamed Mohamed
3 years ago
II. ABO-Incompatible Kidney Transplantation Summarise this article
Transplantation across ABO antibody barrier has emerged as one method to increase donors pool & shorten waiting time for ESRD patients. Waiting times for a DD kidney transplant may exceed 5 years . ABO-i transplant can increase the number of transplants from living donors by up to 30%. The pathogenic importance of anti-A/B antibodies in SOT is well recognized. ABO antigens are mainly expressed on RBCs, but are also present on endothelial, tubular, & glomerular cells; thus are important in real transplantation. ABO subclass A2, which makes 20% of blood group A in white races, has a lower expression & immunogenicity compared to A2 & B groups.
Thus ABO-i with A2 organs has been successfully transplanted with standard IS therapy without extra measures.
Desensitization protocols currently used in ABO-I renal transplantation include: 1. Anti-A/B Ab depletion at the time of transplantation: (i) PP: completely remove plasma proteins (ii) Double-filtration PP/membrane filtration: removes specific fraction of the plasma proteins including the immunoglobulins (iii) IA (selective or unselective): are more specific methods.Studies showed no difference between different IA strategies on clinical outcomes. ========================================================== 2. Immunomodulation by IVIG:often given before transplantation to prevent the anti-A/B antibody rebound in the early post-transplant phase. It also reduces infectious complications by substituting depleted immunoglobulins. ========================================================= 3. B lymphocyte pool reduction by the anti-CD20 antibody rituximab; & rarely splenectomy. Some centers recently omitted rituximab from their protocols & did successful ABO-I transplant with PP & standard IS; however higher rate of death- censored graft was seen loss in CTS study. ============================================= 4. Inhibition of complement activation upon binding of antibodies to the endothelium of the graft. Results on the use of eculizumab after ABO-i kidney transplantation are inconclusive. ============================================== Desensitization protocols & survival after ABO-i living donor kidney transplantation: 1. The largest cohort (1,427 cases) from Japan:
– Desensitization by double-filtration PP, & splenectomy was more recently replaced by rituximab.
– Graft survival rates were excellent. ——————————————————————— 2. Data from the Scientific Registry of Transplant Recipients (738 cases),USA:
– Desensitization by PP & low dose IVIG.
– Incidence of graft loss during the 1st year was 5.9% in ABO-i vs only 2.9% in ABO-c. ——————————————————————– 3. In 2003, Tydén et al.(Sweden):
– Used a protocol based on desensitization by selective IA.
– Splenectomy was replaced by rituximab.
– This protocol led to a return of ABO-i renal transplant in Europe.
– Genberg et al. used this protocol in 45 patients, Patient & graft survival were 93 & 91%, respectively. No early acute AMR that could be linked to anti-A/B antibodies. —————————————————————————- 4. Freiburg group from Germany compared 100 ABO-i kidney with 248 ABO-c:
– 10-year patient & death-censored graft survival were 99 & 94%, respectively in ABO-I transplant; not significantly different from the 80 & 88% survival rates, respectively, in recipients of ABO-c transplants.
– Rates for AMR & TCMR were not significantly different. —————————————————————————– 5. The author(center in Heidelberg):
– Used a protocol for desensitization similar to the Swedish protocol.
– Unselective IA used instead of selective one, allowing also the de- sensitization for HLA-i living donor transplant.
– Successful desensitization of 12 patients (median of 6 IA treatments). Anti- A/B titer reduction with unselective IA was comparable to that of a historical control group that received selective IA.
– More recently 34 ABO-i recipients desensitized with IA were compared to 68 matched, standard risk living donor kidney recipients. Graft survival was insignificantly lower in ABO-i group. A higher incidence of BKI & BKVN in ABO-i group. ———————————————————————– 6. Results from the CTS
– 1,420 ABO-i recipients compared to a matched group of ABO-c recipients & to all ABO-c recipients from centers that performed at least 5 ABO-i procedures.
– No difference in overall graft, death-censored graft, & patient survival groups.
– Higher rate of early infection-associated death in ABO-I group.
– A better 3-year death-censored graft survival in those who received rituximab. ================================================ Complications of ABO-i transplantation
– A higher rate of infections (CMV, HSV, VZV, BKV,P. jirovecii pneumonia, wound, & severe UTIs) are reported. BKVAN was 3 times higher in ABO.i patients vs patients with HLA antibodies(Sharif et al)
– Higher risk of early hemorrhage Risk of bleeding is possibly related to IA & PP.
– Increased rate of surgical complications(especially lymphoceles) due to early intensified IS & removal of coagulation factors by PP. Future potential research areas:
– Reduction of ABO antigen levels in the allograft using endo-beta- galactosidase.
Batool Butt
3 years ago
ABO incompatibility has long been considered a contraindication to kidney transplantation. Because of the shortage of donors and to avoid long waiting times for the deceased ,many strategies have been developed recently to desensitize ABOI patients and transplant them. BLOOD GROUP ANTIGENS AND ANTIBODIES
Blood group antigens are present not only in RBCS but also in the endothelial cells and they include A, B, AB, O. Blood group A is divided into A1 and A2.A2 is less immunogenic and can serve as universal donors but only if the titer of antibodies is low. Naturally occurring anti-A/B antibodies are predominantly of the IgM class but especially in blood group O individuals they also consist of IgG and IgA class . The most commonly method used is tube method .Titer > 1/256 is considered high by most centres while acceptable level pre transplantation vary between 1/4 to 1/32 and this level should be maintained throughout the first 2 weeks DESENSITIZATION FOR ABOi KIDNEY TRANSPLANTATION
Different protocols used in different centers. It includes: Antibody depletion: PP(completely remove plasma proteins) double-“filtration PP/membrane “filtration(methods that remove only a speci”c fraction of the plasma proteins including the immunoglobulins), or selective or non-selective immunoadsorption. Modulation of recipient’s immune system: IVIG(to prevent the anti-A/B antibody rebound in the early phase after transplantation,and to reduce infectious complications by substituting depleted immunoglobulins) B cell depletion: splenectomy previously , or more recently- antiCD20 anti body rituximab. (4) Inhibition of complement activation : emerging new concept- eculizumab.Results inconclusive. Induction therapy using either basiliximab or ATG according to risk assessment. Maintenance Immunosuppression: CNI (tacrolimus-better), MMF started 7-14 days before transplantation, steroids . DESENSITIZATION PROTOCOLS AND SURVIVAL AFTER ABOi LIVING DONOR KIDNEY TRANSPLANTATION
Different protocols for desensitization has been tried and patient and graft survival assessed. A study from the UK showed death-censored graft survival in first year less than ABOi-KT and patient survival was reduced due to infectious complication mostly pneumocystis jirovecii pneumonia. Outcome of majority of studies revealed graft death and patient survival were not statistically significant different when compared to matched group of ABOc kidney transplant recipients. COMPLICATIONS AND HURDLES OF ABOi KIDNEY TRANSPLANTATION Accommodation- Local upregulation of complement regulatory proteins, like CD45, CD55, and CD59, as a consequence of anti-A/B antibody-dependent inactivation of ERK1/2 signaling pathway is the likely mechanism. It is established about 2 weeks after successful transplantation and is often associated with C4d deposition in peritubular capillaries of allograft biopsies. Infection and Malignancy- higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound, and severe urinary tract infections have been observed in such patients. Also increased rate of surgical complications like lymphoceles after ABOi kidney transplantation. FUTURE PERSPECTIVES:
Ex- vivo infusion of endo-beta-galactosidase- new strategy for reduction of antigen levels in allograft patients. CONCLUSION
ABOi-KT signals expand the living donor pool but has increased rates of infectious complication so wherever possible ABOc transplant should be preferred.
Doaa Elwasly
3 years ago
ABO in compatible transplantation (ABO ic Tx) was an option to shorten the waiting time for ESRD patients on dialysis with lack of available grafts .
ABO ic Tx can be done by desensitization strategy aiming at lowering isoagglutinin ,1/32 by tube technique , even when rebound increase of anti A/B antibodies occurs later , accommodation can take place preserving the graft.
Blood group antigens and antibodies
blood group A2 recipients, represent 20% of individuals with blood group A, with low expression on the surface of erythrocytes, leading to lower immunogenicity of organs from blood group A2 donors.
Desensitisation for ABO ic Tx includes
(1)Anti-A/B antibody depletion using PP,DFPP, immunoadsorption (IA)
(2) intravenous immunoglobulins (IVIgs)
(3) B lymphocyte depletion by splenectomy, previously or currently by rituximab
(4) Prevention of complement activation upon anti-A/B antibody binding to the graft endothelium.
Antibody Depletion by Extracorporal Treatment
-Using PP removing specific protiens as Ig
-Selective or non selective IA is used in some protocols
-membrane separation and unselective IA used together can remove efficiently IgG and IgM antibodies and complement C1q component
Intravenous Immunoglobulins
Are administered prior Tx to prevent rebound increase of A/B antibody titer and provide protection against infections meanwhile it was noticed to increase A/B Ab titers after giving it
B-Cell Depletion by Splenectomy or Rituximab
Splenectomy was abandoned due to it’s surgical and infection risks
Rituximab substituted it.
Some studies published favorable outcomes for ABOic Tx using standard immunosuppression without Rituximab another studies demonstrated increased graft loss without Rituximab usage.
Inhibition of Complement Activation
Severe antibody-mediated rejection in patients with anti-A/B antibody rebound increase in the level was successfully treated by eculizumab. Desensitization protocols and survival after ABOi c living donor Tx
Most studies published acceptable and comparable outcomes of ABO ic Tx to ABO c Tx either desensitization using DFPPwith Rituximab or PP and low dose IVIG or selective IA and Rituximab .
ABOic transplant recipients survival was reduced due to infectious complications, mostly Pneumocystis jirovecii pneumonia.
Studies demonstrated also that unselective IA isnot inferior to selective IA
Complications of ABOi Tx Accomodation versus Rejection
accommodation is detected after ABOi ckidney transplantations and is associated with C4d deposition in peritubular capillaries of allograft biopsies could be attributed to upregulation of complement regulatory proteins, leading to inactivation of ERK1/2 signaling pathway Infection and Malignancy
The risk of viral infection in ABO ic Tx is high as CMV, HSV, VZV, and BK virus, and P. jirovecii pneumonia, as well as wound, and severe urinary tract infections.
Studies did not reveal an increased risk of malignancy in ABOi c compared to ABOc patients
ABO ic cases are at higher risk of hemorrhage compared to ABO c cases due to repeated IA
ABO ic cases are at higher risk of surgical complications compared to ABO c cases
-Ex vivo infusion of endo-beta-galactosidase is a new method to decrease blood group Ag level.
-Kidney exchange program is a strategy to avoid ABO antibody barrier
Conclusion
ABO ic Tx is common now meanwhile those patients are exposed to higher risk of early rejection, infection, and infection-associated death.
Abdul Rahim Khan
3 years ago
ABOi- KT was historically considered as a contraindication to renal transplantation. Weith the development of strategies to overcome ABO antibody barriers ABOi- KT is now a reality and an option due to organ shortages. ABOi- KT survival rates are comparable to ABOc- KT. ABOi- KT requires desensitization which can be achieved by apheresis and B cell depletion therapy like Rituximab . Antibodies are aimed to be below a certain threshold at the time of transplantation an d 2weeks post surgery. There after accommodation plays an important role in graft survival.
Blood group antigen system is important in kidney transplantation . These antigens are found at RBCs, Kidney endothelial cells , tubules and glomeruli. Anti A/B antibodies are IgM. For blood group O, these area also IgG and IgA.
Desensitisation for ABOi- KT
One or more of the following along with strong immunosuppression.
1-Anti A/B depletion at the time of transplant using PP( Plasmapheresis) ,Double filtration Pp/membrane filtration or selective or unselective immunoadsorption – IA
2- IVIG for recipient immune system modulation
3- B cell depletion by Splenectomy or anti CD 20- Rituximab
4- Prevention of consequences of compliment activation upon anti A/B antibody binding to graft endothelium.
Antibody depletion by extracorporeal treatment
PP is preferred in US and membrane separation is used in Japan
IVIGs
These are given in before ABOi transplant to prevent rebound of Anti A/B antibodies in early phase post transplant. IVIG preparation contain IgG antibodies against A/B antigens and can increase anti A/B antibody titres upon administration.
B cell depletion- Splenectomy or Rituximab
Splenectomy has now been replaced by Rituximab. Higher death censored if Rituximab is omitted.
Inhibition of compliment activation
The results were not conclusive using Eclizumab
Accommodation
Usually occurs in ABOi -KT and can associated withC4d staining.
Complications
Higher incidence of infections lke CMV, HSV, VZV, BK Virus, UTIs and P jirovecii pneumonia
Manal Malik
3 years ago
Summary of ABO-Incompatible Kidney Transplantation Introduction
ABOi-KT reduce the wating time in the transplantation.
In presence of protocol as many as 90% of patients with ABOi living donor effectively be desensitized and transplant.
Achieve reduction and maintain of antibodies during first 2 week of transplant by desensitization below a threshold that is consisted to be safe e.g <1:32 in tube technique.
BLOOD GROUP ANTIGENS AND ANTIBODIES
ABO Ag system important for kidney transplant as is presence in endothelial .tubule and glommulari
As well as RBCs.
Anti A/B antibodies are IgM class but blood group O consist of IgG ana IgA. DESENSITIZATION FOR ABOi KIDNEY TRANSPLANTATION
Common principles for different protocol for ABOi-KT:
These include together a powerful maintained immunosuppression one or more of the following:
(1)Anti-A/B antibody depletion at the time of transplantation using PP, double-“filtration PP/membrane “filtration, or selective or unselective immunoadsorption (IA) .
2)Modulation of the recipient’s immune system by the use of intravenous immunoglobulins (IVIgs) (3)Reduction of the B lymphocyte pool by splenectomy, or more recently by antiCD20 anti body rituximab.
(4) Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the endothelium. Antibody Depletion by Extracorporal Treatment
Antibodies strategies there are methods:
1-method completely plasma proteins1` such as PP ,
2-method remove only specific fraction of the plasma proteins include the immunoglobulin;
3-selective or unselective1A
Unselective more effective to remove anti A/B IgG
Selective more effective for removal IgM anti A/B antibodies.
Over all methods no significance difference in reduction anti A/B antibodies ,survival ,kidney function, rejection and complication.
. Intravenous Immunoglobulin
To prevent the antiA/B rebound in early transplant
Decrease infectious complication by replace depleted immunoglobulin.
. B-Cell Depletion by Splenectomy or Rituximab
Before anti Bcell thearpies splenectomy was performed as to reduce B lymphocytes pool prior to ABOi-KT.
Anti CD20 antibodies rituximab
Higher rate of death and graft loss if rituximab not used in protocol of ABOi -TK. Inhibition of Complement Activation
Inhibition of complement activity up binding of antibodies to the allograf t,endotheial,it will overcome ABOi -KT barrier.
Single centre study to evaluate the effectivity of eculizumab added to conventual therapy in prevention of antibody mediated rejection.in ABOi- KT living donor. The use of eculizumab inconclusive. Desensitization protocol
Rituximab(antiCD20 Abs ) replace splenectomy recently
PP and low dose of IVIG so the incidence of graft loss on first year is less than ABOc -KT .
A study from the UK showed similar death-censored graft survival in first year less than ABOi-KT is reduce due to infection complication mostly pneumocystis jiverci. pneumonia as these due to intensify immunosuppression such as Rituximab. Result
Patients were compared to match group ABOc -KT in large study so outcome over all graft .death and patient survival were not statistically significant different. COMPLICATIONS AND HURDLES OF ABOi KIDNEY TRANSPLANTATIO
Accommodation versus Rejection
Accommodation frequent phenomena after ABOi -KT and associated with c4d deposition in PTC of all graft biopsy.
Local up regulation of complement regulators proteins like CD45,CD55,and CD54 as consequence of anti A/B ab -dependent inactivation of ERK1/2 signalling pathway are discussed as one possible mechanism. Infection and Malignancy
After ABOi -KT there are conflict result regarding infectious complication in the literature.
Higher frequency of viral infection (CMV.HSV,VZV and BK virus) as well as P.Jirrveveci pneumonia
Wound and sever UTI.
Cancer risk is not found to be higher compared ABOi -KT to match ABOc controls. Additional Observations
In ABOi transplantation a higher risk of bleeding and correlate to the number of pre transplant aphaeresis treatment and peri and post transplant bleeding risk
Higher risk of surgical complication such as lymphocele CONCLUSION.
Recently ABOi-KT has became a routine procedure.
ABOi-KT signals expand the living donor pool.
Presence of ABOi -KT however patient has high risk of rejection .infection and infection associated death .where ever possible ABOi procedures should be preferred.
mohamed hefzy
3 years ago
ABO-incompatible (ABOi) kidney transplantation has long been considered a contraindication to successful kidney transplantation. During the last 25 years, increasing organ shortage enforced the development of strategies to overcome the ABO antibody barrier. In the meantime, ABOi kidney transplantation has become a routine procedure with death-censored graft survival rates comparable to the rates in compatible transplantations. Desensitization is usually achieved by apheresis and B cell-depleting therapies that are accompanied by powerful immunosuppression. Anti-A/B antibodies are aimed to be below a certain threshold at the time of ABOi kidney transplantation and during the !rst 2 weeks after surgery , Pneumocystis jirovecii pneumonia, and severe urinary tract infections are increased after ABOi transplantations
BLOOD GROUP ANTIGENS AND ANTIBODIES
ABOi kidney transplantation with A2 organs has been accomplished with standard immunosuppressive therapy without any additional measures . anti-A/B antibodies are formed upon contact with gut bacteria during early infancy. Naturally occurring anti-A/B antibodies are predominantly of the IgM class but especially in blood group O individuals they also consist of IgG and IgA class . While the pathogenic importance of anti-A/B antibodies in solid organ transplantation is well known, the relative contribution of the different immunoglobulin isotypes and their subclasses to organ rejection remains to be elucidated.
DESENSITIZATION FOR ABOi KIDNEY TRANSPLANTATION
These include together with a powerful maintenance immunosuppression one or more of the following:
(1)Anti-A/B antibody depletion at the time of transplantation using PP, double-filtration PP/membrane filtration, or selective or unselective immunoadsorption (IA)
(2)Modulation of the recipient’s immune system by the use of intravenous immunoglobulins (IVIgs)
(3)Reduction of the B lymphocyte pool by splenectomy, or more recently by the anti-CD20 antibody rituximab
(4) Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the graft endothelium.
Antibody Depletion by Extracorporal Treatment
PP is the preferred antibody removal strategy in the US, membrane separation is popular in Japan. Unselective and selective IAs are often used in Europe
Intravenous Immunoglobulins
are given before ABOi kidney transplantation to prevent the anti-A/B antibody rebound in the early phase after transplantation. In addition, IVIg infusion is believed to reduce infectious complications . But IVIg preparations contain IgG antibodies directed against A/B antigens and can effectively increase anti-A/B antibody titers upon administration .
B-Cell Depletion by Splenectomy or Rituximab
Before the introduction of pharmacological anti-B cell therapies, splenectomy was an integral component for the reduction of the B lymphocyte pool prior to ABOi kidney transplantation. Due to the surgical risk and increased risk of sepsis, splenectomy was gradually substituted by the anti-CD20 antibody rituximab. More recently, several groups completely abandoned anti-B cell therapies from their protocols. Transplantation was accomplished by the use of standard immunosuppressive therapy without rituximab when the patient had reached an anti-A/B antibody titer of less than 1:32 (tube method). We observed in the Collaborative Transplant Study (CTS) a higher rate of death-censored graft loss in ABOi kidney transplant recipients when rituximab was omitted .
Inhibition of Complement Activation
An emerging new concept in the transplantation across ABO antibody barriers is the inhibition of complement activation
DESENSITIZATION PROTOCOLS AND SURVIVAL AFTER ABOi LIVING DONOR KIDNEY TRANSPLANTATION
Most patients were desensitized by PP and lowdose IVIg , splenectomy was replaced by the antiCD20 antibody rituximab
COMPLICATIONS AND HURDLES OF ABOi KIDNEY TRANSPLANTATION
Accomodation versus Rejection
Infection and Malignancy .
Sherif Yusuf
3 years ago
Blood group antigens are present not only in RBCS but also in the endothelial cells and they include A, B, AB, O
Patient with blood group A has antibodies against B antigen, while those with blood group B has anti -A antibodies
Individuals with blood group O has no antibodies so they are universal donors, on the other hand, patients with blood group AB are universal recipient.
Blood group A is subdivided into A1 and A2. A2 antigen is less common accounting for 20 % of white race individuals with blood group A, and is less expressed on RBCS than A1 so recipients with anti-A sera ( those with blood group B, O) can receive kidney from donors with blood group A2 if anti-A sera is low. In other words individuals with blood group A2 can serve as universal donors but only if the titre of antibodies is low
Measurement of antibodies
Used to asses the feasibility and duration required of desensitization and to monitor antibodies post transplantation to anticipate rejection
The most commonly used is tube method
Titre > 1/256 is considered high by most centres while acceptable level pre transplantation vary between 1/4 to 1/32 and this level should be maintained through out the first 2 weeks
Monitoring of antibodies post-transplantation is crucial to anticipate rejection if there is a rebound of antibodies, but duration of monitoring is not known
Desensitization protocol
1- B cell depletion
Using either splenectomy which now is replaced by rituximab due to its side effects including infection with encapsulated organisms and surgical complications
Rituximab produce splenic B cell depletion but spares plasma cells since they contain no CD20 receptors, thus its benefit till now is uncertain
2- Antibodies depletion
Plasmapheresis (provide 1 fold titre reduction per session)
Immunadsorption IA (produce 2-4 fold titre reduction per session)
3- IVIG
IVIG is usually given in low dose after plasmapharesis
It acts as immunomodulator through blocking Fc receptors , so it prevent the rebound increase in antibody by plasma cells, moreover IVIG aid in replacement of immunoglobulins that are removed during PE or IA
On the other hand, IVIG may contain anti A, B antibodies which may impact the graft, especially if using high dose IVIG
Immunosuppression
Induction using either basiliximab or ATG according to other risk factors
Maintenance using CNI better tacrolimus, MMF started 7-14 days before transplantation, steroids ( steroid withdrawal is debatable)
Rejection
There is significant increase in the risk of ABMR but not acute CMR in patients with ABOi transplantation
Accommodation of the graft can occur after the first 2 weeks of transplantation due to a change in the nature and affinity of antibodies with a subsequent increase in antibodies but with no associated ABMR
Diagnosis requires both the presence of histological features of ABMR and the presence of antibodies, C4d can be present in biopsy with no features of ABMR ( due to accommodation) thus the significance of C4d standing is less in ABO I transplantation
Surgical complications
Bleeding is the most common surgical complications related to ABO I transplantation due to removal of clotting factors by plasmapharesis
Moreover lymphoceles occur more frequently in ABOi transplantation due to unclear cause.
Infection
There is an increase in the risk of infections and sepsis in ABOi when compared to compatible transplantation including pneumonia, UTI, wound infection, PCP, CMV and BK virus, which may be attributed to the use of rituximab[28,30,51,55]
So it is important to administer antimicrobial prophylaxis against Pneumocystis pneumonia (PCP), together with Antiviral prophylaxis according to CMV status
Malignancy
No increase in the risk of malignancy was observed in ABOi when compared to ABO c transplantation despite desensitization and aggressive immunosuppression
Cost
ABO I transplantation is expensive, it is estimated that the cost of ABOi transplantation over 20 years is 15% lower than dialysis, thus it is considered cost-effective when compared to dialysis
Ibrahim Omar
3 years ago
Summarise this article :
ABO incompatible kidney transplantation (ABOi-KT) has been contraindicated during the last 25 years due to the possible risk of hyperacute rejection and immediate graft loss.
paired kidney donation has resolved some of the problem of incompatibility but it finally resulted in accumulation of kidney grafts of blood group O+ve in the donor pool.
due to the growing problem of organ shortage, ABOi-KT has been successfully tried with intensive immunosuppression including desensitization protocols.
30 % of living donors who were previously refused due to incompatibility can donate now and this has expanded the donor pool.
desensitization protocols include B-cell depleting agents accompanied by powerful immunosuppression. anti-A/B antibodies are aimed to be below certain threshold during transplantation and for 2 weeks after the procedure.
after the 1st 2 weeks, even with a rebound of antibodies, graft injury is not expected owing to accommodation.
with the intensive immunosuppression, the risk of infection will be increased as severe UTI and also pneumocystitis Jerovicii pneumonia (PJP). recent data revealed an increase of 1% in mortality due to extra infection.
some authors observed an increase in the surgical complications due to 2 main factors. the 1st is the poor healing associated with intensive immunosuppression especially with MMF. the 2nd is the removal of coagulation factors with plasmapharesis used in desensitization. there was an increase of 20 % in lymphocele requiring surgical revisions.
finally, there are some new strategies that may come into clinics in the future. these strategies include reduction of blood group antigen levels in allograft by ex viva infusion of endo-beta-galactosidase.
Ban Mezher
3 years ago
After introduction of desensitization, ABOi transplantation became feasible with comparable outcome to ABOc transplantation. Desensitization aimed to reduce & maintain of anti-A/B Abs in first 2 weeks post transplantation below safe level ( <1:32 in tube method).
ABO Ag is very important in renal transplant because it expressed on RBC, endothelial cells, tubule & glomeruli. ABO Ag expression differ between ABO Ags e.g. A2 Ag expression very low ( low immunogenicity) compared to A1 & B Ags .
There was no standardized desensitization protocol for ABoi recipients, but usually it include high maintenance immunosuppression in addition to one of the following:
Anti-A/B Abs depletion at time of transplantation by PP, DFPP or IA.
IVIG to modulate recipient immune system
Rituximab ( previously splenectomy) to reduce B cells pool
prevention of complement activation.
Abs remaval techniques divided into completely removal of plasma protein e.g. PP or removal of specific portion of plasma protein e.g. membrane separation or selective or non selective IA. There was no significant difference between these techniques regarding Abs reduction, survival, renal function, rejection or complication.
IVIG can be given to prevent Abs rebound in early post transplant period & it may reduce infectious complications. To deplete B cells previously done by splenectomy but now replaced by anti-CD20 rituximab. But ABOi transplantation can be done without using rituximab if Abs titer <1:32 ( by tube methods) without increased risk off graft loss. The result of complement inhibition (eculizumab) in desensitization of ABOi transplantation was inconclusive.
Accommodation is a frequent phenomenon occur in ABOi transplantation & usually associated with C4d positive staining without evidence of AMR even if Ab titer high ( non harmful).
It was found that patient & graft outcome of ABOi transplant were comparable C. jirvecii, BK virus & multi drug resistant bacteria.
Ex-vivo infusion of eddo-beta- galactosidase is a new strategy can be used in future to reduce blood group Ag in graft.
Riham Marzouk
3 years ago
Transplantation from ABO incompatible donor became safe and available in order to increase donor pool and decrease waiting time to stay on dialysis and to shorten the waiting list of NDD and DCD.
ABO antigens are glycoproteins expressed on RBCs, epithelial and endothelial cells. They are 4 groups; A, B, AB, and O.
A group has A antigen and anti-B antibody, B group has B antigen and anti-A antibody, AB has A and B antigen and has no antibody, O group has no antigen and has anti-A and anti-B antibodies.
A group has two phenotypes A1 that is more antigenic and A2, which resemble O group, has no antigens.
In the renal system, ABO expressed on distal and collecting tubules and vascular endothelial cells, when expressed heavily, it is responsible for acute rejection attack.
The reaction of antibody or isoagglutinins with these glycoproteins will lead to complement activation and c4d deposition.
The first trial of transplantation from ABO incompatible donor was done in Japan.
TECHNIQUES OF ABO DESENSITIZATION AND DIFFERENT PROTOCOLS USED OVER TIME:
1- Removal of antibodies by apheresis ; plasma exchange with high permeable filter is less cost, available to remove antibodies by 20% every session, the main concern is its complications as it is non selective removes also clotting factors and other antibodies, so we can do plasmapheresis using double filter as the second filter allows the return of small important molecules try to avoid the complications, also we can use another adding filter or column to selectively IgG which is called immunoadsorption to avoid complications of removal of all antibodies.
2- Immunomodulation using IVIG post plasmapheresis session to replenish the removed beneficial antibodies.
3- Rituximab antiCD20 antibody, is medical splenectomy, it depletes B cells, which are responsible for antibody production.
There is no standard protocol for desensitization prior to transplantation, but in general, we can give rituximab 2 weeks prior to transplantation and do plasmapheresis 4 sessions 1 week before operation and continue it for another 3-4 sessions post transplant, tacrolimus ,MMF and steroid were given from 2-7 days prior to transplantation, keeping trough level of tacrolimus from 12-15 ng/ml.
CLINICAL OUTCOMES AFTER RENAL TRANSPLANTATION INVOLVING ABOI
Mortality in the patients transplanted from ABO incompatible donor is higher at 1, 3 and 5 years post-transplant than the patients transplanted from ABO compatible donor, this mostly related to side effects of heavy immunosuppression given to these patients like infections either bacterial and viral like BK virus, coagulation side effects.
Accommodation:
C4d deposition in absence of any signs and symptoms of AMR, so, this because of accommodation of the graft to that level of antibodies without making graft injury.
BLOOD GROUP ANTIGENS AND ANTIBODIES
ABO antigen system consists of oligosaccharides that are
predominantly expressed on red blood cells and are also found on endothelial cells, tubuli, and glomeruli.
Compared to blood group A1 and blood group B individuals, blood group A2 recipients have a low expression of blood group antigen molecules (30–50%) on the surface of erythrocytes.
Naturally occurring anti-A/B antibodies are predominantly of the IgM class but especially in blood group O individuals they also consist of IgG and IgA class.
DESENSITIZATION FOR ABOi KIDNEY TRANSPLANTATION
powerful maintenance immunosuppression one or more of the following:
(1)Anti-A/B antibody depletion at the time of transplantation
using PP which removes all plasma proteins, double filtration PP/membrane filtration which remove only a specific fraction, or selective or unselective immunoadsorption (IA)
single treatments with unselective IA to be more effective than with selective anti-A/B antibody columns in removing anti-A/B IgG.
unselective IA was less effective in the removal of anti-A/B antibodies of the IgM and IgG3 subclass
(2)Modulation of the recipient’s immune system by the use of intravenous immunoglobulins (IVIgs)
IVIg preparations contain IgG antibodies directed against A/B antigens and can effectively increase anti-A/B antibody titers upon administration.
(3)Reduction of the B lymphocyte pool by splenectomy, or more recently by the anti-CD20 antibody rituximab.
Collaborative Transplant Study (CTS) a higher rate of death-censored graft loss in ABOi kidney transplant recipients when rituximab was omitted.
(4) Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the graft endothelium.
results on the use of eculizumab after ABOi kidney transplantation are inconclusive.
the Japanese data shows that from 2001 to 2010, patient and graft survival rates for the 1,427 analyzed patients were an excellent 98 and 96% for the first year, and 91 and 83% after 9 years, respectively.
A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound, and severe urinary tract nfections have been described in the aboi transplant cohort.
significant correlation between the number of pretransplant apheresis treatments and the peri- and posttransplant bleeding risk.
increased rate of surgical complications after ABOi kidney transplantation was found.
Summary of the article:
ABO incompatibility was considered as an absolute contraindication to transplantation. The shortage in donated organ and development in the transplant management pre and post the procedure, pushed toward acceptance of this risky process after certain and special techniques being accomplished to minimize the risk of rejection. Graft survival rate in ABOi transplantation was found to be comparable to that in compatible transplantation.
Blood group Antigens and Antibodies
· The ABO antigen system consists of oligosaccharides.
· They are predominantly expressed on red blood cells and are also found on endothelial cells, tubuli, and glomeruli making the ABO antigen system important for kidney transplantation.
· Blood group A2 recipients have a low expression of blood group antigen molecules (30–50%) on the surface of erythrocytes, which is believed to be responsible for the lower immunogenicity of organs from blood group A2 donors.
· Naturally occurring anti-A/B antibodies are predominantly of the IgM class but especially in blood group O individuals they also consist of IgG and IgA class
Desensitization for ABOi kidney transplantation
Currently proposed strategies share some common principles, together with a powerful maintenance immunosuppression:
1. (1) Extracorporeal therapy for depletion of Anti-A/B antibody.
2. (2) Modulation of the recipient’s immune system by the use of intravenous immunoglobulins (IVIgs)
3. (3) Reduction of the B lymphocyte pool by splenectomy, or more recently by the anti-CD20 antibody rituximab.
4. Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the graft endothelium.
Antibody depletion by extracorporal treatment
No significant differences were found in clinical studies that compared the impact of different IA strategies on clinical outcomes, including anti-A/B antibody reduction, survival, kidney function, rejection episodes, or complications Antibody removal strategies may be divided into:
· Complete removal of plasma proteins via PP.
· Removal of specific fraction of plasma protein via membrane separation or via more specific method as unselective or selective IA.
· Combination of membrane separation and unselective IA.
Intravenous Immunoglobulins
· It helps prevent the anti-A/B antibody rebound in the early phase after transplantation.
· It reduces infectious complications by substituting depleted immunoglobulins.
· As a note of caution; may increase anti-A/B antibody titers upon administration.
B-Cell Depletion by Splenectomy or Rituximab
· Splenectomy reduces the B-lymphocyte pool. Associated with surgical risk and high risk of infection.
· Anti-B cell therapy as Rituximab reduces lymphocyte pool.
Inhibition of Complement Activation
· The use of Eculizumab was successful in treating anti-A/B antibody rebound. But other study declared that the results on the use of eculizumab after ABOi kidney transplantation are inconclusive.
Desensitization protocols and Survival after ABOi living donor kidney transplantation:
In comparison to ABOc transplantation;
· the rates for antibody- and T-cell-mediated rejections were anot significantly different.
· Similar death-censored graft survival as being showed by study from UK.
· Patient survival in ABOi transplant recipients was reduced due to infectious complications, mostly Pneumocystis jirovecii pneumonia.
Complications and Barriers of ABOi transplantation:
· Accommodation versus Rejection; accommodation appears to be a frequent phenomenon after ABOi kidney transplantations and is often associated with C4d deposi- tion in peritubular capillaries of allograft biopsies.
· Infection; A higher frequency of viral infection ssuch as CMV,HSV,VZV,and BKvirus, as well as P. jirovecii pneumonia, wound, and severe urinary tract infections have been described . The rate of BK virus nephropathy was about three times higher in ABOi patients compared to patients with HLA antibodies.
· Malignancy; No increased cancer risk when comparing ABOi kidney transplant recipients to matched ABOc controls.
· Higher risk of early hemorrhage.
For long time, the ABO-incompatible (ABOi) kidney transplantation was considered a contraindication to successful kidney transplantation.
The solution for the increasing number of ESRD patients with more time in waiting list is to seek for strategies to overcome the ABO antibody barrier.
Nowadays, after development of de-sensitization protocols , the transplantation against ABO barrier can be done and it showed a comparable graft survival with ABOc- transplantation.
Blood group antigens and antibodies
ABO antigen system crucial for kidney transplantation,as its antigens are expressed on red blood cells and are also found on endothelial cells, tubuli, and glomeruli.
Anti-A/B antibodies are predominantly of the IgM class but in blood group O individuals they also consist of IgG and IgA class.
Desensitization for ABOi kidney transplantation
There is no generally accepted desensitization guidelines
Results from the CTS
Study 3-year outcomes of 1,420 ABOi kidney transplant recipients who were transplanted at 101 different centers between 2005 and 2012 showed that the overall graft, death-censored graft, and patient survival were not statistically significant different between ABOi recepients and their matched group of ABOc kidney transplant recipients,but early patient survival was reduced in ABOi kidney transplant recipients due to a higher rate of early infection-associated death versus matched controls.
Complications of ABOi kidney transplantation
Accommodation versus Rejection
About 2 weeks after successful transplantation, accommodation is established and even high anti-A/B antibody exposure does not harm the kidney transplant. Local up-regulation of complement regulatory proteins, like CD45, CD55, and CD59, as a consequence of anti-A/B antibody-dependent inactivation of ERK1/2 signaling pathway are discussed as one possible mechanism.
Infections
A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus,as well as P. jirovecii pneumonia, wound, and severe urinary tract infections have been detected i n ABOi kidney transplantation versus ABOc kidney transplantation.
Malignancy
studies show no an increased risk of malignancy in ABOi compared to ABOc patients
ABO-Incompatible Kidney Transplantation
Introduction
ABO-incompatible (ABOi) kidney transplantation has long been considered a contraindication to successful kidney transplantation but due to the accumulation of the waiting list, many studies evolved in previous decades about ABOi tx as still transplantation is he best modality of renal replacement therapy for the patients with end stage renal disease. Therefore, desensitization protocols used to try to overcome this challenge, the aim of desensitization protocols is the reduction and maintenance of anti-A/B antibodies (isoagglutinins) during the “first 2 weeks after transplantation below a threshold that is considered to be safe (e.g., <1:32 in tube technique). Even when anti-A/B antibodies recur at high levels they will not harm the kidney transplant, a phenomenon that is called accommodation. In recent years, graft survival rates after ABOi kidney transplantation nearly equaled those afterABO-compatible (ABOc) procedures.
BLOOD GROUP ANTIGENS AND ANTIBODIES
Compared to blood group A1 and blood group B individuals, blood group A2 recipients have a low expression of blood group antigen molecules (30–50%) on the surface of erythrocytes, which is believed to be responsible for the lower immunogenicity of organs from blood group A2 donors. ABOi kidney transplantation with A2 organs has been accomplished with standard immunosuppressive therapy without any additional measures.
DESENSITIZATION FOR ABOi KIDNEY TRANSPLANTATION
These include together with a powerful maintenance immunosuppression one or more of the following:
(1) Anti-A/B antibody depletion at the time of transplantation using PP, double-filtration PP/membrane filtration, or selective or unselective immunoadsorption (IA)
(2) Modulation of the recipient’s immune system by the use of intravenous immunoglobulins (IVIgs)
(3) Reduction of the B lymphocyte pool by splenectomy, or more recently by the anti-CD20 antibody rituximab
(4) Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the graft endothelium.
A) Antibody Depletion by Extracorporal Treatment
Antibody removal strategies may be divided into methods that completely remove plasma proteins such as PP, methods that remove only a specific fraction of the plasma proteins including the immunoglobulins (such as membrane separation), and more specific methods such as unselective or selective immunoadsoption; IA
B) Intravenous Immunoglobulins
It is used to reduce anti A/B abs in first 2 weeks post transplant and also to reduce the potential infection complications of PP , As a note of caution, IVIg preparations contain IgG antibodies directed against A/B antigens and can effectively increase anti-A/B antibody titers upon administration.
C) B-Cell Depletion by Splenectomy or Rituximab
Before the introduction of pharmacological anti-B cell therapies, splenectomy was an integral component for the reduction of the B lymphocyte pool prior to ABOi kidney transplantation. Due to the surgical risk and increased risk of sepsis, splenectomy was gradually substituted by the anti-CD20 antibody rituximab
D) Inhibition of Complement Activation
New concept using eculizumab but still the studies are inconclusive.
COMPLICATIONS AND HURDLES OF ABOi KIDNEY TRANSPLANTATION
In contrast to transplantation in the HLA-sensitized patient, accommodation appears to be a frequent phenomenon after ABOi kidney transplantations and is often associated with C4d deposition in peritubular capillaries of allograft biopsies. An accommodation phenotype may be achieved by the controlled anti-A/B antibody exposure to antigens in the early phase after kidney
transplantation. About 2 weeks after successful transplantation, accommodation is established and even high anti-A/B antibody exposure does not harm the kidney transplant. Local upregulation of complement regulatory proteins, like CD45, CD55, and CD59, as a consequence of anti-A/B antibody-dependent inactivation of ERK1/2 signaling pathway are discussed as one possible mechanism.
Infection and Malignancy and other complications
Studies have shown that there is higher risk of infection especially viral infection in ABOi tx more than ABOc tx while no increase in the malignancy in both groups .
In ABOi there is higher risk of
– Bleeding: which was attributed to the unspecific binding of coagulation factors during repeated IA and there is correlation between the number of pretransplant apheresis treatments and the peri- and posttransplant bleeding risk
– an increased rate of surgical complications after ABOi kidney transplantation, which were attributed to early intensified immunosuppression with mycophenolic acid and removal of coagulation factors by apheresis
Blood group antigens are present on the RBCS and on the endothelial cells and they include A, B, AB, O .
Individuals with blood group O has no antibodies so they are universal donors, While with AB are universal recipients.
The first 2 weeks are the most important in measuring the antibodies levels .
Titre > 1/256 is considered high by most centres while acceptable level pre transplantation vary between 1/4 to 1/32.
Desensitization protocols include Rituximab , PTx , IVIG , induction by ATG or Simulect according to the risk
There is increased risk of ABMR in the first 2 weeks of transplantation.
Diagnosis is based on the presence of histological features of ABMR and the presence of antibodies ( C4d can be present in biopsy with no features of ABMR ) .
Summary:
introduction:
ABO antigens structure of oligosaccharide protein which mainly expressed in RBC, endothelial cells, epithelial cells, tubules and glomerulus which is very important in kidney transplantation
ABOI kidney transplant earlier considered as an absolute contraindication for kidney transplant and associated with hyper-acute rejection due to anti A/B antibodies but with the introduction of desensitization protocol since last 25 years the access to ABOi transplant increased with similar outcome to ABO c kidney transplant it helps in expanding the pool of the donors and shortening the waiting list with better survival compared to waiting on dialysis blood group A2 found in about 20% of the white population and less antigenic expression in RBCS so less immunogenic compare to A1 group, so ABOi Kidney transplant from A2 blood group requiring only standard IS without desensitization while anti A/B antibodies including IgM and IgG, immunoglobulin and their pathogenic importance in known in sold organ transplantation with more antigenic density and expression in RBCS.
Desensitization protocols evolving over time not yet standardized and each center have their own protocols based on local experience and available resources, and most of the evidence based on observational trails no RCT yet available
By principle of desensitization protocol aims for antibodies removal to the acceptable value at the date of transplantation also avoid further production of ABS by using immunomodulating agent like IVIG with B cell depleting agents earlier surgical elective splenectomy and recently replace by antiCD20 RITUXIMAB to allow the transplantation and avoid rebound in the first two weeks post-transplant and allowed for graft accommodation after that combination therapy preferable including plasmapheresis 3-5 sessions 10-14 days prior to transplant the therapeutic plasmapheresis each session can remove 30% of IgM abs and 20% of IgG anti B/A abs
IA kind of more selective removal of anti IgM, IgG abs more available in Europe
All kinds of therapeutic plasmapheresis aim for antibodies removal, nonselective or selective all does not show any impact on the graft survival and all associated with the risk of AB rebound post-transplant and AMR so need close monitoring of the ABS titer early post-transplant for the first few weeks. IVIG low dose or high dose used in combination with plasmapheresis to prevent the ABS rebound also replace the Igs removed during plasmapheresis and reduce the rate of infections
B cell depleting agents:
Splenectomy which nowadays replaced by medical therapy with rituximab as its associated with more surgical and infection complication, even rituximab anti CD20, act as B cells depleting agent associated with higher rate of infection and some centers remove it from desensitization protocols or using lower doses of 100-200mg /M2 instead of 375g/m2
CTSs shows higher rate of death censored graft loss death in ABOI KTX without rituximab.
Inhibition of Complement Activation
Eculizumab anti c5 complement monoclonal ABS used for prevention of complement mediated ABMR and one pilot study show s inconclusive results, in addition its use limited due to the high cost .the ABO I kidney transplant graft and patient survival was similar to the control groups of ABOc KTX based on the available evidence from different observational studies from different centers in Europe and Japan which most shows similar graft and death censored graft loss in one year and 3 years and even 9 years in one study , but in some studies shows that the graft survival can be affected earlier post-transplant due to increased rate of infections including BKV nephropathy , bacterial infections like PJP and MDR bacteremia due to intense immunosuppression with desensitization protocol especially with rituximab use .
ABOI kidney transplant did not increased the rate of malignancy based on the available evidence
Accommodation versus Rejection:
Accommodation commonly occurs in ABOi KTX sensitized recipients which characterized by C4D staining but without evidence of acute graft injury.
ABO incompatibility was considered an absolute contraindication to kidney transplantation until 1982 when successful desensitization done together with intensified immunosuppression.
The ABO antigens are expressed not only on RBCs but also on endothelial, tubular, and glomerular cells. Density of antigens on erythrocytes differ between different blood groups and patients with blood group A2 makes up 20% of blood group A in Caucasian individuals have lower immunogenicity compared to blood group A1 or B, so kidney from A2 donor can be transplanted with standard immunosuppressive therapy without any additional measures. To overcome shortage of donors, strategies to manage ABOi living transplantation has been developed.
Different desensitization protocols are used aiming to reduce anti-A/B antibodies below a threshold that is considered to be safe (e.g., <1:8) especially during the first 2 weeks post transplantation
Desensitization for ABOi kidney transplantation consist of one or more of following:
(1)Anti-A/B antibody depletion at the time of transplantation using PP, double-filtration PP/membrane filtration, or selective or unselective immunoadsorption (IA) .IA could be selective and non –selective.
Non selective IA is more effective in removing A/B IgG than selective IA but unselective IA is less effective in removing A/B IgM
(2) Modulation of the recipient’s immune system by the use of intravenous immunoglobulins (IVIgs)
(3) Reduction of the B lymphocyte pool by splenectomy, or more recently by the anti-CD20 antibody rituximab.
(4)Inhibition of Complement Activation :The use of eculizumab as an inhibitor to membrane attacking complex is controversial
DESENSITIZATION PROTOCOLS AND SURVIVAL AFTER ABOi LIVING DONOR KIDNEY TRANSPLANTATION
The cumulative incidence of graft loss during the first year after transplantation was 5.9% in ABOi as compared to only 2.9% in ABO compatible transplantations. Early recognition and prompt action is crucial for graft survival for ABOi kidney transplantation. A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound, and severe urinary tract infections and higher bleeding risk have been described.
CONCLUSION:
In conclusion, ABOi kidney transplant significantly expand the living donor pool by 30%.However,ABOi transplantation carried a higher risk of early rejection, infection, and infection-associated death. Therefore, ABO compatible transplantation should be done whenever possible
ABO-Incompatible Kidney Transplantation.
Desensitizing strategies and early recognition of complications are the keys for successful for ABO-incompatible (ABOi) kidney transplantation. Effective desensitization protocols ensure the reduction and maintenance of anti-A/B antibodies within the recommended range of <1:32 in tube technique during the first 2 weeks after transplantation. The outcome of ABOi kidney transplant almost the same as ABO compatible kidney transplant even with the presentation of accommodation phenomenon.
Desensitization protocol include Anti-A/B antibody depletion by plasmapheresis or immunoadsorption (IA) , IVIG, B cell depletion by splenectomy or Rituximab, and preventive measures for complement activation. Splenectomy less commonly practice due to its surgical risk and future risk of sepsis as compare to Rituximab. Ex-vivo infusion of endo-beta-galactosidase is currently under clinical trial to serve as newer agent to reduce the blood group antigen levels in the allograft.
Early recognition and prompt action is crucial for graft survival for ABOi kidney transplantation. Possible complications include infection from CMV, HSV, VZV, and BK virus, P. jirovecii pneumonia, surgical wound infection, and severe urinary tract infection. There is a report stated that BK virus nephropathy was about three times higher in ABOi recipients. On the other hand, bleeding risk is high in a cohort of pediatric ABOi kidney transplant recipients due to the unspecific binding of coagulation factors during repeated IA. Malignancy risk remain controversial in ABOi kidney transplant.
In conclusion, ABOi kidney transplant significantly expand the living donor pool. However, we should be caution for the mortality risk due early rejections and infections secondary to intensified immunosuppressant. Thus, whenever possible, ABO compatible kidney should be the first choice in kidney transplantation.
ABO-Incompatible Kidney Transplantation
As the ESRD population increases, there is an increase in organ shortage resulting in waiting times for deceased donor kidney transplants exceeding 5 years in some countries. Transplantation across ABO antibody barriers is one possibility to reduce the waiting time. Kidney transplantation across ABO antibody barrier from a living donor can increase the number of kidney transplants by up to 30%. 90% of the patients with an ABOi living donor may be effectively desensitized and transplanted with the currently existing protocols.
Desensitization aimed to decrease and maintain the anti-A/B antibodies (isoagglutinin) below a threshold that is considered to be safe (> 1:32) during the first 2 weeks after transplantation. after that period, even when anti-A/B antibodies rebound to a high level, they will not harm the kidney transplant, a phenomenon called accommodation. The graft survival rate after ABOi kidney transplantation is nearly the same as that of ABOc transplantation.
Blood Group Antigens and Antibodies
The ABO antigens are expressed on RBCs and also on endothelial, tubular, and glomerular cells. different blood groups have different antigen densities on erythrocytes. Blood group A2 makes up 20% of blood group A in Caucasian individuals, it has low blood group antigen expression (30—50%)on the surface of the erythrocytes therefore, it is of lower immunogenicity as compared to group A1 and B. Kidney from A2 donor has been transplanted with standard immunosuppressive therapy without any additional measures.
The anti-A/B antibodies are formed during infancy upon contact with gut bacteria. They are mainly of IgM class, but in group O especially, they also formed of IgG and IgA class. The role of different subclasses in organ transplantation remains to be clarified.
Desensitization for ABOi kidney Transplantation
Although there are no standard desensitization protocols for ABOi transplantation, all currently designed strategies share some common principles.
In addition to powerful maintenance immunosuppression, the desensitization strategy includes one or more of the following:
1- Anti-A/B antibody depletion by PP, double-membrane filtration PP, or selective or unselective IA at the time of transplantation.
2- IVIG
3- B-cells depletion by splenectomy (historical), or by rituximab recently.
4- Prevention of the harmful effect of complement activation as consequence to binding of the anti-A/B antibody to graft endothelium.
Antibody depletion by extracorporeal treatment.
These are divided into:
1- Methods that completely remove plasma proteins (PP).
2- Methods that remove a specific fraction of plasma proteins including immunoglobulins (membrane separation)
3- Methods that are more specific such as unselective or selective IA.
There were no significant differences in clinical studies that compared the impact of different IA strategies on the clinical outcomes.
Intravenous Immunoglobulins (IVIG)
IVIG is given to prevent the anti-A/B antibody rebound in the early period post-transplantation. as well, to reduce the infectious complications by replacing the removed immunoglobulin.
B-cell depletion by splenectomy or Rituximab
Historically, splenectomy was done to reduce the B lymphocyte pool prior to ABOi kidney transplantation. due to surgical risk and increased infectious complications, splenectomy was replaced by the anti-CD20 antibody rituximab.
Results from the CTS
Overall, graft, death-censored graft, and patient survival were not statistically significantly different between the groups (ABOc and ABOi). Early patient survival was reduced in ABOi kidney transplant recipients due to a higher rate of early infection-associated complications.
Complications and hurdles of ABOi kidney transplantation:
Accommodation versus Rejection
Accommodation is a condition in which the graft biopsies show C4d deposition with no other signs of rejection in the presence of normal graft function. It occurs in the early period after kidney transplantation. it may be achieved by controlled exposure of the anti-A/B antibody to antigens. After 2 weeks of kidney transplantation, even a high level of anti-A/B antibody exposure will not harm the graft due to the accommodation.
Infection and Malignancy
There is a higher frequency of viral infections, as well as P. jirovecii pneumonia, wound infection and severe urinary tract infection. Although, there are conflicting results in the literature. This results in increased death in ABOi kidney transplant recipients. In a study by Sharif et al., the rate of BK virus nephropathy was about three times higher in ABOi patients compared with HLA antibodies. US Renal Data System registry found a higher risk of early hemorrhage in ABOi recipients when compared to ABOc recipients. This complication attributed to apheresis treatment. In addition, lymphoceles were reported significantly higher in ABOi recipients than in ABOc controls.
Future perspectives:
Reduction of blood group antigen levels in the allograft by ex vivo infusion of endo-beta-galactosidase is a promising new strategy.
PKD is another way to overcome ABO antibody barrier, although, blood group O patients are still difficult to transplant and they accumulate on the waiting list.
conclusion
ABOi kidney transplantation become possible recently. It increased the living donor pool by 30%. Transplantation of ABO-incompatible, however, carried a higher risk of early rejection, infection, and infection-associated death. Therefore, ABO compatible transplantation should be done whenever possible.
Introduction
ABO incompatibility was considered absolute contraindication to kidney transplantation until 1982 until successful desensitization together with intensified immunosuppression.
Desensitization:
The aim of desensitization protocols is the reduction and maintenance of anti-A/B antibodies during the first 2 weeks post transplantation below threshold to be considered safe.
Antibody Depletion :
Plasma Exchange or Imunoadsorption.
Intravenous Immunoglobulin
IVIG acting by decrease proliferation of B, T cells , inhibit CD8 , inhibit complement activation .
it is given to prevent the anti-A/B antibody rebound in the early period post-transplantation. as well, to reduce the infectious complications by replacing the removed immunoglobulin.
B-Cell Depletion by Splenectomy or Rituximab
Splenectomy which is obsolete and now replaced by Rituximab (anti CD20)
Inhibition of Complement Activation
Inhibition of complement activation by eculizumab, however, the use of eculizumab after ABOi kidney transplantation is inconclusive.
DESENSITIZATION PROTOCOLS AND SURVIVAL AFTER ABOi LIVING DONOR KIDNEY TRANSPLANTATION
Most patients were desensitized by PP and low-dose IVIG.
The cumulative incidence of graft loss during the first year after transplantation was 5.9% in ABOi as compared to only 2.9% in ABOc transplantations.
Patient survival in ABOi transplant recipients was reduced due to infectious complications, mostly Pneumocystis jirovecii pneumonia and BK virus .
Complications
Accommodation versus Rejection:
Infection and Malignancy: A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, higher incidence of BK virus .
ABO-incompatible kidney transplantation has been considered a contraindication for transplantation for a long time. Because of organ shortage, new strategies emerge for overcoming ABO antibodies barrier. With utilizing these strategies including apheresis and B-cell depleting therapies, accompanied by intensive immunosuppression, kidney transplantation survival in ABO incompatible transplants is comparable with ABO compatible patients.
By overcoming ABO barrier, the number of living donor kidney transplantation can increase by up to 30%, and about 90% of recipients with ABOi living donor may successfully be transplanted.
The aim of these therapies is to decline ABO antibodies below a threshold level (less than 1:32 in tube technique) at the time of ABOi kidney transplantation and within two weeks after kidney transplantation. It is approved that because of the phenomenon of accommodation even rebound in ABO antibodies are not associated with harm consequences in kidney transplantation. Although intensive immunosuppressive therapy may be related to increased risk of infections consist of BK virus replication and BK virus nephropathy, and colonization with multi-drug resistant bacteria.
Blood group antigens and antibodies
In addition to RBCs, ABO antigens are expressed on endothelial cells, tubules and glomeruli, thus they are important in kidney transplantation. Density of antigens on erythrocytes differ between different blood groups and patients with blood group A2 have lower antigen density on erythrocytes compared to blood group A1 or B. consequently, ABOi kidney transplant with A2 organ has been managed with standard immunosuppressive therapy. Anti AB antibodies are primarily of IgM class, but blood group O also consists of IgA and IgG classes.
Desensitization for ABOi KT
Other than powerful maintenance immunosuppression, desensitization for ABOi kidney transplantation consist of one or more of following:
(1) Anti-A/B antibody depletion at the time of transplantation using PP, double-filtration PP/membrane filtration, or selective or unselective immunoadsorption (IA)
(2) Modulation of the recipient’s immune system by the use of intravenous immunoglobulins (IVIgs)
(3) Reduction of the B lymphocyte pool by splenectomy, or more recently by the anti-CD20 antibody rituximab
(4) Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the graft endothelium.
Antibody depletion by extracorporeal treatment
Antibody removing strategies consist of PP, membrane separation, and unselective and selective IA.
Unselective IA is more effective in removal of anti AB IgG antibodies and less effective in removal of anti AB IgM antibodies compared to selective immunoadsorption.
Combination of unselective IA and membrane separation can effectively remove IgM, IgG and C1q complement components.
Intravenous immunoglobulins
IVIG is administered for prevention of anti AB antibody rebound early after kidney transplantation and reduce the probability of infictiins. Although it can increase anti AB antibody titers upon administration.
B-cell depletion by splenectomy or Rituximab
Prior to development of anti B cell therapies, splenectomy was considered for reduction of B cell pool. Splenectomy is mainly replaced by Rituximab. In recent studies B cell depletion therapy is eliminated from desensitization protocols, although it can be associated with higher risk of graft loss.
Inhibition of complement activation
Eculizumab has been utilized for inhibition of complement activation on endothelium in ABOi KT, but the results were inconclusive.
Desensitization protocols and survival after ABOi living donor kidney transplantation.
The results of ABOi KT including graft survival were comparable with ABOc KT in different studies by utilizing various desensitization protocols.
A recent meta-analysis of 101 different centers, comparing ABOi with ABOc KT, Overall graft, death-censored graft, and patient survival were not statistically significant different between the groups. Early patient survival was reduced in ABOi kidney transplant recipients due to a higher rate of early infection-associated death. Anti B-cell therapy was associated with better death-censored graft survival in the setting of ABO incompatibility.
Complications and hurdles of ABOi kidney transplantation
Accommodation versus Rejection
Accommodation in the setting of ABO incompatibility is related to C4d deposition in peritubular capillaries. An accom modation phenotype may be achieved by the controlled anti AB Antibodies to antigens interaction in the early phase kidney transplantation (About 2 weeks after successful transplantation). Local upregulation of complement regulatory proteins, such as CD45, CD55, and CD59 are proposed as a possible mechanism.
Infection, malignancy and bleeding risk
A higher incidence of viral infections such as CMV, HSV, VZV, and BK virus as well as P. jirovecii pneumonia, wound, and severe urinary tract infections have been reported, especially an increased risk for early severe infection and increased risk of infection associated death.
It is not reported increased risk of malignancy in ABOi compared to ABOc kidney transplantations.
Higher bleeding risk that was reported in ABOi kidney transplantation may be attributed to unspecific binding of coagulation factors during repeated IA. In addition, an increased rate of surgical complications such as lymphoceles were also reported, which may be due to early intensified immunosuppression.
Future perspective
Another emerging strategy is reduction of blood group antigen levels in the allograft by ex vivo infusion of endo-beta-galactosidase. Another approach to overcome ABO antibody barrier is involving in kidney exchange programs.
With increasing organ shortage and increasing number of patients with ESKD, ABOi-KT become a solution. It was contraindication for KT, but recently there are increasing number of successful ABOi-KT which can increase living donors. This is done by desensitization protocols to reduce isoagglutinins during TX and first 2 weeks post-TX. After this time rebound of isoagglutinins would not be problematic, because of accommodation:
ABO Ags are present on endothelial cells, tubules and glomeruli beside RBCs, making them an important Ag during KT. A2 recipients (20 %) have lower expression of Abo Ags. So ABOi-KT in A2 organs could be done by standard immune suppression. By contact with bowel bacteria, most people have anti-A / B Abs early in the infancy. So desensitization and a powerful maintenance immunosuppression are mandatory to overcome ABO Ags. These strategies include:
1) PP, DFPP, IA for depletion of Abs.
2) Using IVIG in recipient.
3) B cell reduction by splenectomy in the past and Rituximab nowadays.
4) Complement inhibitors
IA is the most successful method of removing anti -A / B Abs.
Outcome of ABOi-KT was acceptable in 20 years’ cohort in Japan. Patient and graft survival were 98 and 96 % for the First year and 91 and 83 % after 9 years (1427 patients were analyzed). In the US outcome of 738 ABOi-KTs were published that showed 5.9 % incidence of graft loss. Recently in Europe ABOi-KT among 43 patients had overall patient and graft survival of 93 and 91 % during 4.5 years. Another in the Germany and the UK showed similar results. Since 2006 in Heidelberg using a desensitization protocol of unselective IAs and additional PP the day before TX, graft survival was significantly lower in these patients comparing standard risk group. Two patients died, due to infection. In another recently published study among 1420 ABOi-KTs, showed a need for anti-B cell therapy in ABOi-KT. After two weeks accommodations is established and kidney is safe in spite of high titers of anti-A / B Abs.
Higher risk of infections such as CMV, BKV, HSV and VZV resulted in one additional patient death in loo ABOi-KT during the first year.
There was no increasing rate of malignancy among these patient. A higher rate of bleeding episodes was seen in three patients due to binding of coagulation factors during IA. Another complication was an increased rate of surgical complications such as lymphocele. So, whenever possible, ABO compatible KTs are preferred.
Summary
The ABO antigen system consists of oligosaccharides that are predominantly expressed on red blood cells and are also found on endothelial cells, tubuli, and glomeruli making the ABO antigen system important for kidney transplantation.
ABOi kidney transplantation with A2 organs has been accomplished with standard immunosuppressive therapy without any additional measures because of their low immunogenicity
During the last 25 years, increasing organ shortage enforced the development of strategies to overcome the ABO antibody barrier.
In the meantime, ABOi kidney transplantation has become a routine procedure with death-censored graft survival rates comparable to the rates in compatible transplantations.
Desensitization is usually achieved by
Apheresis
B cell-depleting therapies that are accompanied by powerful immunosuppression.
Anti-A/B antibodies are aimed to be below a certain threshold at the time of ABOi kidney transplantation and during the first 2 weeks after surgery.
Thereafter, even a rebound of anti-A/B antibodies does not appear to harm the kidney transplant, a phenomenon that is called accommodation, but is poorly understood.
There is still concern, however, that infectious complications such as viral disease, Pneumocystis jirovecii pneumonia, and severe urinary tract infections are increased after ABOi transplantations.
Recent data from the Collaborative Transplant Study show that during the first year after kidney transplantation, one additional patient death from an infectious complication occurs in 100 ABOi kidney transplant recipients.
Introduction
Major ABO incompatibility has been considered a contraindication to kidney transplantation until 1982, when desensitization protocols is the reduction and maintenance of anti-A/B antibodies (isoagglutinin) during the first 2 weeks post-transplantation below to be considered safe.
Blood group A2 donors are of lower immunogenicity than other groups.
Desensitization
High maintenance immunosuppression together with the use of these strategies including anti-A/B antibody depletion at the time of transplantation using Plasma Exchange or immunoadsorption, modulation of the recipient’s immune system by the use of intravenous immunoglobulin, reduction of the B lymphocyte pool by anti-CD20 antibody rituximab.
Plasma Exchange or Imunoadsorption.
Deduce infectious complications by substituting depleted immunoglobulins, and apoptosis induced by IgG
Rituximab is the gold standard nowadays instead of splenectomy
Inhibition of complement activation by eculizumab, however, the use of eculizumab after ABOi kidney transplantation is inconclusive.
DESENSITIZATION PROTOCOLS AND SURVIVAL AFTER ABOi LIVING DONOR KIDNEY TRANSPLANTATION
Patient and graft survival rates were excellent. Most patients were desensitized by PP and low-dose IVIG. The cumulative incidence of graft loss during the first year after transplantation was 5.9% in ABOi as compared to only 2.9% in ABOc transplantations. Splenectomy was replaced by the anti CD20 antibody rituximab.
Patient survival in ABOi transplant recipients was reduced due to infectious complications, mostly Pneumocystis jirovecii pneumonia. Kidney recipients were a higher incidence of BK virus replication and BK virus nephropathy (SV 40 positive in biopsy). A higher prevalence of colonization with multidrug-resistant bacteria was also noted.
RESULTS
Overall graft, death-censored graft, and patient survival were not statistically significantly different.
Early patient survival was reduced in ABOi kidney transplant recipients due to a higher rate of early infection-associated death.
Complications
Accommodation versus Rejection: accommodation appears to be a frequent phenomenon after ABOi kidney transplantations and is often associated with C4d deposition in peritubular capillaries of allograft biopsies. Two weeks after successful transplantation, accommodation is established and even high anti-A/B antibody exposure does not harm the kidney transplant by local up-regulation of complement regulatory proteins, like CD45, CD55, and CD59, as a consequence of anti-A/B antibody-dependent inactivation of ERK1/2 signaling pathway are possible mechanisms.
Infection and Malignancy: A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound, and severe urinary tract infections, have been demonstrated to result in approximately one additional patient death in 100 ABOi kidney transplant recipients during the first year after surgery. A higher incidence of BK virus replication and BK virus-associated nephropathy was also observed. Bentall et al. hypothesized that different blood group antigens may influence binding of viral pathogen receptors to sialic acid on renal tubular cells. While for malignancy, Hall et al. found no increased cancer risk when comparing 318 ABOi kidney transplant recipients to matched ABOc controls.
Additional Observations
US Renal Data System registry found a two times higher risk of early hemorrhage in 119 ABOi kidney transplant recipients when compared to ABOc controls. A significant correlation between the number of pre-transplant apheresis treatments and the peri- and post-transplant bleeding risk.
Conclusion
Till 1982 with the sturdy of Alexander et al., ABOi was considered a contraindication. The earlier protocols, including splenectomy, plasmapheresis, donor thrombocyte infusion etc, led to success. the 1-year survival was around 75%. after the spread of ABOİ transplantation overall in the world. Although compatibility is better, the shortage of organs led to the utilisation of desensitisation protocols to transplant against ABO compatibility.
the aim of desensitisation is the reduction and maintenance of anti A/B antibodies during the first two weeks below the safe threshold (<1:32 in tube technique, for example)
The elevation of the antibodies later seems to be of no harm due to accommodation, a phenomenon not well explained.
ABO blood groups differ in their immunogenicity and presentation on glomerular and tubular endothelşm as well as RBCs. Blood group A is nearly 20% of the blood group a and less expressed. Transplantation of A2 group was accomplished by standard immunosuppression.
Desensitization against ABO compatibility aims can be summarized as: ant-A/B antibodies depletion by plasmapheresis, modulation of recipients immune system by IVIG, reduction of B lymphocytes by either splenectomy or more recently by depletion with Rituximab.
Antibodies removal can be partial or complete specific immunoglobulin removal can be performed with adsorption and membrane separation. Studies showed same results for these different techniques.
Many centres give IVIG with aim of modulation and reducing infection. Of note, IVIG may increase the titers of anti A/B antibodies.
After the introduction of rituximab, splenectomy is not integral in desensitisation protocols. Many centres even do not give Rituximab if the antibody titers are lower below 1/32.
The role of eculizumab was not studied well because the study was terminated due to poor enrollment.
The earlier protocols used splenectomy but then was replaced with Rituximab. The ABOi Tx increased. A report from Japan regarding patients from 2001to 2010 showed 96% success and excellent survival in the first year. Another study from the US using PP and low dose IVIG showed graft loss of around %5,9 compared to 2.6 %in ABOc group.
Accommodation seen in ABO-incompatible transplants shows no harm after the second week even in presence of high titers.
To conclude, ABOi kidney transplantation became routine in recent years (in many countries) but this will put the patient at high risk of infection etc. So, ABO compatibility should be preferred whenever possible.
Antigens are present on surface of RBCs, renal tubules, glomeruli, and endothelial cells.
Antibodies of A/B are essentially of IgM class and in group O mostly of IgG and IgA.
Desensitization in case of ABOI-KT:
– Antibody depletion :
1-PE
2-Immunoadosorption: could be selective and non -selective
non selective IA is more effective in removing A/B IgG than selective IA
but unselective IA is less effective in removing A/B IgM
B- IVIG:
prevent A/B rebound following KT with additional benefit of decreasing the risk of infections
C-Splenectomy or RTX :
Splenectomy was replaced by an antiCD20 AB (Rituximab) to avoid surgical risk and risk of infections.
Inhibition of Complement Activation :
The use of eculizumab as an inhibitor to membrane attacking complex is controversial.
Kidney allograft outcome in ABOi kidney transplantation with using different desensitization protocols:
Double filtration PP with Rituximab is associated with patients and graft survival 98% and 96 % in the first year; respectively.
Desensitization with PP and low dose IVIG is associated with graft loss 5.9 % in the first year and overall graft loss in ABOi KT patients and graft survival of 4.5 years was 93 and 91 % during follow-up.
There is higher risk of infection increasing risk of death in the first year of ABOi transplantation compared with ABOc transplantation.
Complications:
Accommodation is more likely to occur in ABOi transplantation than HLA sensitized patients despite higher exposure to the kidney to A/B antibodies; not causing harm to the kidney by C4d deposition in peritubular capillaries of kidney allograft.
Infections: increase risk of BK virus in ABOi transplantation 3 times in comparison with HLA sensitized patients in addition to higher risk of viral infections of CMV, HSV, and VZV in addition to . jirovecii pneumonia.
There is no higher risk of malignancy in ABOi than ABOc KT.
Conclusion:
ABOi kidney transplantation has advantage of expanding the pool of living donors but increases the risk of rejection, infection, and death due to increasing infection rates.
Introduction
ABO incompatibility was considered absolute contraindication to kidney transplantation until 1982 until successful desensitization together with intensified immunosuppression.
Desensitization:
The aim of desensitization protocols is the reduction and maintenance of anti-A/B antibodies during the first 2 weeks post transplantation below threshold to be considered safe.
Antibody Depletion :
Plasma Exchange or Imunoadsorption.
Intravenous Immunoglobulin
IVIG acting by decrease proliferation of B, T cells , inhibit CD8 , inhibit complement activation .
it is given to prevent the anti-A/B antibody rebound in the early period post-transplantation. as well, to reduce the infectious complications by replacing the removed immunoglobulin.
B-Cell Depletion by Splenectomy or Rituximab
Splenectomy which is obsolete and now replaced by Rituximab (anti CD20)
Inhibition of Complement Activation
Inhibition of complement activation by eculizumab, however, the use of eculizumab after ABOi kidney transplantation is inconclusive.
DESENSITIZATION PROTOCOLS AND SURVIVAL AFTER ABOi LIVING DONOR KIDNEY TRANSPLANTATION
Most patients were desensitized by PP and low-dose IVIG.
The cumulative incidence of graft loss during the first year after transplantation was 5.9% in ABOi as compared to only 2.9% in ABOc transplantations.
Patient survival in ABOi transplant recipients was reduced due to infectious complications, mostly Pneumocystis jirovecii pneumonia and BK virus .
Complications
Accommodation versus Rejection:
Infection and Malignancy: A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, higher incidence of BK virus .
ABoi transplant was contraindicated, till the breakthrough made by Alexandre et al. from
Belgium where successful transplantation was done. Successful desensitization was
achieved by repeated plasmapheresis (PP), splenectomy, donor thrombocyte
transfusion, and infusion of A or B trisaccharide, together with intensive
immunosuppression. One-year graft survival in this study was a remarkable 75%
.
This led to a wider utilization of ABoi, first in Japan then USA and latter in Europe.
It improved the chances of transplant for high-risk patient and increased. The pool of
donors.
BLOOD GROUP ANTIGENS AND ANTIBODIES:
Are oligosacride antigen.
Blood group A2 less antigenic, so less transplant rejection.
DESENSITIZATION FOR ABoi KIDNEY TRANSPLANTATION:
Anybody Depletion by Extra corporal Treatment:
Antibody removal strategies may be divided into methods:
that completely remove plasma proteins such as PP.
methods that remove only a specific fraction of the plasma proteins including the
immunoglobulins (such as membrane separation),
and more specific methods such as unselective or selective IA.
Intravenous Immunoglobulins:
given by many centers before ABOi kidney transplantation to prevent the anti-A/B
antibody rebound in the early phase after transplantation.
B. Cell Depletion by Splenectomy or Rituximab.
Before the introduction of pharmacological anti-B cell therapies, splenectomy was an
integral component for the reduction of the B lymphocyte pool.
to the surgical risk and increased risk of sepsis, splenectomy was gradually substituted
by the anti-CD20 antibody rituximab.
More recently, several groups completely abandoned anti-B cell therapies from their
protocols.
Patient and graft survival in this cohort was 100% after a median of 26 months after transplantation.
observed in the Collaborative Transplant Study (CTS) a higher rate of death-censored
graft loss in ABOi kidney transplant.
Inhibition of Complement Activation:
Can reduce incidence of allograft rejection if added to the standard protocol but studies
are not conclusive.
Desensitization PROTOCOLS AND SURVIVAL AFTER ABOi LIVING DONOR KIDNEY
TRANSPLANTATION:
Patient and graft survival rates were an excellent. Graft loss more in first two weeks
posttransplant.
RESULTS FROM THE CTS:
We recently published 3-year outcomes of 1,420 ABOi kidney transplant recipients who
were transplanted at 101 deferent centers between 2005 and 2012 .
Overall graft and death-censored graft and patient survival were not statistically Signiant
different between the groups. Patients were compared to a matched group of ABOc
kidney transplant recipients and to all ABOc kidney transplant recipients from centers.
Early patient survival was reduced in ABOi kidney transplant recipients due to a higher
rate of early infection-associated death.
Complication:
A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as
P. jirovecii pneumonia, wound, and severe urinary tract infections have been described.
A higher bleeding risk. High surgical risk.
FUTURE PERSPECTIVES:
A new strategy that may come into clinics in the future is the reduction of blood group
antigen levels in the allograft by ex vivo infusion of endo-beta-galactosidase.
Conclusion:
In recent years, ABOi kidney transplantation has become a routine procedure. By this
approach, about 30% of living donors who were refused in the past can now donate their
kidneys and thereby significantly expand the living donor pool.
Transplantation in the presence of major ABO incompatibility, however, places the
patient at a somewhat higher risk of early rejection, infection, and infection-associated
death.
Therefore, whenever possible, ABOc procedures should be preferred.
INTRODUCTION
Major ABO incompatibility has been considered a contraindication to kidney transplantation till 1982, with the “first large study on ABOi kidney transplantation by Alexandre et al. after successful desensitization was achieved together with intensified immunosuppression one-year graft survival in this study was a remarkable 75%.
The aim of desensitization protocols is the reduction and maintenance of anti-A/B antibodies (isoagglutinins) during the first 2 weeks post transplantation below threshold to be considered safe.
Even after anti-A/B antibodies recur at high levels they will not harm the graft, a phenomenon that is called accommodation.
BLOOD GROUP ANTIGENS AND ANTIBODIES
Blood group A2 donors are of lower immunogenicity than other groups.
DESENSITIZATION FOR ABOi KIDNEY TRANSPLANTATION
A powerful maintenance immunosuppression together with the use of these strategies including anti-A/B antibody depletion at the time of transplantation using PP or immunoadsorption, modulation of the recipient’s immune system by the use of intravenous immunoglobulin, reduction of the B lymphocyte pool by anti-CD20 antibody rituximab.
Antibody Depletion by Extracorporeal Treatment
Antibody removal strategies methods that completely remove plasma proteins such as PP or immunoadsorption. No significant differences were found in clinical studies that compared the impact of different IA strategies on clinical outcomes, including anti-A/B antibody reduction, survival, kidney function, rejection episodes, or complications.
Intravenous Immunoglobulin
To prevent the anti-A/B antibody rebound in the early phase after transplantation. IVIG infusion is believed to reduce infectious complications by substituting depleted immunoglobulins.
B-Cell Depletion by Splenectomy or Rituximab
Due to the surgical risk and increased risk of sepsis, splenectomy was gradually substituted by the anti-CD20 antibody rituximab. The use of standard immunosuppressive therapy without rituximab when the patient had reached an anti-A/B antibody titer of less than 1:32.
Inhibition of Complement Activation
Inhibition of complement activation upon binding of antibodies to the allograft endothelium by inhibiting the assembly of the membrane attack complex by eculizumab so severe antibody-mediated rejection during anti-A/B antibody rebound can be successfully treated. However the use of eculizumab after ABOi kidney transplantation are inconclusive.
DESENSITIZATION PROTOCOLS AND SURVIVAL AFTER ABOi LIVING DONOR KIDNEY TRANSPLANTATION
Patient and graft survival rates were excellent. Most patients were desensitized by PP and low dose IVIG. The cumulative incidence of graft loss during the first year after transplantation was 5.9% in ABOi as compared to only 2.9% in ABOc transplantations. Splenectomy was replaced by the anti CD20 antibody rituximab.
Patient survival in ABOi transplant recipients was reduced due to infectious complications, mostly Pneumocystis jirovecii pneumonia. Kidney recipients were a higher incidence of BK virus replication and BK virus nephropathy (SV 40 positive in biopsy). A higher prevalence of colonization with multidrug-resistant bacteria was also noted.
RESULTS
Overall graft, death-censored graft, and patient survival were not statistically significant different.
Early patient survival was reduced in ABOi kidney transplant recipients due to a higher rate of early infection-associated death.
COMPLICATIONS AND HURDLES OF ABOi KIDNEY TRANSPLANTATION
Accommodation versus Rejection: accommodation appears to be a frequent phenomenon after ABOi kidney transplantations and is often associated with C4d deposition in peritubular capillaries of allograft biopsies. Two weeks after successful transplantation, accommodation is established and even high anti-A/B antibody exposure does not harm the kidney transplant by local up regulation of complement regulatory proteins, like CD45, CD55, and CD59, as a consequence of anti-A/B antibody-dependent inactivation of ERK1/2 signaling pathway are possible mechanisms.
Infection and Malignancy: A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound, and severe urinary tract infections have been demonstrated resulting in approximately one additional patient death in 100 ABOi kidney transplant recipients during the first year after surgery. Higher incidence of BK virus replication and BK virus-associated nephropathy was also observed. Bentall et al. hypothesized that different blood group antigens may influence binding of viral pathogen receptors to sialic acid on renal tubular cells. While for malignancy, Hall et al. found no increased cancer risk when comparing 318 ABOi kidney transplant recipients to matched ABOc controls.
Additional Observations
US Renal Data System registry found a two times higher risk of early hemorrhage in 119 ABOi kidney transplant recipients when compared to ABOc controls. A significant correlation between the number of pre-transplant apheresis treatments and the peri- and post-transplant bleeding risk.
FUTURE PERSPECTIVES
The reduction of blood group antigen levels in the allograft by ex vivo infusion of endo-beta-galactosidase may be a new strategy in the future. Kidney exchange programs are good options as well.
CONCLUSION
Desensitization for ABOi kidney transplantation was the only way to transplant these patients within a reasonable period of time.
Transplantation in the presence of ABO incompatibility places the patient at a higher risk of early rejection, infection, and infection-associated death. So, whenever possible, ABOc procedures should be preferred.
ABO incompatibility was considered a contraindication to transplantation but advances in immunosuppssion and desensitization protocols led to more ABOi kidney transplantations, even today, kidney transplantation is best performed in the absence of (major) ABOi but the increasing number of patients on dialysis and organ shortage directed many centres to ABOi -KT.
Different desensitization protocols are used aiming to reduce isoagglutinins and keep it at low levels below a threshold that is considered to be safe (e.g., <1:32 in tube technique) especially during the first 2 weeks post transplantation
after that accommodation Occure and even rebound rise in antibodies won't affect the graft it was found that survival rates of ABOi kidney transplantation nearly equal to ABOc transplant.
▪︎BLOOD GROUP ANTIGENS AND ANTIBODIES
ABO antigen expressed on red blood cells , endothelial cells, tubuli, and glomeruli.
antigen density on erythrocytes differs accordingto bl.group .
blood group A1 and B individuals have high antigen expression on erythrocytes and can elicit strong immuneresponse,while individuals with blood group A2 showes a low expression of the blood group antigen So it has lower immunogenicity and transplantation with A2 organs can be done without intensified immunosuppression.
▪︎DESENSITIZATION FOR ABOi KIDNEY TRANSPLANTATION
There is no standard protocol for desensitization for ABOI-KT
But there are common principles :
Generally a powerful maintenance immu-nosuppression is needed with one or more of the following:
*Anti-A/B antibody depletion at the time of transplantation using PP, double- filtration PP/membrane filtration, or selective or unselective immunoadsorption (IA)
PP is the preferred antibody removal strategy in the US, membrane separation is popular in Japan. Unselective and selective IAs are used in Europe.
*use of intravenous immunoglobulins (IVIgs) aiming to modulate the recipient’s immune system,prevent rebound AB rise early after transplantation also may reduce infectious complications by substituting depleted immunoglobulins.
*splenectomy, or more recently by the anti-CD20 antibody rituximab to Reduce B cells and decrease antibody production some groups has recently performed ABOI-KT without rituximab when antibody titer of less than 1:32 with Patient and graft survival was 100% after a median of 26months. Two antibody-mediated rejection episodes were successfully reversed. But CTS observes a higher rate of death-censored graft loss when rituximab wasn't used.
*Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the graft endothelium but still
results on the use of eculizumab after ABOi kidney transplantation are inconclusive.
Most of studies on ABOi kidney transplantation with different desensitization protocols showed good long term graft and patient survival for up to 9 years without significant difference than ABOC transplantation.
▪︎COMPLICATIONS AND HURDLES OF ABOi KIDNEY TRANSPLANTATION
*Accomodation versus Rejection
accommodation is a phenomenon that occurs within the first 2 weeks after ABOi kidney transplantations with C4d deposition in peritubular capillaries of allograft.
Might be due to the controlled anti-A/B antibody exposure to antigens in the early phase after transplantation and further rise in antibodies will not harm the graft .
The exact mechanism is not clear but Local upregulation of complement regulatory proteins, like CD45, CD55, and CD59 is one possible mechanism .
▪︎Infection and Malignancy
patient survival in ABOi transplant recipients was reduced due to infectious complications, mostly Pneumocystis jirovecii pneumonia.
In some cases there were higher incidence of BK virus replication and BK virus nephropathy and a higher prevalence of colonization with multidrug-resistant bacteria .
higher frequency of viral infections such as CMV, HSV, VZV, wound, and severe urinary tract infections were also noted.
Hall et al. found no increased cancer risk when comparing 318 ABOi kidney transplant recipients to matched ABOc controls.
▪︎Other complications included ,risk of hemorrhage, surgical complications.
▪︎In conclusion
ABOI-KT is widly used today provides more donors to reduce waiting list but stil transplantation in the presence of major ABO incompatibility, places the patient at a somewhat higher risk of early rejection, infection, and infection-associated death.
BLOOD GROUP ANTIGENS AND ANTIBODIES
The ABO antigen system consists of oligosaccharides that are predominantly expressed on red blood cells and are also found on endothelial cells, tubuli, and glomeruli making the ABO antigen system important for kidney transplantation. Patients with different blood groups differ with respect to their antigen density on erythrocytes and consequently immunogenicity of organs and immunosuppressive therapy.
DESENSITIZTION FOR ABOi KIDNEY TRANSPLATATION
All currently proposed strategies share some common principles. These include together with a powerful maintenance immunosuppression one or more of the following:
(1)Anti-A/B antibody depletion at the time of transplantation using PP, double-infiltration PP/membrane “filtration, or selective or unselective immunoadsorption (IA)
(2)Modulation of the recipient’s immune system by the use of intravenous immunoglobulins (IVIgs)
(3)Reduction of the B lymphocyte pool by splenectomy, or more recently by the anti-CD20 antibody rituximab
(4) Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the graft endothelium
Antibody depletion by extracorporal treatment
Antibody removal strategies may be divided into:
A-Methods that completely remove plasma proteins such as PP;
B-Methods that remove only a specific fraction of the plasma proteins including the immunoglobulins (such as membrane separation);
C- Specific methods such as unselective or selective IA – no significant diferences were found in clinical studies that compared the impact of diferent IA strategies on clinical outcomes, including anti-A/B antibody reduction, survival, kidney function, rejection episodes, or complications;
Intravenous Imunoglobulins
Intravenous immunoglobulins are given by many centers before ABOi kidney transplantation to prevent the anti-A/B antibody rebound in the early phase after transplantation. In addition, IVIg infusion is believed to reduce infectious complications by substituting depleted immunoglobulins. As a note of caution, IVIg preparations contain IgG antibodies directed against A/B antigens and can efectively increase anti-A/B antibody titers upon administration.
B-Cell Depletion by Splenetomy or Rituximab
Before the introduction of pharmacological anti-B cell therapies, splenectomy was an integral component for the reduction of the B lymphocyte pool prior to ABOi kidney transplantation. Due to the surgical risk and increased risk of sepsis, splenectomy was gradually substituted by the anti-CD20 antibody rituximab. More recently, several groups completely abandoned anti-B cell therapies from their protocols when the patient had reached an anti-A/B antibody titer of less than 1:32 (tube method).
Inhibition of Complement Activation
An emerging new concept in the transplantation across ABO antibody barriers is the inhibition of complement activation upon binding of antibodies to the allograft endothelium. Severe antibody-mediated rejection in this patient during anti-A/B antibody rebound was successfully treated by inhibiting the assembly of the membrane attack complex by eculizumab.
DESENSITIZATION PROTOCOLS AND SURVIVAL AFTER ABOi LIVING DONOR KIDNEY TRANSPLANTATION
In Japan, desensitized by double-filtration PP, and splenectomy was more recently replaced by the anti-CD20 antibody rituximab. For the most recent area from 2001 to 2010, patient and graft survival rates for the 1,427 analyzed patients were an excellent 98 and 96% for the first year, and 91 and 83% after 9 years, respectively.
In US, most patients were desensitized by PP and low-dose IVIg. The cumulative incidence of graft loss during the first year after transplantation was 5.9% in ABOi as compared to only 2.9% in ABOc transplantations and occurred mainly during the first 2 weeks after surgery due to rejection.
A study from the UK showed similar death-censored graft survival in 62 patients 3 years after ABOi kidney transplantation when compared to ABOc controls. However, patient survival in ABOi transplant recipients was reduced due to infectious complications, mostly Pneumocystis jirovecii pneumonia.
RESULTS FROM CTS
Patients were compared to a matched group of ABOc kidney transplant recipients and to all ABOc kidney transplant recipients from centers that performed at least have ABOi procedures. Overall graft, death-censored graft, and patient survival were not statistically significant diffferent between the groups. Early patient survival was reduced in ABOi kidney transplant recipients due to a higher rate of early infection-associated death (P = 0.037 versus matched controls and P < 0.001 versus center controls). Specifically, one additional death per 100 patients occurred in the first year after ABOi kidney transplantation from an infectious complication.
COMPLICATIONS AND HURDLES OF ABOi KIDNEY TRANSPLANTATION
Accomodation versus Rejection
An accommodation phenotype may be achieved by the controlled anti-A/B antibody exposure to antigens in the early phase after kidney transplantation. About 2 weeks after successful transplantation, accommodation is established and even high anti-A/B antibody exposure does not harm the kidney transplant.
Infection and Malignancy
There are conflicting results on infectious complications after ABOi kidney transplantation in the literature. A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound, and severe urinary tract infections have been described.
Hall et al. found no increased cancer risk when comparing 318 ABOi kidney transplant recipients to matched ABOc controls. The analysis of 1,420 ABOi transplantations from the CTS study also did not show an increased risk of malignancy in ABOi compared to ABOc patients.
Additional Observation
A study from the US Renal Data System registry found a two times higher risk of early hemorrhage in 119 ABOi kidney transplant recipients when compared to ABOc controls (adjusted HR, 1.96, P < 0.05). This assumption is supported by the findings of de Weerd et al. who found a significant correlation between the number of pre-transplant apheresis treatments and the peri- and posttransplant bleeding risk.
CONCLUSION
In recent years, ABOi kidney transplantation has become a routine procedure. By this approach, about 30% of living donors who were refused in the past can now donate their kidneys and thereby significantly expand the living donor pool. Transplantation in the presence of major ABO incompatibility, however, places the patient at a somewhat higher risk of early rejection, infection, and infection-associated death. Therefore, whenever possible, ABOc procedures should be preferred
Blood group antigens and antibodies:
Antigens are present n the surface of RBCs, renal tubules, glomeruli, and endothelial cells.
Antibodies of A/B are mainly of IgM class but in group O mostly of IgG and IgA.
Desensitization for ABOi kidney transplantation :
A- Antibody depletion :
1-Plasmapheresis: removal of plasma containing immunoglobulins
2-Immunoadosorption: may be selective and unselective
Unselective IA is more effective in removing A/B IgG than selective IA
however unselective IA is less effective in removing A/B IgM
B- Intravenous Immunoglobulin:
prevent A/B rebound after kidney transplantation with added benefit as it decreases the risk of infections
C-Splenectomy or Rituximab :
Splenectomy was substituted by an antiCD20 antibody (Rituximab) due to surgical risk and increased risk of infections.
With trials for Rituximab withdrawal when the titer of A/B antibodies < 1/32 (tube method)
Inhibition of Complement Activation :
The use of eculizumab as an inhibitor to membrane attacking complex wasn’t inconclusive.
Kidney allograft outcome in ABOi kidney transplantation according to different desensitization protocols:
Double filtration PP + Rituximab: Patients and graft survivals were 98% and 96 % in the first year.
desensitization with PP with low dose IVIG: graft loss was only 5.9 % in the first year
of overall graft loss in ABOi renal transplantation patients and graft survival of 4.5 years was 93 and 91 % during follow-up.
A higher rate of infection increases the risk of death in the first year of ABOi transplantation in comparison to ABOc transplantation.
Complications:
Accommodation is more likely to occur in ABOi transplantation than HLA sensitized patients despite higher exposure to the kidney to A/B antibodies, these don’t cause harm to the kidney
with C4d deposition in peritubular capillaries of kidney allograft.
Infections: increase risk of BK virus in ABOi transplantation three times more HLA sensitized patients
with more risk of viral infections of CMV, HSV, and VZV in addition to . jirovecii pneumonia.
Malignancy: there is no increase in the risk of malignancy in ABOi compared to ABOc transplantation.
Conclusion:
ABOi kidney transplantation has expanded the pool of living donors however increases the risk of rejection, infection, and death related to increasing infection rates.
-The number of kidney transplantations from living donors can be increased by up to 30% when patients are transplanted across the ABO antibody barrier.
-With currently existing protocols, as many as 90% of patients with an ABOi living donor may effectively be desensitized and transplanted.
-The aim of desensitization protocols is the reduction and maintenance of anti-A/B antibodies (isoagglutinins) during the first 2weeks after transplantation below a threshold that is considered to be safe (e.g., <1:32 in tube technique).
-Thereafter, even when anti-A/B antibodies recur at high levels they will not harm the kidney transplant, a phenomenon that is called accommodation.
– In recent years, graft survival rates after ABOi kidney transplantation nearly equaled those after ABO-compatible (ABOc) procedures.
– -Compared to blood group A1 and blood group B individuals, blood group A2 recipients, who make up 20% of all Caucasian individuals with blood group A, have a low expression of blood group antigen molecules (30–50%) on the
the surface of erythrocytes, which is believed to be responsible for the lower immunogenicity of organs from blood group A2 donors.
– ABOi kidney transplantation with A2 organs has been accomplished with standard immunosuppressive therapy without any additional measures .
-Anti-A/B antibodies are formed upon contact with gut bacteria during early infancy.
-Naturally occurring anti-A/B antibodies are predominantly of the IgM class but especially in blood group O individuals they also consist of IgG and IgA class .
-All currently proposed strategies share some common principles include together with a powerful maintenance immunosuppression one or more of the following:
(1) Anti-A/B antibody depletion at the time of transplantation using PP, double-filtration PP/membrane filtration, or selective or unselective immunoadsorption (IA)
(2) Modulation of the recipient’s immune system by the use of intravenous immunoglobulins (IVIgs)
(3) Reduction of the B lymphocyte pool by splenectomy, or more recently the anti-CD20 antibody rituximab
(4) Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the graft endothelium.
-Antibody removal strategies may be divided into methods that completely remove plasma proteins such as PP, methods that remove only a specific fraction of the plasma proteins including the immunoglobulins (such as membrane separation), and more specific methods such as unselective or selective IA.
-Intravenous immunoglobulins are given by many centers before ABOi kidney transplantation to prevent the anti-A/B antibody rebound in the early phase after transplantation.
– IVIg infusion is believed to reduce infectious complications by substituting depleted immunoglobulins.
-IVIg preparations contain IgG antibodies directed against A/B antigens and can effectively increase anti-A/B antibody titers upon administration .
-Due to the surgical risk and increased risk of sepsis, splenectomy was gradually substituted by the anti-CD20 antibody rituximab.
-More recently, several groups completely abandoned anti-B cell therapies from their protocols.
-Patient survival in ABOi transplant recipients was reduced due to infectious complications, mostly Pneumocystis jirovecii pneumonia.
-Important differences between ABOi and standard risk kidney recipients were a higher incidence of BK virus replication and a higher prevalence of colonization with multidrug-resistant bacteria .
-In contrast to transplantation in the HLA-sensitized patient, accommodation appears to be a frequent phenomenon after ABOi kidney transplantations and is often associated with C4d deposition in peritubular capillaries of allograft biopsies.
-About 2weeks after successful transplantation, accommodation is established and even high anti-A/B antibody exposure does not harm the kidney transplant.
-A study from the US Renal Data System registry found a two times
higher risk of early hemorrhage in 119 ABOi kidney transplant recipients when compared to ABOc controls .
-An increased rate of surgical complications after ABOi kidney transplantation, which were attributed to early intensified immunosuppression with mycophenolic acid and removal of coagulation factors by apheresis.
-Significantly higher number of lymphoceles in ABOi patients than in ABOc controls that required surgical revisions .
DESENSITIZATION FOR ABOi KIDNEY TRANSPLANTATION
Despite the absence of a generally accepted desensitization protocol for the transplantation across the ABO antibody barrier,all currently proposed strategies share some common principles
these include together with a powerful maintenance immunosuppression one or more of the following:
(1) Anti-A/B antibody depletion at the time of transplantation using one of the aphresis methods
(2) Modulation of the recipient’s immune system by the use of (IVIgs) which has many immunologic effects besides replacing Ig depleted by aphresis and thereby reduces infections .
(3) Reduction of the B lymphocyte pool by the anti-CD20 antibody rituximab
(4) Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the endothelium by using anti C5 Eculizumab , although results of its use in ABOi KT are inconclusive
SURVIVAL AFTER ABOi KT :
Althogh several studies show that ABOi KT has comparable results to ABOc KT , however , However, patient survival in ABOi transplant recipients was reduced due to infectious complications, mostly Pneumocystis jirovecii pneumonia.Other important differences between ABOi and standard risk kidney recipients were a higher incidence of BK virus replication (>104!copies/mL plasma, 21 versus 6%, P!=!0.04) and BK virus
nephropathy (SV 40 positive in biopsy, 12 versus 0%, P!=!0.01) and a higher prevalence of colonization with multidrug-resistant bacteria (15 versus 1%, P!=!0.02).
regarding the theoratically higher risk of malignancies in ABOi KT , studies have shown no increased cancer risk as compared to ABOc KT
A study from the US Renal Data System registry found a two times higher risk of early hemorrhage in 119 ABOi kidney transplant recipients when compared to ABOc controls which was attributed to the unspecific binding of coagulation factors during repeated IA where a signifcant correlation between the number of pretransplant apheresis treatments and the peri- and posttransplant bleeding risk
CONCLUSION
In recent years, ABOi kidney transplantation has become a routine procedure. By this approach, about 30% of living donors who were refused in the past can now donate their kidneys and thereby significantly expand the living donor pool.
Transplantation in the presence of major ABO incompatibility, however, places the
patient at a somewhat higher risk of early rejection, infection, and infection-associated death. $erefore, whenever possible, ABOc procedures should be preferred.
Increasing the number of living donors through ABO-incompatible kidney transplantation has lately become more common, because of new effective desensitization methods and increased graft survival.
Antigens and antibodies specific to blood groups
RBCs, endothelial cells, tubules, and glomeruli are all known to express the ABO antigen system.
Organs from blood type A2 donors are less immunogenic than organs from other blood groups because of the limited expression of blood group antigen on the surface of red blood cells (RBCs).
Anti-A/B antibodies are well-known for their pathogenic potential, although the relative contributions of different immunoglobulin isotypes and subclasses are not well understood in this context.
Desensitization for kidney transplantation in patients with ABO-incompatible (ABOi) blood types
There is no singular desensitization procedure that has been developed.
Extracorporeal therapy for the elimination of antibodies:
Plasmapheresis is used to fully remove all plasma proteins, whereas membrane separation is used to remove a particular percentage of plasma proteins, such as immunoglobulins.
IA can be either non-selective or selective.
IVIG is used to modulate the immune system. IVIG is utilized to prevent anti-A/B antibody rebound in the early post-transplant period.
Substitute immunoglobulins that lower the risk of infection associated with plasmapheresis are available.
Antibody removal by plasmapheresis or immunoadsorption (IA) is a concept of desensitization that is more selective and specific than plasma exchange. It is preferred for HLA I and ABOI transplantation because it removes anti-A and anti-B antibodies with an average reduction rate of 3-4 fold and is associated with fewer infectious or bleeding side effects than plasma exchange, but it is more expensive.
Immunomodulating agent IVIG is a complementary treatment after plasmapheresis that replaces removed antibodies while also performing other important functions such as complement inhibition, FC receptor binding, inhibiting B and T cell proliferation, CD8 T cell inhibition, and inducing B cell apoptosis, among other things.
Although there is no standardized dosage, there are many side effects, including infusion-related allergic reactions, increased risk of thromboembolic events, and acute kidney injury (AKI). Its use in combination with plasmapheresis is the preferred and widely used protocol, with or without Rituximab, and it is the preferred and widely used protocol with or without Rituximab.
The anti-CD20 antibody is used to remove B cells from the body. Rituximab has taken the role of surgical splenectomy, and while rituximab is administered in a variety of dosages and frequencies depending on local centre guidelines, the current tendency is to provide low-dose rituximab 14 days before surgery.
Infection and malignancy are two of the risks associated with desensitization treatment.
In spite of the fact that extensive immunosuppression raises the risk of malignancy in HLA incompatible transplantation, the risk of cancer was not observed to be greater when ABOi-KT recipients were compared to ABOc controls. In the aftermath of ABOi-KT, there is a lot of disagreement on whether or not there will be an infectious complication.
According to the findings, a higher prevalence of viral infection (CMVSHVVZV and BK virus) as well as P. jiroveci pneumonia were seen, as well as wound infection and severe UTI.
· New advances in immunosuppression made the outcomes of ABO I kidney transplantation near that of ABO c ones..
· It increased the pool of living donor by up to 30% and hence shortened the waiting time list.
· Available desensitization protocols served to decrease or remove the anti A and anti B isoagglutinin to prevent hyper acute rejection and AMR which moistly occurs in 1st 4 weeks post transplant. After which, accommodation can occur and risk can be declined.
· Pretransplant isoagglutinin titer of <1:32 can be considered safe.
Desensitization protocols:
· No consensus about ideal protocol, it depends on available expertise and facilities.
· It includes antibody removal either non selectively by PEX or selectively by IA to minimize loss of coagulation proteins and other IgG which can increase risk of infection.
· B cell depletion by rituximab and antibody neutralization with IVIG.
· Powerful tacrolimus based triple maintenance immunosuppression greatly improved outcomes.
· Medical splenectomy by Rituximab has replaced surgical splenectomy with minimization of surgical risk.
Different available protocols:
· Japan (double-filtration PP, and splenectomy was more recently replaced by rituximab) with good outcome.
· US patients desensitized by PP and low dose IVIg. With coparable outcome to ABO c kidney transplant.
· European protocol (desensitization by selective IA + Rituximab) with good outcomes.
· Heidelberg using (unselective IA +one PP session one day before surgery + Rituximab ) led to successful desensitization of 12 patients after a median of six IA treatments, After a median postoperative follow-up of 22 months.
Accommodation means : C4d deposition in peritubular capillaries of allograft biopsies without pathological injuries which occur mainly after 2 weeks from transplantation despite of high anti-A/B antibody exposure.
Complications of large cumulative dose of immunosupressives:
· Viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound sepsis, severe UTI.
· Malignancy
In conclusion, it can be considered the last resort in those who failed to get ABO c offer through PKD.
ABO-Incompatible Kidney Transplantation.
Graft survival rates after ABOi kidney transplantation comparable to those ABOc.
ABOi KT increased the number of kidney transplantations from living donors by up to 30% and able to shorten the waiting time for KT
Through current protocols about 90% of patients with an ABOi LKT may effectively be desensitized.
The role of desensitization protocols is reduction and maintenance of anti-A/B antibodies at low level (isoagglutinin) during the first 2 weeks after transplantation (<1:32) to allow accommodation occur.
BLOOD GROUP ANTIGENS AND ANTIBODIES
These oligosaccharides are expressed on the surface of a variety of different cell types, including RBCs, endothelial cells, and kidney parenchymal cells.
Antigenic expression of A2 is quantitatively and qualitatively less than that of A1, immunogenic risk based on antigen expression alone is A1>B>A2.
DESENSITIZATION FOR ABOi KIDNEY TRANSPLANTATION:
Protocol of desensitization based on centre experiences so there are many different protocols but generally they depends on antibody removal by PEX or IA with anti-CD20 as B cell depletion and IVIG with powerful triple tacrolimus based immunosuppression.
Antibody Depletion by Extracorporeal Treatment:
There are 3 methods:
PP completely remove plasma proteins
membrane separation-Remove only a specific fraction of the plasma proteins including the immunoglobulins
unselective or selective IA -More specific methods
Unselective IA is more effective than selective anti-A/B antibody columns in removing anti-A/B IgG than IgM.
Intravenous Immunoglobulins.
The role is to prevent the anti-A/B antibody rebound in the early phase after transplantation decrease rate of infection but sometimes it is associated with IgG against A/B antigens also.
B-Cell Depletion by Splenectomy or Rituximab.
Anti-CD 20 now is considered medical splenectomy and used in most protocols.
There is emerging protocols that did not use rituximab in patient with an anti-A/B antibody titre of less than 1:32 and showed good graft survival.
DESENSITIZATION PROTOCOLS AND SURVIVAL AFTER ABOi LKT
Study from Japan used (double-filtration PP, and splenectomy was more recently replaced by the anti-CD20 antibody rituximab) showed patient and graft survival rates 98 and 96% for the first year, and 91 and 83% after 9 years.
Study in US patients were desensitized by PP and low dose IVIg. the incidence of graft loss during the first year after transplantation was 5.9% in ABOi as compared to only 2.9% in ABOc.
European protocol (recipient desensitization by selective IA + Rituximab) patient and graft survival after a mean follow-up of 4.5 years was 93 and 91%, respectively.
Heidelberg desensitization protocol using (unselective IA +one PP session one day before surgery + Rituximab) led to successful desensitization of 12 patients after a median of six IA treatments, after a median postoperative follow-up of 22 months, graft survival in ABOi kidney transplant recipients was insignificantly lower compared to standard risk recipients.
CTS:
Death-censored graft and patient survival were not statistically significant different between the groups.
Early patient survival was reduced in ABOi kidney transplant recipients due to a higher rate of early infection-associated death.
ISSUES OF ABOi KIDNEY TRANSPLANTATION
Accommodation versus Rejection:
C4d deposition in peritubular capillaries of allograft biopsies without pathological injuries which occur mainly after 2 weeks from transplantation despite of high anti-A/B antibody exposure .
Infection and Malignancy
There is higher incidence of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound, and severe urinary tract infections.
Cumulative incidence of death due to infection in recipients of an ABOi living donor graft is higher than matched controls receiving an ABOc living donor graft.
Some studies shown increasing in bleeding tendency and surgical complications in ABOi group than ABOc GROUP.
Summary:
ABO-Incompatible Kidney Transplantation is considered now one of the important option to decrease time in waiting list for KTX.
It has its merits and demerits, and we should dealing with it in combination with other PKD and KAS for improving graft and patient survival.
Introduction:
ABO incompatibility has been considered a contraindication to kidney transplantation.
In 1982, the first large study on ABOi kidney transplantation come from Belgium and led to a wider utilization of ABOi kidney transplantations.
Blood group antigens and antibodies:
ABO antigen system consists of oligosaccharides that are predominantly expressed on red blood cells and are also found on endothelial cells, tubules, and glomeruli making the ABO antigen system important for kidney transplantation.
Patients with different blood groups differ with respect to their antigen density on erythrocytes. Compared to blood group A1 and blood group B individuals, blood group A2 recipients, who make up 20% of all Caucasian individuals with blood group A, have a low expression of blood group antigen molecules (30–50%) on the surface of erythrocytes, which is believed to be responsible for the lower immunogenicity of organs from blood group A2 donors. ABOi kidney transplantation with A2 organs has been accomplished with standard immunosuppressive therapy without any additional measures. Of interest, anti-A/B antibodies reformed upon contact with gut bacteria during early infancy. Naturally occurring anti-A/B antibodies are predominantly of the IgM class but especially in blood group O individuals they also consist of IgG and IgA class. The relative contribution of the different immunoglobulin isotypes and their subclasses to organ rejection remains to be elucidated.
Desensitization for ABOi Tx:
There is no generally accepted protocol for desensitization in ABOi Tx,
They include one or more of the following:
In addition, powerful maintenance IS is required.
Antibody Depletion by Extracorporeal Treatment:
Antibody removal strategies may be divided into:
No significant differences were found in clinical studies that compared the impact of different IA strategies on clinical outcomes, including anti-A/B antibody reduction, survival, kidney function, rejection episodes, or complications
IVIG:
Intravenous immunoglobulins are given by many centers before ABOi kidney transplantation to prevent the anti-A/B antibody rebound in the early phase after transplantation.
In addition, it reduces infectious complications by substituting depleted immunoglobulins, but it contains IgG antibodies directed against A/B antigens and can effectively increase anti-A/B antibody titers upon administration.
B-Cell Depletion by Splenectomy or Rituximab:
splenectomy was used for the reduction of the B lymphocyte pool prior to ABOi kidney transplantation.
Due to the surgical risk and increased risk of sepsis, splenectomy was gradually substituted with the anti-CD20 antibody rituximab.
More recently, several groups completely abandoned anti-B cell therapies from their protocols, patient and graft survival were good and ABMR episodes were successfully reversed, but a high rate of death censored graft loss was observed.
Inhibition of Complement Activation:
An emerging new concept in the ABOi Tx.
It was used in ABOi kidney-pancreas transplantation. Severe antibody-mediated rejection during anti-A/B antibody rebound was successfully treated by inhibiting the assembly of the membrane attack complex by eculizumab.
Still, results on the use of eculizumab after ABOi kidney transplantation are inconclusive.
Desensitization protocols and survival after ABOi LD KTx:
the largest cohort of patients after ABOi kidney transplantation with the longest follow-up of more than 20 years is reported from Japan. Most patients were desensitized by double-filtration PP, and splenectomy was more recently replaced by the anti-CD20 antibody rituximab.
In the US, most patients were desensitized by PP and low-dose IVIg.
In 2003, Sweden published a protocol for ABOi transplantation that is based on recipient desensitization by selective IA using Glycosorb columns, splenectomy was replaced by rituximab. this protocol led to a renaissance of ABOi kidney transplantation in Europe. Good patient and graft survival were obtained by using this protocol and no evidence of ABMR was observed.
Using the Stockholm protocol, they achieved a 10-year patient and death-censored graft survival of 99 and 94%, respectively, which did not differ significantly from recipients of ABOc transplants. also, rates for antibody- and T-cell-mediated rejections were also not significantly different.
A study from the UK showed similar death-censored graft survival when compared to ABOc controls, however, patient survival in ABOi transplant recipients was reduced due to infectious complications, mostly Pneumocystis jirovecii pneumonia.
Complications of ABOi KTx:
Accommodation appears to be a frequent phenomenon after ABOi kTx and is often associated with C4d deposition in peritubular capillaries of allograft biopsies.
An accommodation phenotype may be achieved by the controlled anti-A/B antibody exposure to antigens in the early phase after kidney transplantation. About 2 weeks after successful transplantation, accommodation is established and even high anti-A/B antibody exposure does not harm the kidney transplant.
Local upregulation of complement regulatory proteins, like CD45, CD55, and CD59, as a consequence of anti-A/B antibody-dependent inactivation of the ERK1/2 signalling pathway, is one possible mechanism.
There are conflicting results on infectious complications after ABOi kidney transplantation in the literature. A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound, and severe urinary tract infections have been described.
Some showed an increased risk of BK virus infection and nephropathy and they hypothesized that the different blood group antigens may influence the binding of viral pathogen receptors to sialic acid on renal tubular cells.
ABOi transplant previously considered a contraindication now is a possibility with 30%increase in tx rate due to dire need of organs.
ABO ag is an oligosaccharide Ag which is present on rbc,glomerulus,tubules, endothelium which reacts with anti-A and B titre that will cause early rejection.So the sole purpose of desensitization is reduction of ab titre to a safe limit of B>A2 in line of immunogenicity.
Here the main culprits are-
1.Antibody(IgG is imp than IgM,because IgM is intravascular hence amenable to removal)
2.B-cell/plasma cell
3.complement
Mode of removal/suppression-
1.ANTIBODY
A.plasmapheresis(nonspecific,albumin,coagulation proteins also removed)
B.double filtration plasmapheresis(more specific,only albumin loss)
C.immuneadsorption(specific IA against anti-A or anti-B)(no loss of albumin)
2.B-CELL
A.splenectomy (not practised now)
B.Rituximab (low to high dose, replaced splenectomy with increase in death censored graft function and prevent rebound of ab titre during initial tx weeks)
3.COMPLEMENT-
A.eculizumab (very expensive)
B.IVIG-modulate the immunity by neutralization of antibody,complement,T-cell inhibition,supplement immunoglobulin deficiency, but increases antibody titre)
4.ATG/BASILIXIMAB induction with triple immunosuppression.
OUTCOME-patient survival is less due to more infections,mdr bacteria colonization,bkvirus nephropathy, but malignancy risk is equal.
ABOi tx graft survival,patient survival ,death censored graft survival is equivalent to ABOc tx but initial survival is less due to increased infections and rejection.
ABOi transplantation has over come the shortage of kidney transplantation. Recently it becomes a routine procedure with comparable graft survival to compatable ABO transplantation.The number of kidney transplantation can increase by 30% when patients are transplanted against ABO antibody barrier.
The scope of desensitization protocols in ABOi transplant is the reduction and maintenance of anti A/B antibodies (isoagglutinin) during the first 2 weeks post transplantation below a threshold that considered to be safe which is 1/32 in tube technique .
ABO Antigen system:
Oligosaccharide present on red blood cells,endothelial cells,tubular and glomeruli.
Patients with different blood groups differe with respect to their ABO antigen expression in RBC and different tissues.
A2 HLA antigen:
1)Blood group A2 is making up 20% of total people with blood group A antigen .
2)It has low expression of A2 molecules on surface of RBCs 30 to 50% less.
3) It explains the lower immunogenicity of organs from blood group A2 donors
4) A2 organs transplantation can be accomplished by standard immunosuppressive protocoles without any additional measures
ANTI ABO antibodies:
Anti A/B antibodies are predominantly of the IgM class, in the contrary ,in blood group O,they consist of IgG and IgA.
The relative contribution of different ig classes to solid organ rejection is yet to be elucidated
Desensitization of ABOi kidney transplantation:
Includes one or more of the following;
1)Anti A/B depletion at the time of transplantation.,
These involve PP, double filtration PP,and the IA that is commonly adopted in North Europe protocol .Frequency depend on level of antibodies and usually started 14 days prior to transplantation . Cutoff target antibody titer is less than 32% . Post transplant IA is not routinly indicated, but depend on the antibody rebound and post transplant antibody titer. Accomodati9n is a common phenomina in ABOi transplantation, wherein ,despite the higher rebound with prominent C4d deposition in PTC, no rejection could be detected in this context, this phenomina would be fully mature 2 weeks post ABOi transplantation.
2) Modulation of recipients immune system by the use of IVIG:
High dose IVIG 2gm/kg used to be given one day before the transplantation, It has several roles in transplantation including neutralization of antibodies,inducing apoptosis of B and T lymphocytes,apoptosis of plasma cells.Its usually given after PP or IA to reconstitute the immunoglobine profile of the patients.
3) Depletion of B lymphocytes population . As B lymphocytes react with antigenic stimulation maturing to antibody producing plasma cells.This step was accomplished previously by splenectomy, that was replaced by anti CD 20 antibody Rituximab.
Due to over immune suppression incured by Rituximab and the subsequent immunosuppressive protocols with high potential risk of malignancy and opportunistic infections, Rituximab was omitted from the protocol, especially North Europe protocol. However it’s still considered in other centers. Usually administered in 2 doses 28 and 1 day before transplantation.
4) An emerging new concept in ABOi transplantation is the inhibition of complement activation upon binding of antibodies to endothelial antigens. Anti C5 Eculizumab prevent the formation of membrane attack complex. Used in special cases where othe measures fail to treat the AMR.
5) Immunosuppressive protocol: include anti IL-2 receptor antibodies Basiliximal on day 1 and 4 post transplantation. Tacrolimus ,MMF and prednisone started 14 days prior to transplantation.
In conclusion ABOi transplantation has eme4ged as a salvage procedure to expand the living donor transplantation.however down side include infection, malignancy and early rejection.
I would prefer non ABOi kidney transplant whenever possible.
ABO-Incompatible Kidney Transplantation
With currently existing protocols, as many as 90% of patients with an ABOi living donor may effectively be desensitized and transplanted. The aim of desensitization protocols is the reduction and maintenance of anti-A/B antibodies (isoagglutinins) during the first 2 weeks after transplantation below a threshold that is considered to be safe . Thereafter, even when anti-A/B antibodies recur at high levels they will not harm the kidney transplant, a phenomenon that is called accommodation.
Blood group antigens and antibodies ;
ABO antigens are predominantly expressed on red blood cells and are also found on endothelial cells, tubuli, and glomeruli making the ABO antigen system important for kidney transplantation. Blood group A2 recipients, have a low expression of blood group antigen molecules (30–50%) on the surface of erythrocytes, which is believed to be responsible for the lower immunogenicity of organs from blood group A2 donors.
Desensitization for ABOi kidney transplanation;
These include together with a powerful maintenance immune suppression one or more of the following:
(1) Anti-A/B antibody depletion at the time of transplantation using PP, double-“ltration PP/membrane “ltration, or selective or unselective immunoadsorption (IA).
(2) Modulation of the recipient’s immune system by the use of intravenous immunoglobulins (IVIgs).
(3) Reduction of the B lymphocyte pool by splenectomy, or more recently by the anti-CD20 antibody rituximab.
(4) Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the graft endothelium.
Extracorporal treatment ;
Antibody removal strategies may be divided into;
1-methods that completely remove plasma proteins such as PP.
2- methods that remove only a specific fraction of the plasma proteins including the immunoglobulins .
3-more specific methods such as unselective or selective IA.
They prevent the anti-A/B antibody rebound in the early phase after transplantation. IVIg infusion is believed to reduce infectious complications by substituting depleted immunoglobulins.
B-cell depletion by splenectomy or rituximab;
Due to the surgical risk and increased risk of sepsis, splenectomy was gradually substituted by the anti-CD20 antibody rituximab.
Inhibition of complement activation;
An emerging new concept in the transplantation across ABO antibody barriers is the inhibition of complement activation upon binding of antibodies to the allograft endothelium.
Desensitization protocols and survival after ABOi living donor kidney transplantation;
Patient survival in ABOi transplant recipients was reduced due to infectious complications .Other important differences between ABOi and standard risk kidney recipients were a higher incidence of BK virus replication and BK virus nephropathy and a higher prevalence of colonization with multidrug-resistant bacteria .
Complications of ABOi kidney transplantation;
1- Accomodation ;
Accommodation appears to be a frequent phenomenon after ABOi kidney transplantation and is often associated with C4d deposition in peritubular capillaries of allograft biopsies.
2- Infection and Malignancy ;
There are conflicting results on infectious complications after ABOi kidney transplantation in the literature.
A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound, and severe urinary tract infections have been described .
Studies found no increased cancer risk when comparing ABOi kidney transplant recipients to matched ABOc controls.
· Summarise this article
ABO incompatibility was once considered a contraindication for kidney transplant, but not anymore and it can increase the number of living donor kidney transplants by 30%.
The blood group antigens are present on RBCs, endothelial cells, tubules and glomeruli, contributing to their importance in kidney transplantation. The immunogenic strength of the blood group antigens is A1>B>A2.
Desensitization for ABO incompatible transplant includes:
1) Antibody depletion is performed using:
a. Plasmapheresis: It removes plasma proteins
b. Double filtration plasmapheresis (DFPP/ membrane separator): It removes specific fractions of plasma proteins
c. Immunoadsorption (IA):
i. Selective IA: removes specific anti-A or B antibody selectively, but reduce total IgG and IgG against polysaccharide antigens also.
ii. Unselective IA: Better removal of anti-A or B IgG, but poorly remove IgM and IgG3.
It has been seen that membrane separation and unselective IA combination effectively removed IgG, IgM as well as C1q.
2) Immunomodulation using intravenous immunoglobulin (IVIG) decreases rebound and infection risk, but can increase anti A/B antibody titres due to IgG antibodies present in them.
3) B cell depletion involves using either splenectomy (abandoned nowadays due to its surgical and infectious complications) or rituximab (preferred nowadays). Few centers have shown good results without rituximab use. Rituximab non-use has been shown to have increased death censored graft loss.
4) Prevention of complement activation using eculizumab has been tried, but with inconclusive results.
Results of ABO incompatible transplants, in comparison with ABO compatible transplants, show similar patient survival, graft survival as well as death censored graft survival, although with higher rates of early rejection. Early patient survival is reduced due to increased infections causing mortality in ABO incompatible transplants. There is a trend towards better death censored graft survival at 3 years if antiCD20 antibody is used.
Increased incidence of viral infections like CMV, HSV, Varicella zoster virus, BK virus nephropathy and multidrug resistant bacterial infections is seen in ABO incompatible transplants. The risk of malignancy remains similar to that in ABO compatible transplants.
There is 2 times increased risk of haemorrhage due to removal of coagulation factors during antibody depletion, increased risk of surgical complications, lymphocele formation and increased need of surgical revision in ABO incompatible transplants.
Due to these complications, whenever possible, a blood group compatible transplant should be performed. Kidney paired donation programs are an alternative to ABO incompatible transplants, especially with living donor programs.
In the past ABOI is contraindicated because high risk of rejection at moment of transplant.
Now kidney transplant possible in patients with ABOI due to improving immunological technology in detection of anti A/B antibodies and strategies to removal and maintenance of anti A/B antibodies titres. The survival of graft reach to 98% in first year post transplant and from 90% to 88% within 9 years post transplant.
Anti A/B antibodies are oligosaccharides that expressed on surface of endothelial cell of RBC and varieties of cell in the body especially glomeruli.
These antibodies responsible for hyperacute AMR; different type of blood group has different antigen expressed on the surface of cell. blood group A2 present in 20% of Caucasians population has low immunological reactions in comparison to blood group A1 and blood group B. All blood group has anti A/B antibodies with predominantly IgM class but blood group O has IgM class and Class IgG / IgA.
Strategies of desensitisation depend on
– [ ] Removal of anti A/B antibodies pre and post transplant in first 2 weeks by plasma pharesis or by immunoadsorption
– [ ] Intravenous immunoglobulin help to decrease risk of infection
– [ ] depletion of B cell by splenectomy plus rituximab
Splenectomy recently replaced by anti CD20 (rituximab).
– [ ] inhibition of complement activation by eculizumab
Maintenance by triple immunosuppressive agents MMF and low dose steroid and CIN.
Disadvantages of desensitisation protocol are high risk of fatal infection such as TB CMV BK virus and pneumacystic Jirvici and high risk of malignancy.
Case report study shows patient with ABOi kidney transplant die from sepsis and biopsy results show evidence of AMR and presence of C4d deposition along peritubular arteries.
Many reports shows no significant difference in incidence of malignancy between ABOI and ABOc.
Conclusion:
Kidney transplant the best option in patients with ESRD and patients with ABOi has chance to get transplant with good graft function by detection and reduction level of anti A/B antibodies and using desensitisation protocol.
ABO-Incompatible Kidney Transplantation.
INTRODUCTION:
Nowadays, graft survival rates after ABOi kidney transplantation nearly equaled those after ABO-compatible (ABOc) procedures.
When ABO-Incompatible Kidney Transplantation emerged , the number of kidney transplantations from living donors increased by up to 30% and it is an important factor to shortening the waiting time on waiting list.
Specially with currently protocols, as many as 90% of patients with an ABOi living donor may effectively be desensitized.
The role of desensitization protocols is the reduction and maintenance of anti-A/B antibodies (isoagglutinins) during the first 2 weeks after transplantation below a threshold that is considered to be safe (e.g., <1:32).
Deepening on Accommodation phenomena which till now not completely understood as no harmful effect despite of rebound of the anti A/B antibodies.
BLOOD GROUP ANTIGENS AND ANTIBODIES
These oligosaccharides are expressed on the surface of a variety of different cell types, including RBCs, endothelial cells and kidney parenchymal cells.
Antigenic expression of A2 is quantitatively and qualitatively less than that of A1, immunogenic risk based on antigen expression alone is A1>B>A2.
DESENSITIZATION FOR ABOi KIDNEY TRANSPLANTATION:
Protocol of desensitization based on center experiences so there are many different protocol but generally they depends on antibody removal by PEX or IA with anit-CD20 as B cell depletion and IVIG with powerful triple tacrolimus based immunosuppression.
A-Antibody Depletion by Extracorporeal Treatment :
There are 3 methods :
completely remove plasma proteins such as PP .
Remove only a specific fraction of the plasma proteins including the immunoglobulins (such as membrane separation)
More specific methods such as unselective or selective IA.
Unselective IA to be more effective than with selective anti-A/B antibody columns in removing anti-A/B IgG than IgM.
B- Intravenous Immunoglobulins.
The role is to prevent the anti-A/B antibody rebound in the early phase after transplantation decrease rate of infection but sometimes it is associated with IgG against A/B antigens also.
C-B-Cell Depletion by Splenectomy or Rituximab.
Anti-CD 20 Rituximab now is considered medical splenectomy
For B-cell depletion is used now by rituximab in most protocols.
Also some protocols not used rituximab at all if patient had reached an anti-A/B antibody titer of less than 1:32 with good graft survival.
DESENSITIZATION PROTOCOLS AND SURVIVAL AFTER ABOi LIVING DONOR KIDNEY TRANSPLANTATION
Study from Japan used (double-filtration PP, and splenectomy was more recently replaced by the anti-CD20 antibody rituximab) showed patient and graft survival rates 98 and 96% for the first year, and 91 and 83% after 9 years.
Study in US patients were desensitized by PP and low dose IVIg. the incidence of graft loss during the first year after transplantation was 5.9% in ABOi as compared to only 2.9% in ABOc.
European protocol (recipient desensitization by selective IA + Rituximab) patient and graft survival after a mean follow-up of 4.5 years was 93 and 91%, respectively.
Heidelberg desensitization protocol using (unselective IA +one PP session one day before surgery + Rituximab ) led to successful desensitization of 12 patients after a median of six IA treatments, After a median postoperative follow-up of 22 months, graft survival in ABOi kidney transplant recipients was insignificantly lower compared to standard risk recipients.
RESULTS FROM THE CTS
Death-censored graft and patient survival were not statistically significant different between the groups.
Early patient survival was reduced in ABOi kidney transplant recipients due to a higher rate of early infection-associated death.
COMPLICATIONS AND HURDLES OF ABOi KIDNEY TRANSPLANTATION
Accommodation versus Rejection:
C4d deposition in peritubular capillaries of allograft biopsies without pathological injuries which occur mainly after 2 weeks from transplantation despite of high anti-A/B antibody exposure .
Infection and Malignancy
There is higher incidence of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound, and severe urinary tract infections.
Cumulative incidence of death due to infection in recipients of an ABOi living donor graft is higher than matched controls receiving an ABOc living donor graft.
Some studies shown increasing in bleeding tendency and surgical complications in ABOi group than ABOc GROUP.
CONCLUSION:
ABO-Incompatible Kidney Transplantation is considered now one of the important option to decrease time in waiting list for KTX.
It has its merits and demerits and we should dealing with it in combination with other PKD and KAS for improving graft and patient survival.
Article II
ABO-Incompatible Kidney Transplantation
major ABO incompatibility has been considered a contraindication to kidney transplantation
theoretically, the number of kidney transplantations from living donors can be increased by up to 30% when patients are transplanted across the ABO antibody barrier
The aim of desensitization protocols is the reduction and maintenance of anti-A/B antibodies (isoagglutinin) during the first 2 weeks after transplantation below a threshold that is considered to be safe (e.g., <1:32 in tube technique). thereafter, even when anti-A/B antibodies recur at high levels they will not harm the kidney transplant, a phenomenon that is called accommodation.
DESENSITIZATION FOR ABOi KIDNEY TRANSPLANTATION
these include together with a powerful maintenance immunosuppression one or more of the following: (1) Anti-A/B antibody depletion at the time of transplantation using PP, double-filtration PP/membrane “filtration, or selective or unselective immunoadsorption (IA) (2) Modulation of the recipient’s immune system by the use of intravenous immunoglobulins (IVIgs) (3) Reduction of the B lymphocyte pool by splenectomy, or more recently by the anti-CD20 antibody rituximab (4) Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the graft endothelium.
Antibody Depletion by Extracorporal Treatment
Antibody removal strategies may be divided into methods that completely remove plasma proteins such as PP, methods that remove only a specific fraction of the plasma proteins including the immunoglobulins (such as membrane separation), and more specific methods such as unselective or selective IA. While PP is the preferred antibody removal strategy in the US, membrane separation is popular in Japan. Unselective and selective IAs are often used in Europe.
Intravenous Immunoglobulins
– to prevent the anti-A/B antibody rebound in the early phase after transplantation
– to reduce infectious complications by substituting depleted immunoglobulins
B-Cell Depletion by Splenectomy or Rituximab
We observed in the Collaborative Transplant Study (CTS) a higher rate of death-censored graft loss in ABOi kidney transplant recipients when rituximab was omitted
Inhibition of Complement Activation
results on the use of eculizumab after ABOi kidney transplantation are inconclusive.
DESENSITIZATION PROTOCOLS AND SURVIVAL AFTER ABOi LIVING DONOR KIDNEY TRANSPLANTATION
Different protocols were suggested for desensitization. Actually, all with great results with the same core treatments.
COMPLICATIONS AND HURDLES OF ABOi KIDNEY TRANSPLANTATION
Accommodation versus Rejection
An accommodation phenotype may be achieved by the controlled anti-A/B antibody exposure to antigens in the early phase after kidney transplantation. About 2 weeks after successful transplantation, accommodation is established and even high anti-A/B antibody exposure does not harm the kidney transplant.
Infection and Malignancy
A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound, and severe urinary tract infections have been described
No increased risk of malignancy in ABOi compared to ABOc patients
Additional Observations
two times higher risk of early hemorrhage in 119 ABOi kidney transplant recipients when compared to ABOc controls
Some authors observed an increased rate of surgical complications after ABOi kidney transplantation, which were attributed to early intensified immunosuppression with mycophenolic acid and removal of coagulation factors by apheresis.
1- Antibody Depletion by Extracorporal Treatment ,pp,or slective IA,or unslective IA
2- Intravenous Immunoglobulins .
3-Cell Depletion by Splenectomy or Rituximab .
4-Inhibition of Complement Activation for example ecluizimab.
ABO incompatible kidney transplantation is recently used to increase the number of living donors, this was helped by new successful desensitization protocols and improved graft survival.
Blood group antigens and antibodies
ABO antigen system is expressed in RBCs, endothelial cells, tubuli and glomeruli.
Organs from blood group A2 donors are less immunogenic due to low expression of blood group antigen on surface of RBCs
Pathogenic importance of anti-A/B antibodies is well known but the relative contribution of different immunoglobulin isotypes and subclasses is not well determined.
Desensitization for ABO incompatible (ABOi) kidney transplantation
No single desensitization protocol is defined
Antibody depletion by extracorporeal treatment:
Plasmapheresis completely remove all plasma proteins
membrane separation remove specific fraction of plasma proteins including immunoglobulins.
Unselective or selective IA
Modulation of immune system by IVIG:
IVIG used to prevent anti-A/B antibody rebound early post transplant.
Substitute immunoglobulins which reduce the risk of infection due to plasmapheresis.
Reduction of B lymphocytes by rituximab or splenectomy:
Splenectomy is replaced by anti-CD20 rituximab.
Several centers recently omitted B cell depletion from its protocol with controversial results regarding graft survival.
Inhibition of complement activation:
New strategy in ABOi kidney transplantation but with inconclusive results about its efficacy.
Desensitization protocols and survival after ABOi living donor kidney transplantation
Desensitization with double filtration PP and splenectomy which was replaced recently by rituximab was associated with excellent patient and graft survival.
Desensitization with PP and low dose IVIG was associated with higher incidence of graft loss compared to ABOc transplants.
Desensitization with selective IA and splenectomy recently replaced by rituximab was successful with comparable graft and patient survival.
Desensitization with unselective IA without IVIG was associated with insignificantly lower graft survival compared to standard risk transplants and higher prevalence of infectious complications.
Complications of ABOi kidney transplantation
Accommodation versus rejection:
Accommodation is frequent and may be achieved by controlled anti-A/B antibody exposure in early phase post transplant.
Infection and malignancies:
ABOi kidney transplantation is associated with increased risk of early severe infections, higher frequency of viral infection and increased incidence of BK nephropathy.
It was not associated with increased risk of malignancy post transplant.
Additional observations:
Higher risk of early bleeding mostly due to PP and unselective IA.
Increased rate of surgical complications mostly due to coagulopathy and intensified immunosuppression.
Future perspectives
Reducing blood group antigen levels in allograft.
Kidney paired donation programs.
Introduction
At the begining in 1955 ABOi KT was contraindicated until 1982 where Alexander et al.published first large cohort on ABOi KT with 1 year survival of 75 % after successful desensitization and aggressive immune-suppression [2,3]. Due to accumulation of large numbers of patients in the waiting list and shortages of the donors organ, ABOi KT became a valid option to increase the living donors pool. This study reviewed the latest data on ABOi KT.
Blood group antigens and antibodies
The ABO system are oligosacharrides expressed mainly on RBS. They are also expressed on kidney cells namely endothelial cells, tubuli, and glomeruli. This makes the kidney important targets to antibodies against ABO system.
The A antigen is divided into sub-type A1 and A2. A2 is less immuno-genic and expressed is ~ 20% of white people [4,5]. ABOi KT with A2 organs was successful with standard immune-suppression without the need for any extra measures [6]
Anti A/B antibodies are developed upon contact with gut bacteria during infancy.They are mainly IgM but blood type O individuals they are of IgG/IgA subclass.
Desensitization for ABOi Kidney Transplantation
1.Antibody depletion by Extra-corporal Treatment
2.Intravenous Immunoglobulin
3.B cell depletion
I.Splenectomy ;
II.Rituximab ;
III.Standard immune-suppressive therapy WITHOUT Rituximab ;
4.Inhibition of Complement Activation e.g. Eculizumab
Desensitization protocols and Survival After ABOi-living Donor Kidney Transplantation
Results from the CTS
Complications and Hurdle of ABOi-KT
Accommodation versus Rejection ;
Infection and Malignancy
Additional Observations
Future perspectives
Conclusion
At the moment ABOi-KT is used routinely in some centers and it has increased the living kidney donors pool by ~30%. Despite this success, ABOi-KT is associated with increasede mortality due high rate of infectious complications. Therefore ABOc-KT should always be the standard practice unless one is foreced to proceed towards the direction of ABOi-KT.
To reduce the waiting time is the transplantation across ABO antibody barriers, there is a lot of options including transplantation with ABOi. Theoretically, the number of kidney transplantations from living donors can be increased by up to 30% when patients are transplanted across the ABO antibody barrier.
The aim of desensitization protocols is the reduction and maintenance of anti-A/B antibodies during the first 2 weeks after transplantation below a threshold that is considered to be safe (e.g., <1:32 in tube technique). thereafter, even when anti-A/B antibodies recur at high levels they will not harm the kidney transplant, a phenomenon that is called accommodation.
Blood group antigens and antibodies
The ABO antigen system consists of oligosaccharides that are predominantly expressed on red blood cells and are also found on endothelial cells, tubuli, and glomeruli.
anti-A/B antibodies are formed upon contact with gut bacteria during early infancy. Naturally occurring anti-A/B antibodies are predominantly of the IgM class. blood group O individuals they also consist of IgG and IgA class.
Desensitization protocols for ABOI kidney transplantation are changing with time and remain center based. yet not standardized, each center have their own protocol based on their experience, facilities, resources and infrastructure.
Plasmaphersis and IA- The concept of desensitization based on antibodies removal by plasmapheresis or immunoadsorption (IA) which is more selective and specific , preferred for HLA I , ABOI transplant with specific removal of anti-A,anti B abs with average reduction rate by 3-4 fold and associated with less infectious or bleeding side effects compared to plasma-exchange but more expensive.
Immunomodulating agent IVIG-is complementary treatment after plasmapheresis to replace removed antibodies along with other important functions as complement inhibition, FC receptors binding, inhibit B and T cells proliferation, CD8 T cell inhibition, with B cells apoptosis.
No standardized dose, high dose, low dose usually given after plasmapheresis many side effects including infusion related allergic reaction, risk of thromboembolic events, AKI, its use in combination with plasmapheresis the preferred and widely used protocol with or without Rituximab.
B cell depletion- B cell depletion using anti-CD20 Rituximab replaced surgical splenectomy, while rituximab with used in different doses and frequency based on local center protocols but trend nowadays to use low dose rituximab usually 14 days before surgery.
Complications of desensitization therapy include Infection and Malignancy
Although aggressive immunosuppression increases the risk of malignancy in HLA incompatible transplantation,cancer risk was not found to be higher compared ABOi -KT to match ABOc controls. After ABOi -KT there are conflict result regarding infectious complication in the literature.
Higher frequency of viral infection (CMV.HSV,VZV and BK virus) as well as P. Jiroveci pneumonia along with wound infection and severe UTI were reported.
II. ABO-Incompatible Kidney Transplantation
Summarise this article
Transplantation across ABO antibody barrier has emerged as one method to increase donors pool & shorten waiting time for ESRD patients.
Waiting times for a DD kidney transplant may exceed 5 years .
ABO-i transplant can increase the number of transplants from living donors by up to 30%.
The pathogenic importance of anti-A/B antibodies in SOT is well recognized.
ABO antigens are mainly expressed on RBCs, but are also present on endothelial, tubular, & glomerular cells; thus are important in real transplantation.
ABO subclass A2, which makes 20% of blood group A in white races, has a lower expression & immunogenicity compared to A2 & B groups.
Thus ABO-i with A2 organs has been successfully transplanted with standard IS therapy without extra measures.
Desensitization protocols currently used in ABO-I renal transplantation include:
1. Anti-A/B Ab depletion at the time of transplantation:
(i) PP: completely remove plasma proteins
(ii) Double-filtration PP/membrane filtration: removes specific fraction
of the plasma proteins including the immunoglobulins
(iii) IA (selective or unselective): are more specific methods.Studies
showed no difference between different IA strategies on clinical
outcomes.
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2. Immunomodulation by IVIG: often given before transplantation to prevent the anti-A/B antibody rebound in the early post-transplant phase. It also reduces infectious complications by substituting depleted immunoglobulins.
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3. B lymphocyte pool reduction by the anti-CD20
antibody rituximab; & rarely splenectomy.
Some centers recently omitted rituximab from their
protocols & did successful ABO-I transplant with PP
& standard IS; however higher rate of death-
censored graft was seen loss in CTS study.
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4. Inhibition of complement activation upon binding of
antibodies to the endothelium of the graft.
Results on the use of eculizumab after ABO-i kidney
transplantation are inconclusive.
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Desensitization protocols & survival after ABO-i living donor kidney transplantation:
1. The largest cohort (1,427 cases) from Japan:
– Desensitization by double-filtration PP, & splenectomy was more recently
replaced by rituximab.
– Graft survival rates were excellent.
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2. Data from the Scientific Registry of Transplant Recipients (738 cases),USA:
– Desensitization by PP & low dose IVIG.
– Incidence of graft loss during the 1st year was 5.9% in ABO-i vs only 2.9% in
ABO-c.
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3. In 2003, Tydén et al.(Sweden):
– Used a protocol based on desensitization by selective IA.
– Splenectomy was replaced by rituximab.
– This protocol led to a return of ABO-i renal transplant in Europe.
– Genberg et al. used this protocol in 45 patients,
Patient & graft survival were 93 & 91%, respectively. No early acute AMR that
could be linked to anti-A/B antibodies.
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4. Freiburg group from Germany compared 100 ABO-i kidney with 248 ABO-c:
– 10-year patient & death-censored graft survival were 99 & 94%, respectively
in ABO-I transplant; not significantly different from the 80 & 88% survival
rates, respectively, in recipients of ABO-c transplants.
– Rates for AMR & TCMR were not significantly different.
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5. The author(center in Heidelberg):
– Used a protocol for desensitization similar to the Swedish protocol.
– Unselective IA used instead of selective one, allowing also the de-
sensitization for HLA-i living donor transplant.
– Successful desensitization of 12 patients (median of 6 IA treatments). Anti-
A/B titer reduction with unselective IA was comparable to that of a historical
control group that received selective IA.
– More recently 34 ABO-i recipients desensitized with IA were compared to 68
matched, standard risk living donor kidney recipients. Graft
survival was insignificantly lower in ABO-i group.
A higher incidence of BKI & BKVN in ABO-i group.
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6. Results from the CTS
– 1,420 ABO-i recipients compared to a matched group of ABO-c recipients &
to all ABO-c recipients from centers that performed at least 5 ABO-i
procedures.
– No difference in overall graft, death-censored graft, & patient survival
groups.
– Higher rate of early infection-associated death in ABO-I group.
– A better 3-year death-censored graft survival in those who received
rituximab.
================================================
Complications of ABO-i transplantation
– A higher rate of infections (CMV, HSV, VZV, BKV,P. jirovecii pneumonia,
wound, & severe UTIs) are reported. BKVAN was 3 times higher in ABO.i
patients vs patients with HLA antibodies(Sharif et al)
– Higher risk of early hemorrhage
Risk of bleeding is possibly related to IA & PP.
– Increased rate of surgical complications(especially lymphoceles) due to early
intensified IS & removal of coagulation factors by PP.
Future potential research areas:
– Reduction of ABO antigen levels in the allograft using endo-beta-
galactosidase.
ABO incompatibility has long been considered a contraindication to kidney transplantation. Because of the shortage of donors and to avoid long waiting times for the deceased ,many strategies have been developed recently to desensitize ABOI patients and transplant them.
BLOOD GROUP ANTIGENS AND ANTIBODIES
Blood group antigens are present not only in RBCS but also in the endothelial cells and they include A, B, AB, O. Blood group A is divided into A1 and A2.A2 is less immunogenic and can serve as universal donors but only if the titer of antibodies is low. Naturally occurring anti-A/B antibodies are predominantly of the IgM class but especially in blood group O individuals they also consist of IgG and IgA class . The most commonly method used is tube method .Titer > 1/256 is considered high by most centres while acceptable level pre transplantation vary between 1/4 to 1/32 and this level should be maintained throughout the first 2 weeks
DESENSITIZATION FOR ABOi KIDNEY TRANSPLANTATION
Different protocols used in different centers. It includes:
Antibody depletion: PP(completely remove plasma proteins) double-“filtration PP/membrane “filtration(methods that remove only a speci”c fraction of the plasma proteins including the immunoglobulins), or selective or non-selective immunoadsorption.
Modulation of recipient’s immune system: IVIG(to prevent the anti-A/B antibody rebound in the early phase after transplantation,and to reduce infectious complications by substituting depleted immunoglobulins)
B cell depletion: splenectomy previously , or more recently- antiCD20 anti body rituximab.
(4) Inhibition of complement activation : emerging new concept- eculizumab.Results inconclusive.
Induction therapy using either basiliximab or ATG according to risk assessment.
Maintenance Immunosuppression: CNI (tacrolimus-better), MMF started 7-14 days before transplantation, steroids .
DESENSITIZATION PROTOCOLS AND SURVIVAL AFTER ABOi LIVING DONOR KIDNEY TRANSPLANTATION
Different protocols for desensitization has been tried and patient and graft survival assessed. A study from the UK showed death-censored graft survival in first year less than ABOi-KT and patient survival was reduced due to infectious complication mostly pneumocystis jirovecii pneumonia. Outcome of majority of studies revealed graft death and patient survival were not statistically significant different when compared to matched group of ABOc kidney transplant recipients.
COMPLICATIONS AND HURDLES OF ABOi KIDNEY TRANSPLANTATION
Accommodation- Local upregulation of complement regulatory proteins, like CD45, CD55, and CD59, as a consequence of anti-A/B antibody-dependent inactivation of ERK1/2 signaling pathway is the likely mechanism. It is established about 2 weeks after successful transplantation and is often associated with C4d deposition in peritubular capillaries of allograft biopsies.
Infection and Malignancy- higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound, and severe urinary tract infections have been observed in such patients. Also increased rate of surgical complications like lymphoceles after ABOi kidney transplantation.
FUTURE PERSPECTIVES:
Ex- vivo infusion of endo-beta-galactosidase- new strategy for reduction of antigen levels in allograft patients.
CONCLUSION
ABOi-KT signals expand the living donor pool but has increased rates of infectious complication so wherever possible ABOc transplant should be preferred.
ABO in compatible transplantation (ABO ic Tx) was an option to shorten the waiting time for ESRD patients on dialysis with lack of available grafts .
ABO ic Tx can be done by desensitization strategy aiming at lowering isoagglutinin ,1/32 by tube technique , even when rebound increase of anti A/B antibodies occurs later , accommodation can take place preserving the graft.
Blood group antigens and antibodies
blood group A2 recipients, represent 20% of individuals with blood group A, with low expression on the surface of erythrocytes, leading to lower immunogenicity of organs from blood group A2 donors.
Desensitisation for ABO ic Tx includes
(1)Anti-A/B antibody depletion using PP,DFPP, immunoadsorption (IA)
(2) intravenous immunoglobulins (IVIgs)
(3) B lymphocyte depletion by splenectomy, previously or currently by rituximab
(4) Prevention of complement activation upon anti-A/B antibody binding to the graft endothelium.
Antibody Depletion by Extracorporal Treatment
-Using PP removing specific protiens as Ig
-Selective or non selective IA is used in some protocols
-membrane separation and unselective IA used together can remove efficiently IgG and IgM antibodies and complement C1q component
Intravenous Immunoglobulins
Are administered prior Tx to prevent rebound increase of A/B antibody titer and provide protection against infections meanwhile it was noticed to increase A/B Ab titers after giving it
B-Cell Depletion by Splenectomy or Rituximab
Splenectomy was abandoned due to it’s surgical and infection risks
Rituximab substituted it.
Some studies published favorable outcomes for ABOic Tx using standard immunosuppression without Rituximab another studies demonstrated increased graft loss without Rituximab usage.
Inhibition of Complement Activation
Severe antibody-mediated rejection in patients with anti-A/B antibody rebound increase in the level was successfully treated by eculizumab.
Desensitization protocols and survival after ABOi c living donor Tx
Most studies published acceptable and comparable outcomes of ABO ic Tx to ABO c Tx either desensitization using DFPPwith Rituximab or PP and low dose IVIG or selective IA and Rituximab .
ABOic transplant recipients survival was reduced due to infectious complications, mostly Pneumocystis jirovecii pneumonia.
Studies demonstrated also that unselective IA isnot inferior to selective IA
Complications of ABOi Tx
Accomodation versus Rejection
accommodation is detected after ABOi ckidney transplantations and is associated with C4d deposition in peritubular capillaries of allograft biopsies could be attributed to upregulation of complement regulatory proteins, leading to inactivation of ERK1/2 signaling pathway
Infection and Malignancy
The risk of viral infection in ABO ic Tx is high as CMV, HSV, VZV, and BK virus, and P. jirovecii pneumonia, as well as wound, and severe urinary tract infections.
Studies did not reveal an increased risk of malignancy in ABOi c compared to ABOc patients
ABO ic cases are at higher risk of hemorrhage compared to ABO c cases due to repeated IA
ABO ic cases are at higher risk of surgical complications compared to ABO c cases
-Ex vivo infusion of endo-beta-galactosidase is a new method to decrease blood group Ag level.
-Kidney exchange program is a strategy to avoid ABO antibody barrier
Conclusion
ABO ic Tx is common now meanwhile those patients are exposed to higher risk of early rejection, infection, and infection-associated death.
ABOi- KT was historically considered as a contraindication to renal transplantation. Weith the development of strategies to overcome ABO antibody barriers ABOi- KT is now a reality and an option due to organ shortages. ABOi- KT survival rates are comparable to ABOc- KT. ABOi- KT requires desensitization which can be achieved by apheresis and B cell depletion therapy like Rituximab . Antibodies are aimed to be below a certain threshold at the time of transplantation an d 2weeks post surgery. There after accommodation plays an important role in graft survival.
Blood group antigen system is important in kidney transplantation . These antigens are found at RBCs, Kidney endothelial cells , tubules and glomeruli. Anti A/B antibodies are IgM. For blood group O, these area also IgG and IgA.
Desensitisation for ABOi- KT
One or more of the following along with strong immunosuppression.
1-Anti A/B depletion at the time of transplant using PP( Plasmapheresis) ,Double filtration Pp/membrane filtration or selective or unselective immunoadsorption – IA
2- IVIG for recipient immune system modulation
3- B cell depletion by Splenectomy or anti CD 20- Rituximab
4- Prevention of consequences of compliment activation upon anti A/B antibody binding to graft endothelium.
Antibody depletion by extracorporeal treatment
PP is preferred in US and membrane separation is used in Japan
IVIGs
These are given in before ABOi transplant to prevent rebound of Anti A/B antibodies in early phase post transplant. IVIG preparation contain IgG antibodies against A/B antigens and can increase anti A/B antibody titres upon administration.
B cell depletion- Splenectomy or Rituximab
Splenectomy has now been replaced by Rituximab. Higher death censored if Rituximab is omitted.
Inhibition of compliment activation
The results were not conclusive using Eclizumab
Accommodation
Usually occurs in ABOi -KT and can associated withC4d staining.
Complications
Higher incidence of infections lke CMV, HSV, VZV, BK Virus, UTIs and P jirovecii pneumonia
Summary of ABO-Incompatible Kidney Transplantation
Introduction
ABOi-KT reduce the wating time in the transplantation.
In presence of protocol as many as 90% of patients with ABOi living donor effectively be desensitized and transplant.
Achieve reduction and maintain of antibodies during first 2 week of transplant by desensitization below a threshold that is consisted to be safe e.g <1:32 in tube technique.
BLOOD GROUP ANTIGENS AND ANTIBODIES
ABO Ag system important for kidney transplant as is presence in endothelial .tubule and glommulari
As well as RBCs.
Anti A/B antibodies are IgM class but blood group O consist of IgG ana IgA.
DESENSITIZATION FOR ABOi KIDNEY TRANSPLANTATION
Common principles for different protocol for ABOi-KT:
These include together a powerful maintained immunosuppression one or more of the following:
(1)Anti-A/B antibody depletion at the time of transplantation using PP, double-“filtration PP/membrane “filtration, or selective or unselective immunoadsorption (IA) .
2)Modulation of the recipient’s immune system by the use of intravenous immunoglobulins (IVIgs) (3)Reduction of the B lymphocyte pool by splenectomy, or more recently by antiCD20 anti body rituximab.
(4) Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the endothelium.
Antibody Depletion by Extracorporal Treatment
Antibodies strategies there are methods:
1-method completely plasma proteins1` such as PP ,
2-method remove only specific fraction of the plasma proteins include the immunoglobulin;
3-selective or unselective1A
Unselective more effective to remove anti A/B IgG
Selective more effective for removal IgM anti A/B antibodies.
Over all methods no significance difference in reduction anti A/B antibodies ,survival ,kidney function, rejection and complication.
. Intravenous Immunoglobulin
To prevent the antiA/B rebound in early transplant
Decrease infectious complication by replace depleted immunoglobulin.
. B-Cell Depletion by Splenectomy or Rituximab
Before anti Bcell thearpies splenectomy was performed as to reduce B lymphocytes pool prior to ABOi-KT.
Anti CD20 antibodies rituximab
Higher rate of death and graft loss if rituximab not used in protocol of ABOi -TK.
Inhibition of Complement Activation
Inhibition of complement activity up binding of antibodies to the allograf t,endotheial,it will overcome ABOi -KT barrier.
Single centre study to evaluate the effectivity of eculizumab added to conventual therapy in prevention of antibody mediated rejection.in ABOi- KT living donor. The use of eculizumab inconclusive.
Desensitization protocol
Rituximab(antiCD20 Abs ) replace splenectomy recently
PP and low dose of IVIG so the incidence of graft loss on first year is less than ABOc -KT .
A study from the UK showed similar death-censored graft survival in first year less than ABOi-KT is reduce due to infection complication mostly pneumocystis jiverci. pneumonia as these due to intensify immunosuppression such as Rituximab.
Result
Patients were compared to match group ABOc -KT in large study so outcome over all graft .death and patient survival were not statistically significant different.
COMPLICATIONS AND HURDLES OF ABOi KIDNEY TRANSPLANTATIO
Accommodation versus Rejection
Accommodation frequent phenomena after ABOi -KT and associated with c4d deposition in PTC of all graft biopsy.
Local up regulation of complement regulators proteins like CD45,CD55,and CD54 as consequence of anti A/B ab -dependent inactivation of ERK1/2 signalling pathway are discussed as one possible mechanism.
Infection and Malignancy
After ABOi -KT there are conflict result regarding infectious complication in the literature.
Higher frequency of viral infection (CMV.HSV,VZV and BK virus) as well as P.Jirrveveci pneumonia
Wound and sever UTI.
Cancer risk is not found to be higher compared ABOi -KT to match ABOc controls.
Additional Observations
In ABOi transplantation a higher risk of bleeding and correlate to the number of pre transplant aphaeresis treatment and peri and post transplant bleeding risk
Higher risk of surgical complication such as lymphocele
CONCLUSION.
Recently ABOi-KT has became a routine procedure.
ABOi-KT signals expand the living donor pool.
Presence of ABOi -KT however patient has high risk of rejection .infection and infection associated death .where ever possible ABOi procedures should be preferred.
ABO-incompatible (ABOi) kidney transplantation has long been considered a contraindication to successful kidney transplantation. During the last 25 years, increasing organ shortage enforced the development of strategies to overcome the ABO antibody barrier. In the meantime, ABOi kidney transplantation has become a routine procedure with death-censored graft survival rates comparable to the rates in compatible transplantations. Desensitization is usually achieved by apheresis and B cell-depleting therapies that are accompanied by powerful immunosuppression. Anti-A/B antibodies are aimed to be below a certain threshold at the time of ABOi kidney transplantation and during the !rst 2 weeks after surgery , Pneumocystis jirovecii pneumonia, and severe urinary tract infections are increased after ABOi transplantations
BLOOD GROUP ANTIGENS AND ANTIBODIES
ABOi kidney transplantation with A2 organs has been accomplished with standard immunosuppressive therapy without any additional measures . anti-A/B antibodies are formed upon contact with gut bacteria during early infancy. Naturally occurring anti-A/B antibodies are predominantly of the IgM class but especially in blood group O individuals they also consist of IgG and IgA class . While the pathogenic importance of anti-A/B antibodies in solid organ transplantation is well known, the relative contribution of the different immunoglobulin isotypes and their subclasses to organ rejection remains to be elucidated.
DESENSITIZATION FOR ABOi KIDNEY TRANSPLANTATION
These include together with a powerful maintenance immunosuppression one or more of the following:
(1)Anti-A/B antibody depletion at the time of transplantation using PP, double-filtration PP/membrane filtration, or selective or unselective immunoadsorption (IA)
(2)Modulation of the recipient’s immune system by the use of intravenous immunoglobulins (IVIgs)
(3)Reduction of the B lymphocyte pool by splenectomy, or more recently by the anti-CD20 antibody rituximab
(4) Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the graft endothelium.
Antibody Depletion by Extracorporal Treatment
PP is the preferred antibody removal strategy in the US, membrane separation is popular in Japan. Unselective and selective IAs are often used in Europe
Intravenous Immunoglobulins
are given before ABOi kidney transplantation to prevent the anti-A/B antibody rebound in the early phase after transplantation. In addition, IVIg infusion is believed to reduce infectious complications . But IVIg preparations contain IgG antibodies directed against A/B antigens and can effectively increase anti-A/B antibody titers upon administration .
B-Cell Depletion by Splenectomy or Rituximab
Before the introduction of pharmacological anti-B cell therapies, splenectomy was an integral component for the reduction of the B lymphocyte pool prior to ABOi kidney transplantation. Due to the surgical risk and increased risk of sepsis, splenectomy was gradually substituted by the anti-CD20 antibody rituximab. More recently, several groups completely abandoned anti-B cell therapies from their protocols. Transplantation was accomplished by the use of standard immunosuppressive therapy without rituximab when the patient had reached an anti-A/B antibody titer of less than 1:32 (tube method). We observed in the Collaborative Transplant Study (CTS) a higher rate of death-censored graft loss in ABOi kidney transplant recipients when rituximab was omitted .
Inhibition of Complement Activation
An emerging new concept in the transplantation across ABO antibody barriers is the inhibition of complement activation
DESENSITIZATION PROTOCOLS AND SURVIVAL AFTER ABOi LIVING DONOR KIDNEY TRANSPLANTATION
Most patients were desensitized by PP and lowdose IVIg , splenectomy was replaced by the antiCD20 antibody rituximab
COMPLICATIONS AND HURDLES OF ABOi KIDNEY TRANSPLANTATION
Accomodation versus Rejection
Infection and Malignancy .
Blood group antigens are present not only in RBCS but also in the endothelial cells and they include A, B, AB, O
Patient with blood group A has antibodies against B antigen, while those with blood group B has anti -A antibodies
Individuals with blood group O has no antibodies so they are universal donors, on the other hand, patients with blood group AB are universal recipient.
Blood group A is subdivided into A1 and A2. A2 antigen is less common accounting for 20 % of white race individuals with blood group A, and is less expressed on RBCS than A1 so recipients with anti-A sera ( those with blood group B, O) can receive kidney from donors with blood group A2 if anti-A sera is low. In other words individuals with blood group A2 can serve as universal donors but only if the titre of antibodies is low
Measurement of antibodies
Desensitization protocol
1- B cell depletion
2- Antibodies depletion
3- IVIG
Immunosuppression
Rejection
Surgical complications
Infection
Malignancy
Cost
Summarise this article :
After introduction of desensitization, ABOi transplantation became feasible with comparable outcome to ABOc transplantation. Desensitization aimed to reduce & maintain of anti-A/B Abs in first 2 weeks post transplantation below safe level ( <1:32 in tube method).
ABO Ag is very important in renal transplant because it expressed on RBC, endothelial cells, tubule & glomeruli. ABO Ag expression differ between ABO Ags e.g. A2 Ag expression very low ( low immunogenicity) compared to A1 & B Ags .
There was no standardized desensitization protocol for ABoi recipients, but usually it include high maintenance immunosuppression in addition to one of the following:
Abs remaval techniques divided into completely removal of plasma protein e.g. PP or removal of specific portion of plasma protein e.g. membrane separation or selective or non selective IA. There was no significant difference between these techniques regarding Abs reduction, survival, renal function, rejection or complication.
IVIG can be given to prevent Abs rebound in early post transplant period & it may reduce infectious complications. To deplete B cells previously done by splenectomy but now replaced by anti-CD20 rituximab. But ABOi transplantation can be done without using rituximab if Abs titer <1:32 ( by tube methods) without increased risk off graft loss. The result of complement inhibition (eculizumab) in desensitization of ABOi transplantation was inconclusive.
Accommodation is a frequent phenomenon occur in ABOi transplantation & usually associated with C4d positive staining without evidence of AMR even if Ab titer high ( non harmful).
It was found that patient & graft outcome of ABOi transplant were comparable C. jirvecii, BK virus & multi drug resistant bacteria.
Ex-vivo infusion of eddo-beta- galactosidase is a new strategy can be used in future to reduce blood group Ag in graft.
Transplantation from ABO incompatible donor became safe and available in order to increase donor pool and decrease waiting time to stay on dialysis and to shorten the waiting list of NDD and DCD.
ABO antigens are glycoproteins expressed on RBCs, epithelial and endothelial cells. They are 4 groups; A, B, AB, and O.
A group has A antigen and anti-B antibody, B group has B antigen and anti-A antibody, AB has A and B antigen and has no antibody, O group has no antigen and has anti-A and anti-B antibodies.
A group has two phenotypes A1 that is more antigenic and A2, which resemble O group, has no antigens.
In the renal system, ABO expressed on distal and collecting tubules and vascular endothelial cells, when expressed heavily, it is responsible for acute rejection attack.
The reaction of antibody or isoagglutinins with these glycoproteins will lead to complement activation and c4d deposition.
The first trial of transplantation from ABO incompatible donor was done in Japan.
TECHNIQUES OF ABO DESENSITIZATION AND DIFFERENT PROTOCOLS USED OVER TIME:
1- Removal of antibodies by apheresis ; plasma exchange with high permeable filter is less cost, available to remove antibodies by 20% every session, the main concern is its complications as it is non selective removes also clotting factors and other antibodies, so we can do plasmapheresis using double filter as the second filter allows the return of small important molecules try to avoid the complications, also we can use another adding filter or column to selectively IgG which is called immunoadsorption to avoid complications of removal of all antibodies.
2- Immunomodulation using IVIG post plasmapheresis session to replenish the removed beneficial antibodies.
3- Rituximab antiCD20 antibody, is medical splenectomy, it depletes B cells, which are responsible for antibody production.
There is no standard protocol for desensitization prior to transplantation, but in general, we can give rituximab 2 weeks prior to transplantation and do plasmapheresis 4 sessions 1 week before operation and continue it for another 3-4 sessions post transplant, tacrolimus ,MMF and steroid were given from 2-7 days prior to transplantation, keeping trough level of tacrolimus from 12-15 ng/ml.
CLINICAL OUTCOMES AFTER RENAL TRANSPLANTATION INVOLVING ABOI
Mortality in the patients transplanted from ABO incompatible donor is higher at 1, 3 and 5 years post-transplant than the patients transplanted from ABO compatible donor, this mostly related to side effects of heavy immunosuppression given to these patients like infections either bacterial and viral like BK virus, coagulation side effects.
Accommodation:
C4d deposition in absence of any signs and symptoms of AMR, so, this because of accommodation of the graft to that level of antibodies without making graft injury.
Thank you Riham
BLOOD GROUP ANTIGENS AND ANTIBODIES
ABO antigen system consists of oligosaccharides that are
predominantly expressed on red blood cells and are also found on endothelial cells, tubuli, and glomeruli.
Compared to blood group A1 and blood group B individuals, blood group A2 recipients have a low expression of blood group antigen molecules (30–50%) on the surface of erythrocytes.
Naturally occurring anti-A/B antibodies are predominantly of the IgM class but especially in blood group O individuals they also consist of IgG and IgA class.
DESENSITIZATION FOR ABOi KIDNEY TRANSPLANTATION
powerful maintenance immunosuppression one or more of the following:
(1)Anti-A/B antibody depletion at the time of transplantation
using PP which removes all plasma proteins, double filtration PP/membrane filtration which remove only a specific fraction, or selective or unselective immunoadsorption (IA)
single treatments with unselective IA to be more effective than with selective anti-A/B antibody columns in removing anti-A/B IgG.
unselective IA was less effective in the removal of anti-A/B antibodies of the IgM and IgG3 subclass
(2)Modulation of the recipient’s immune system by the use of intravenous immunoglobulins (IVIgs)
IVIg preparations contain IgG antibodies directed against A/B antigens and can effectively increase anti-A/B antibody titers upon administration.
(3)Reduction of the B lymphocyte pool by splenectomy, or more recently by the anti-CD20 antibody rituximab.
Collaborative Transplant Study (CTS) a higher rate of death-censored graft loss in ABOi kidney transplant recipients when rituximab was omitted.
(4) Prevention of the deleterious consequences of complement activation upon anti-A/B antibody binding to the graft endothelium.
results on the use of eculizumab after ABOi kidney transplantation are inconclusive.
the Japanese data shows that from 2001 to 2010, patient and graft survival rates for the 1,427 analyzed patients were an excellent 98 and 96% for the first year, and 91 and 83% after 9 years, respectively.
A higher frequency of viral infections such as CMV, HSV, VZV, and BK virus, as well as P. jirovecii pneumonia, wound, and severe urinary tract nfections have been described in the aboi transplant cohort.
significant correlation between the number of pretransplant apheresis treatments and the peri- and posttransplant bleeding risk.
increased rate of surgical complications after ABOi kidney transplantation was found.