II. Induction with Thymoglobulin in High-Risk Renal Transplant Patients; Beauty and the Beast
- In your own words, summarise this article
- How do you define high-risk patients in your centre (you can refer to the national and international guidelines)?
- How would you manage high risk-patients in your centre (you can refer to the national and international guidelines)?
In the 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines, for example, risk factors for acute rejection include the following :
●One or more human leukocyte antigen (HLA) mismatches
●Younger recipient and older donor age
●Being African American (in the United States)
●Panel reactive antibody (PRA) greater than 0 percent
●Presence of a donor-specific antibody (DSA)
●Blood group incompatibility
●Delayed onset of graft function
●Cold ischemia time greater than 24 hours
So use ATG and if not tolerated use basiliximab
The protocol for induction in high risk renal transplant recipient in our center is to use Inj ATG (antithymocyte globulin) 1.5mg/Kg IV for 3 to 5 days. Inj ATG is always administered with pre medications namely Inj Diphenhydramine, Inj Hydrocortisone and Tab paracetamol. We monitor the differential count and platelet count. We hold further doses of ATG if TLC<3000 and platelet count<1,00,000 cells/cumm.
In 2009, Kdigo guidelines defined high-risk individual poost transplantation as those who have:
for their management:
1- Use of ATG for induction
2- basiliximab or alemtuzumab if ATG is contraindicated.
Improving long term graft survival is the most important purpose of immunotherapy. Induction therapy decreased graft rejection and made reduction of immunosuppression doses possible and help for tolerance .However, optimal induction therapy is not established yet. It was found that induction with biologic agents with conventional IS is preferred to use of conventional agents alone. Induction therapy improved delayed graft function. Antibodies used either lymphocyte depleting like ATG ,Atgam &alemtuzumab ;or non depleting like basiliximab and daclizumab .According to KDIGO 2009 guidelines, depleting lymphocytes are recommended for use in high risk patients who have one or more of the following :HLA mismatching ,high PRA, old age donor, prolonged cold ischemia time AFRO-AMERICAN ethnicity ,DSA ,ABO incompatibility.
ATG vs ATGAM
ATG has lower incidence of acute rejection, and better graft survival and associated with more leucopenia and lower CMV infection.
ATG vs Basiliximab
ATG use is associated with lower incidence of acute ,graft loss and graft rejection and death . In addition, ATG was associated with lower incidence of de novo DSA.ATG was associated with fever ,cytokine reaction and lymphopenia. Basiliximab was associated with lesser infection.
ATG and Alemtuzumab have comparable effect on acute rejection rate.
Induction therapy using ATG in a dose pf 1.5 mg/kg daily for 10 days achieved tolerance in 75% of HLA matched recipients for 5 years.
ATG average dose is 1.5 mg/kg/day for 3-5 days.
Its use decreased mortality in hepatitis C positive patients. In HIV patients risk of infection and hospitalization were increased .Lower dose are used safely in elderly patients. On the pediatric side ,its use decreased immunosuppression therapy. Graft survival was comparable in both obese and non obese patients.
ATG allowed proceeding to Tx in high risk patients which is a common practice.
induction of tolerance is the main objective in kidney transplantation .
to achieve this target and to avoid acute rejection immune supressant is used .
the degree of immune suppression used and type of drug used depends on the degree of immunological risk . the high risk patients need potent immune suppression .
there is no optimum universally accepted protocol in this group of patients .
biological agents commonly used which are save and effective in preventing rejections and improving graft survival .
biological ab are divided into
depleting agent —- rATG – alemmtuzmab .
non depleting —— basilixmab .
they give an advantage of preventing acute rejection and give a chance of reducing the dose of immune suppressant post operatively and even withdrawal or avoidance of some of them .
although there is controversy regarding the optimum induction therapy but generally it classified in to two main category
conventional drug therapy
-higher doses causes side effects
antibody induction
–many studies showed that using biological agents is superior to conventional drug in regard of acute rejection and graft survival .
–antibody induction is also proved to reduce the incidence of delayed graft function.
kdigo suggest to use ab biological agent in the presence one or more of the following
1) High panel reactive antibody (PRA).
2) Increased number of HLA mismatch.
3) Old aged donor.
4) Afro-American ethnicity.
5) Prolonged cold ischemia time.
6) The presence of donor-specific antibody (DSA).
7) ABO-incompatible transplantation.
Antibody Induction in High-Risk Renal Transplant Patients
biological agent classified
ATG is most commonly used ab agents . it affects T cell , B cell ,bone marrow resident plasma cells
rATG is produced from rabbit serum ..
ATAGAM is produced from horse serum ,
rATG SIDE EFFECTS
Comparing Thymoglobulin versus ATGAM
Acute rejection , graft survival , cmv infection is better with rATG tham ATGAM .
rATG IS ABIOLOGICAL AGENT OF CHOICE IN INDUCTION IN HIGH RISK PATIENT ,
Comparing Thymoglobulin with Basiliximab
in one study , after five years of follow-up, Thymoglobulin a lower incidence
of acute rejection, graft loss or death
On the other hand, a meta-analysis compared IL-2 receptor antibodies versus ATG found that there was no difference in graft survival or clinically diagnosed acute rejection between both induction modalities at any time point, however, ATG had a lower incidence of biopsy-proven acute rejection (BPAR) at
one year but at the cost of increased adverse effects including ( malignancy increase in CMV disease . ATG patients had significantly more adverse reactions to drug administration like fever, cytokine release syndrome and more leukopenia .
Brokhof et al. They concluded that induction with ATG was not only associated with the lower incidence of de novo donor-specific antibodies, but it also associated with a decrease in the antibody-mediated rejection when compared
with basiliximab at three years follow-up .
based on the above data — rATG remain the drug of choice in high risk patients .
Comparing Thymoglobulin to Alemtuzumab:
Alemtuzumab is a humanized monoclonal antibody targeting
CD52, which is present on almost all B and T lymphocytes, natural killer cells, macrophages and some granulocytes. Alemtuzumab induces marked lymphocyte depletion via antibody dependent cell lysis, an effect that will persist for several months .
in one study ,With a median follow-up of 2 years, patients and graft survival
were similar for both group ( alemtuzmab ) as well as incidence of infection
and malignancy, but the incidence of BPAR was higher in Thymoglobulin group
In the high-risk group, there was no difference in the incidence
of acute rejection between patients who received Alemtuzumab
and their comparative group who received thymoglobulin
With a median follow-up of 2 years, patients and graft survival
were similar for both groups as well as incidence of infection
and malignancy, but the incidence of BPAR was higher in
Thymoglobulin group after a follow-up for three years.
Dosing Regimen of Thymoglobulin
in one study comparing total high ( 5mg /kg ) dose with lower( 4.5 mg/kg ) dose
the lower dose is associated with less cost with same effect .
different doses ( 1-6mg/kg ) with different duration ( 1-10 days ) .
but most accepted regimen 1.5 mg/kg 3-5 days .
Thymoglobulin in Special Populations:
obesity : – there is no difference in patient and graft survival between obese and non obese patients .
paediatric patients :- rATG induction and steroid minimization results in favourable linear growth, stable graft function, stable or improved
cardiovascular risk and normal bone density in paediatric
recipients.
Elderly recipients:- The conclusion of one study is
that induction protocol was safe and effective in this age
group .
Conclusions
1. There is no ideal induction protocol. Rather there are
different approaches based on risk stratification of each
patient.
2. Antibody induction therapy proved to be safe and efficient,
with an excellent patient and graft survival, especially in highrisk
transplantation.
3. Thymoglobulin (rATG) is more potent and provide a
therapeutic advantage over other biological antibodies used
in induction therapy, yet it’s optimum dose and regimen is
uncertain.
4. Thymoglobulin has a markedly heterogeneous cell receptors
target antigens, which explain the potent lymphocytic
depletive action of this agent, this may be used in the induction
of tolerance protocols in the future
there is no universal definition of high risk immunological risk .one data suggest high risk patient in apatient whith one oor more of the following
high risk patient treatment include
1- assessment of patient for the need of desensitiztion .( by plasmaphresis, IVIG , +_ rituximab )
2- methyl prednisolone (500- 1000 mg ) at 6.00 oclock to changed to oral dose of 1mg/kg to be tapered tp atarget of 5mg /day by month three .
3- mmf tab 2 gm per day
4- tacrolimus at adose of 0.1 mg/kg divided in two dose to target atrouph level 8-10 ng/ml
Induction with Thymoglobulin in High-Risk Renal Transplant Patients; Beauty and the Beast
The main aim of a transplant physician is to provide the optimum management for the transplant recipient in order to improve the long-term patient and graft survival. Acute rejection and delayed graft function (DGF) are important factors that affect long-term graft survival.
The risk of acute rejection is highest in the early posttransplant period, so induction therapy was developed to decrease the incidence of acute rejection, this will allow the use of lower doses of maintenance immune suppression and even may assist in the development of tolerance in solid organ transplantation.
Up till now, there is controversy regarding the optimum induction immune suppression protocol
High immunologic risk of acute rejection can be anticipated in the presence of one or more of the following factors:
1) High panel reactive antibody (PRA).
2) Increased number of HLA mismatch.
3) Old aged donor.
4) Afro-American ethnicity.
5) Prolonged cold ischemia time.
6) The presence of donor-specific antibody (DSA).
7) ABO-incompatible transplantation
Antibody Induction in High-Risk Renal Transplant Patients
Antibodies used in induction protocols, are either monoclonal (e.g. basiliximab), which is targeted to a single cell surface receptor as illustrated in figure 2 [8], or polyclonal ATG, which
is directed against many different cell receptors (e.g. CD3/TCR, CD25, CD28, CD40, CD80, and CD86), adhesion molecules and cell trafficking molecules (e.g. CD11a/CD18 (LFA-1), CD54
(ICAM-1), and CD195 (CCR5)), and other pathways mediators like CD2 and CD45
potent drug has well-recognized adverse effects that are mostly due to the animal origin of antithymocyte immunoglobulin, it ranges from serious events like anaphylaxis, cytokine release syndrome and serum sickness, to more tolerable leukopenia, thrombocytopenia, flu-like
symptoms and increased risk of infection.
Our Protocol for Induction Therapy In High-Risk Cases:
The immune suppression is commenced at 6.0 AM on the day of transplantation by giving the patient 500 mg intravenous (IV) prednisolone, then the intraoperative infusion of 1.5 mg/
kg Thymoglobulin. Thymoglobulin will be given daily for another four days.
Oral immunosuppression will start from day 1 (second day post-operative). We start 0.05 mg/kg Tacrolimus twice daily adjusted to achieve a trough level of 7 to 10 ng/ml, 500 mg (MMF) twice daily and oral prednisolone 1 mg/kg once daily (maximum 60 mg per day) that will be decreased by 5 mg every 3 days till we reach 20 mg daily. After that, tapering will be more slowly over weeks to reach 10 mg final maintenance steroid dose.
In the first few days post-surgery, we hold Thymoglobulin and MMF if the white blood cell (WBC) count drops to less than 2000/microL or the platelet count decreases to less than 75,000/microL. And they are not restored till WBC count became more than 3000/microL and platelet count more than 100,000/microL
no universal dosing recommendations for Thymoglobulin, yet most of the trials showed that low dose for 3 – 7 days was sufficient to achieve acceptable results.
Conclusions
1. There is no ideal induction protocol. Rather there are different approaches based on risk stratification of each patient.
2. Antibody induction therapy proved to be safe and efficient, with an excellent patient and graft survival, especially in high risk transplantation.
3. Thymoglobulin (rATG) is more potent and provide a therapeutic advantage over other biological antibodies used in induction therapy, yet it’s optimum dose and regimen is
uncertain.
4. Thymoglobulin has a markedly heterogeneous cell receptors target antigens, which explain the potent lymphocytic depletive action of this agent, this may be used in the induction of tolerance protocols in the future.
1. In your own words, summarise this article
Induction immunosuppression in kidney transplantation is considered to be any medications given within the perioperative period
Advantages of this protocol was reduction in the occurrence of DGF (delayed graft function), which was common among patients with long standing waiting list on hemodialysis, and grafts from deceased and elderly donor.
On the other hand Induction immunosuppression reduces the risk of acute rejection , and helps lower doses of maintenance immune suppression up to complete withdrawal. Acute rejection and delayed graft function (DGF) are important factors that affect long-term graft survival [1].
The most important of all that it was of great value in induction of tolerance [2].
Types of induction therapy : conventional (utilizing high doses of IS drugs; steroids, antimetabolites ,CNIs) and biological antibodies. Somehow this latter was proved to be superior to the conventional approach in achieving better graft and patient survival [3].
Biological antibodies can be categorized into depletive (e.g. Antithymocyte globulin (ATG) and Alemtuzumab) and non-depletive antibodies (e.g. Basiliximab).
induction therapy strategy is based on risk stratification: High-Risk Renal Transplant Patients receive biological antibodies, while low to moderate risk receive high-dose conventional immune suppression drugs
Classification of biological Antibodies induction therapy : monoclonal, polycolonal, / depleting and non depleting
monoclonal (e.g. basiliximab), which is targeted to a single cell surface receptor 8], or polyclonal ATG, which is directed against many different cell receptors (e.g. CD3/TCR, CD25, CD28, CD40, CD80, and CD86), adhesion molecules.
OKT3 (Anti-CD3 antibody) is a chimeric depletive monoclonal antibody, now obsolete due to massive hazards and major side effects.
ATG: is a polyclonal depleting antibody . target cells are : T-cells, naive and activated B cells and bone marrow resident plasma cells [4]
Mechanism of action : T-cell depletion through via, complement dependant cytotoxicity, antibody dependant cell mediated cytotoxicity, opsonisation and phagocytosis by macrophages and induction of apoptosis .
On the other hand ATG increase expansion of Treg cells (CD4+CD25+Foxp3+ T cells), which play a role in long-term immunomodulation [5]
Side effects and interaction : anaphylaxis, cytokine release syndrome and serum sickness, leukopenia, thrombocytopenia, flu-like symptoms and increased risk of infection. increased incidence of post-transplant lymphoproliferative disease (PTLD) [5].
Comparing ATG to other Induction biological AB:
ATG Vs Basliximab proved to be more potent in reduction of incidence of acute rejection but on the expence of increased adverse reactions, cytokine release syndrome. Leucopenia, malignancy and CMV infection. [6]
ATG Vs Alemtuzumab ( humanized depleting monoclonal antibody,anti CD52, which is present on almost all B and T lymphocytes, natural killer cells, macrophages and some granulocytes [7].
In astudy conducted over a 3 year follow up duration , patients with high-risk risk showed similar benefits of both ATG Vs Alemtuzumab on incidence of acute rejection and graft survival as well as incidence of infection and malignancy,
While in the low-risk group, there was a therapeutic advantage of Alemtuzumab over basiliximab in the form of lower BPAR at three years follow- up (8)
ATG in induction of Tolerance: Tolerance can be defined as a well-functioning graft without any histological signs of rejection, while the recipient (who is immune competent) is not on any immunosuppression drugs for at least one year (9)
2. How do you define high-risk patients in your centre (you can refer to the national and international guidelines)?
1) High panel reactive antibody (PRA).
2) Increased number of HLA mismatch.
3) Old aged donor.
4) Afro-American ethnicity.
5) Prolonged cold ischemia time
6) The presence of donor-specific antibody (DSA).
7) ABO-incompatible transplantation. (7)
3. How would you manage high risk-patients in your centre (you can refer to the national and international guidelines)?
As was mentioned in the centre policy within the review article
Induction Therapy In High-Risk Cases:
Day 0:
500 mg intravenous (IV) prednisolone,
intraoperative infusion of ATG 1.5 mg/ kg. ( continue ATG on day 1,2,3,4).
Day 1: Oral IS, 0.05 mg/kg Tacrolimus twice daily adjusted to achieve a trough level of 7 to 10 ng/ml, 500 mg (MMF) twice daily and oral prednisolone 1 mg/kg once daily (maximum 60 mg per day) that will be decreased by 5 mg every 3 days till reach 20 mg daily. Followed by slower tapering over weeks to reach 10 mg final maintenance steroid dose.
Precautions: withhold ATG and MMF if (WBC) count < 2000/microL or the platelet count < 75,000/microL. Restored only if WBC count > 3000/microL and platelet count >100,000/microL.
References:
(1). Popat R, Syed A, Puliatti C et al. Outcome and Cost Analysis of Induction Immunosuppression with IL2Mab or ATG in DCD Kidney Transplants. Transplantation. 2014, 97 (11): 1161- 1165. 3. Fernández-
(2) Burgos I, Casado MC, JA Pérez-Daga, et al. Induction Therapy in Simultaneous Pancreas-Kidney Transplantation: Thymoglobulin Versus Basiliximab. Transplantation Proceedings. 2015, 47(1): 120-122.
(3). Szczech LA, Berlin JA, Aradhye S et al. Effect of antilymphocyte induction therapy on renal allograft survival: a meta-analysis. J Am Soc Nephrol. 1997, 8(11): 1771-1777
(4). Zand MS, Vo T, Huggins J, et al. Polyclonal rabbit antithymocyte globulin triggers B-cell and plasma cell apoptosis by multiple pathways. Transplantation. 2005, 79(11): 1507-1515.
(5). Lopez M, Clarkson MR, Albin M et al. A novel mechanism of action for anti-thymocyte globulin: induction of CD4+ CD25+ Foxp3+ regulatory T cells. J Am Soc Nephrol. 2006, 17(10): 2844-2853. 12. Steddon S, Ashman N, Chesser A et al. Oxford Handbook of Nephrology and Hypertension. Second edition, Oxford University Press, 2014.
(6) . Webster AC, Ruster LP, McGee R et al. Interleukin 2 receptor antagonists for kidney transplant recipients. Cochrane Database Syst Rev. 2010, 1(1):CD003897.
(7). Gundroo A, Zachariaha M, Singhd N et al. Alemtuzumab (Campath-1H) experience in kidney transplantation what we have learned; current practices; and scope for the future?. Curr Opin Organ Transplant. 2015, 20(6): 638–642.
(8). Hanaway MJ, Woodle ES, Mulgaonkar S et al. Alemtuzumab induction in renal transplantation. N Engl J Med. 2011, 364(20): 1909-1919.
(9). Page EK, Dar WA, Knechtle SJ. Tolerogenic therapies in transplantation. Front Immunol. 2012, 3: 198
The major role of renal transplantation is to provide better long term survival of the graft and recipients,with the aim to decrease acute rejection and DGF which affect the long term survival.
The using of biological agents as induction provides better and safer results with improving in the long term survival.
Biological antibodies can be divided into depletive (e.g. Antithymocyte globulin (ATG) and Alemtuzumab) and non-depletive antibodies (e.g. Basiliximab).
There use allows to decrease the use of the maintenance drugs and even withdrawal of some of them with decrease it’s side effects.
And also assist in the development of tolerance of solid organ transplantation.
There are different protocols for induction therapy but they found that the biological agent is superior in improving graft and patients survival and decrease the occurrence of AR, than the use of conventional agents.
The biological agents either depleted or non-depleted.monoclonal or polyclonal.
The lymphocytes depleted agents include
rATG
eATG
Alemtuzumab
OKT3
While the non -depleting agents include:
Basiliximab
Daclizumab
It’s use mainly in high-risk transplantation
The advantages of it include:
Potent and effective immune- suppression.
– Allow lower doses of
maintenance immune-
suppression (and even avoidance
of some of them)
Disadvantages include:
Expensive.
– Higher risk of infection.
– Complex prescription and
monitoring.
In 2009, Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group has suggested using one of the lymphocytes depleting agents in high-risk transplantation
High immunologic risks recipients include :
1) High panel reactive antibody (PRA). 2) Increased number of HLA mismatch. 3) Old aged donor.
4) Afro-American ethnicity.
5) Prolonged cold ischemia time.
6) The presence of donor-specific antibody (DSA).
7) ABO-incompatible transplantation.
Antibody Induction in High-Risk Renal Transplant Patients
ATG is a depleting agent with potent immune suppressant activity. It contains antibodies that affect T-cells and broad range of other immune system cells e.g. naive and activated B cells together with bone marrow resident plasma cells .It is prepared by immunization of an animal with human thymocytes. The animal is either rabbit (in this case it will be named rATG or Thymoglobulin), or horse (called ATGAM)
Thymoglobulin is a potent agent that is useful in preventing ischemia-reperfusion injury.
The mechanisms by which it induce T-cells depletion including complement dependant cytotoxicity, antibody dependant cell mediated cytotoxicity, opsonisation and phagocytosis by macrophages and induction of apoptosis .Thymoglobulin is also thought to selectively increase expansion of Treg cells (CD4+CD25+Foxp3+ T cells), which attracts great attention due to its role in long-term immunomodulation
Side effects of ATG:
Anaphylaxis
Cytokine release syndrome
Serum sickness
Leukopenia
Thrombocytopenia
Flu-like symptoms
Increased risk of infection
Increase PTLD incidence.
This increased side effects due to the animal origin of antithymocyte immunoglobulin.
Daily check of the WBC and platelets are mandatory.
Comparing Thymoglobulin versus ATGAM
lower incidence of acute rejection and better one-year graft survival with Thymoglobulin .Thymoglobulin had more leukopenia, yet they had a lower incidence of CMV disease .There were no differences in patient survival and graft function at 12 months; none of both groups’ patients develop PTLD .At ten year follow up of the same group, the incidence of acute rejection was lower in Thymoglobulin group ,while patient and graft survival were similar in both groups. It is worth to mention here that mean serum creatinine was higher and eGFR was lower in the Thymoglobulin group .
Based on the above data, we conclude that the use of Thymoglobulin as the antithymocyte globulin of choice is justifiable and appropriate.
Comparing Thymoglobulin with Basiliximab
At one-year follow-up, there was no significant difference in patient and graft survival, however, Thymoglobulin group had lower incidence of acute rejection and cytomegalovirus (CMV) disease ,while infectious complications were lower in basiliximab group .
Moreover, after five years of follow-up, Thymoglobulin group had maintained efficacy in the form of a lower incidence of the composite end point (development of acute rejection, graft loss or death)
ATG patients had significantly more adverse reactions to drug administration like fever, cytokine release syndrome and more leukopenia
induction with ATG was not only associated with the lower incidence of de novo donor-specific antibodies, but it also associated with a decrease in the antibody-mediated rejection when compared with basiliximab at three years follow-up
Comparing Thymoglobulin to Alemtuzumab:
Alemtuzumab is a humanized monoclonal antibody targeting CD52, which is present on almost all B and T lymphocytes, as well as natural killer cells, macrophages and some granulocytes .Alemtuzumab induces marked lymphocyte depletion via antibody dependant cell lysis, an effect that will persist for several months
After 2 years of follow up
Both are similar in patients and graft survival as well as incidence of infection and malignancy
But BPAR were more in ATG
lower cumulative dose of Thymoglobulin provides a chance for cost saving without compromising the efficacy of the drug
At one-year evaluation, there were no differences in incidence of acute rejection, patient and graft survival were similar in both groups(3 days versus 8days).The duration of hospitalization post-transplantation was shorter in the 3 days’ group (6.1 versus 8 days), and they have also more profound lymphocytic depletion that persists for longer duration as compared to the 7 days’ group
Thymoglobulin in Special Populations:
Recipient obesity:
There was no difference in patient and graft survival between obese and non-obese recipients who received Thymoglobulin
Paediatric recipients:
Use of thymoglobuline lead to favorable effect on linear growth, stable renal function, stable cardiovascular function and normal bone density and allow for steroid minimizing maintenance drugs.
Elderly recipients:
The use of low dose thymoglobuline in patients aged more than 60 years as induction
Was safe and effective in this age group with a three-year patient and graft survival comparable to that observed in younger age recipients
Hepatitis C virus-seropositive (HCV+) recipients:
Induction with biological agents lead to decreased patients death.in those group of recipients.
Human immunodeficiency virus (HIV) positive recipients:
The development of highly active antiretroviral therapy (HAART) had markedly improved the survival of HIV-infected patients, and this led to include patients with well-controlled HIV infection in the transplantation waiting list .The use of Thymoglobulin in this special population was not associated with increased risk of progression to acquired immunodeficiency syndrome (AIDS) or death .However, it was associated with marked CD4+ T-cell and total lymphocyte depletion, this increased risk of severe infection requiring hospitalization
Induction with Thymoglobulin in High-Risk Renal Transplant Patients; Beauty and the Beast
Induction therapy is the mainstay of treatment of transplantation, and it help in reducing the incidence of acute rejection whilst reducing the incidence of DGF.
KDIGO has recommended using lymphocyte depleting agents in high immunological risk patients.
High immunological risk:
· High PRA
· Increased no. of HLA mismatches
· Old donor
· Afro-american ethnicity
· Prolonged cold ischaemia time
· Presence of DSA
· ABO-I
Comparing Thymoglobulin versus ATGAM
Brennan et al – lower incidences of AR ( 4.2% vs 25%) and better graft survival (98% vs 83%) with Thymol
· Thymol- more leukopenia but lower incidence of CMV
· No diff in patient survival and graft function at 12/12
· 10 years f/up- AR is lower in Thymol
· Sr creat higher and lower eGFR in Thymol
Thymoglobulin as the anti-thymocyte globulin of choice is justifiable and appropriate.
Comparing Thymoglobulin with Basiliximab
1. Large, prospective, randomized, multicentre study
· Thymol 1.5mg/kg for 5/7 vs Basiliximab 20mg D0,D4
· CyA,MMF and Pred as maintenance
· no significant difference in patient and graft survival at 12 months
· Thymoglobulin group -lower incidence of acute rejection (15.6 % vs 25.5%)
· Thymoglobulin group- lower CMV disease ( 7.8 % vs 17.5%)
· basiliximab group -infectious complications were lower (75.2% versus 85.8%; p = 0.03)
· Thymoglobulin group – maintained efficacy in the form of a lower incidence after 5 years (37% vs 51%)
2. Webster AC et al (meta – analysis)
· no difference in graft survival or clinically diagnosed acute rejection between both induction modalities at any time point
· ATG – lower incidence of biopsy-proven acute rejection (BPAR) at one year
· ATG- increased adverse effects including 75% increase in malignancy and increase in CMV disease
3. Brokhof et al. (2014)
· Studied on moderately sensitised RTR with had history of DSA but negative FCXM
· ATG – lower incidence of de novo donor-specific antibodies and associated with a decrease in the antibody-mediated rejection
ATG -best choice in high-risk kidney transplantation
Comparing Thymoglobulin to Alemtuzumab
1. Farney and his colleagues 2009
· median follow-up of 2 years
· patients and graft survival were similar for both groups and incidence of infection and malignancy
· Thymoglobulin group- incidence of BPAR was higher (26%vs 14%)
2. Hanaway MJ et al
· randomly assigned to receive Alemtuzumab, basiliximab, thymoglobulin according to immunological risk
· high risk group- no diff thymol vs alemtuzumab in AR after 3 years f/up
· low risk group- alemtuzumab had therapeutic advantage over basiliximab – lower BPAR at 3 years f/up
3. Opelz et al
· showed a clear benefit of antibody induction in high-risk transplant
· fails to prove statistical benefit of this strategy in low-risk transplantation
· hospitalization secondary to infection was increased with both induction agents
Role of Thymoglobulin in Tolerance Induction Protocol
Dosing Regimen of Thymoglobulin
1. Pennington et al
· Thymol cumulative dose of 5mg/kg or higher vs lower than 5mg/kg
· BPAR was similar (8.7% for the first group versus 8.9% in the second group, P =0.944)
· Patient survival, graft survival and graft function -similar at 12 months of follow-up
2. Agha et al
· Thymol 3mg/kg intraop and 1.5mg/kg on D1, D2 vs Thymol 1.5mg/kg for 7 days
· no differences in incidence of acute rejection, patient, and graft survival
· duration of hospitalisation was shorter in 3 days regime and & day regime had mor eprofound lymphodepletion
Thymoglobulin in Special Populations
Obese ( BMI more than 30)
Patel et al. (2011)
· Thymoglobulin versus basiliximab induction in obese and non-obese patients
· Thymol- graft survival was better in both obese and non obese
· No diff between obese and non-obese in graft and patient survival who received thymol
Elderly recipients
Laftavi et al. (2011)
· Thymol induction protocol was safe and effective in this age group with a three-year patient and graft survival comparable to that observed in younger age recipients
Hepatitis C virus-seropositive recipients
Luan FL et al
· induction with biological antibodies was associated with decreased hazard ratio (HR) for patient death (HR = 0.75, 95% CI 0.61-0.90, P=0.003), an effect that
· also noticed in patients treated with mycophenolate mofetil (MMF)
Human immunodeficiency virus positive recipient
Carter JT et al
· Thymoglobulin -not associated with increased risk of progression to acquired immunodeficiency syndrome (AIDS) or death
· Thymoglobulin -associated with marked CD4+ T-cell and total lymphocyte depletion, this increased risk of severe infection requiring hospitalization
In your own words, summarise this article
Induction immunosuppressive therapy is the IS given in the peri-operative transplant operation to allow better graft survival and lower incidence of acute rejection and delayed graft function.
Induction immunosuppressive options are divided into:
1- Conventional drugs induction: using high dose CNIs+ anti-metabolites + steroids, usually indicated for low immunological risk transplant.
2- Antibody induction: using depleting and non-depleting agents + lower doses of conventional drugs, usually used for high immunological risk transplant.
from Figure 1 Data from USA from 1997-2006 showing that most recently used induction agents in USA 2006: Thymoglobulin (45%), Daclizumab (20%), Basiliximab(15%), Amemtuzumab (10%).
Antibody induction includes:
1- Lymphocyte depleting agents: ATG (Thymoglobulin, ATGAM), Alemtuzumab (Campath), and OKT3 (not used nowadays).
2- Lymphocyte non-depleting agents: Daclizumab, and Basiliximab.
Advantages: Potent IS, and allow lower doses of maintenance IS.
Disadvantages: Expensive, higher risk of infection and complex prescription and monitoring.
High immunological risk transplant recipients are more liable for acute rejection especially in presence of one or more of the following risk factors (KDIGO guidelines):
1) High PRA>80%. 2) Increased number of HLA mismatch.
3)Old-aged-donor. 4) Afro-American ethnicity.
5) Prolonged cold ischemia time. 6) The presence of DSA.
7) ABO-incompatible transplantation.
Side effects of ATG:
1- Anaphylaxis,
2- Cytokine release syndrome and serum sickness.
3- Leukopenia, thrombocytopenia, flu-like symptoms.
4- Increased risk of infection. It is also accused for the
5- increased incidence of PTLD.
Comparing Thymoglobulin versus ATGAM
Thymoglobulin is ATG prepared by injecting human lymphocytes into rabbits then collecting theses polyclonal antibodies.
ATGAM is prepared in the same way like thymoglobulin but in the horse.
Brennan et al. study in 1999 had demonstrated the following differences:
1- Less acute rejection with Thymoglobulin, at ten year follow up, the incidence of acute rejection was lower in Thymoglobulin group.
2- Better one-year graft survival with Thymoglobulin.
3- Thymoglobulin group had more leukopenia,
4- Thymoglobulin group had a lower incidence of CMV disease.
5- It is worth to mention here that mean serum creatinine was higher and eGFR was lower in the Thymoglobulin group.
There were no differences in patient survival and graft function at one year; none of both groups’ patients develop PTLD.
At ten year follow up, patient and graft survival were similar in both groups.
Comparing Thymoglobulin with Basiliximab:
Outcome of a large prospective randomized multi-center study, metanalysis of 18 RCTs and Brokhof et al. (2014) had shown the following results comparing thymoglobulin group and Basiliximab group:
The following differences after one year follow up:
1- Thymoglobulin group had lower incidence of acute rejection.
2- Thymoglobulin group had lower incidence of CMV disease.
3- Thymoglobulin group had higher incidence of infectious complications.
4- There was no significant difference in patient and graft survival.
5- There was no difference in graft survival or clinically diagnosed acute rejection between both induction modalities at any time point.
6- ATG had a lower incidence of biopsy-proven acute rejection (BPAR) at one year.
7- The cost of increased adverse effects including 75% increase in malignancy, 32% increase in CMV disease.
8- ATG patients had significantly more adverse reactions to drug administration like fever, cytokine release syndrome and more leukopenia.
9- ATG group was associated with lower incidence of de novo DSA.
After 3 years follow up:ATG group was associated with a decrease in ABMR when compared with Basiliximab at 3 years follow-up.
After five years of follow-up:Thymoglobulin group had maintained a lower incidence of the development of acute rejection, graft loss or death.
Thymoglobulin remains the best choice to be used whenever high-risk kidney transplantation.
Comparing Thymoglobulin to Alemtuzumab:
Farney at al. in 2009 studied the efficacy of Alemtuzumab in comparison to Thymoglobulin as an induction agent and concluded the following:
1- The incidence of BPAR was higher in Thymoglobulin group.
2- After 2years follow up: patient and graft survival, incidence of infection and malignancy were similar in both groups.
Role of Thymoglobulin in Tolerance Induction Protocol:
Tolerance means maintaining a normal renal graft function in absence of histo-pathological evidence of rejection, one year after transplantation without being on immunosuppressive drugs.
Stanford University study of inducing tolerance by giving the recipients thymoglobulin and total lymphoid irradiation.
The study included 38 kidney transplant candidates who had living donors. The patients were given combined kidney and enriched CD34+ hematopoietic cell transplants to achieve mixed chimerism.
About 75% of HLA matched recipients achieved complete withdrawal of immune suppression medications for up to 5 years without evidence of rejection or recurrence of renal disease, none of the patients suffered from graft versus host disease or kidney graft loss.
Dosing Regimen of Thymoglobulin:
The lower cumulative dose of Thymoglobulin provides a chance for cost saving without compromising the efficacy of the drug.
Thymoglobulin in Special Populations:
Recipient obesity:Patel et al. (2011) studied the outcome of low dose thymoglobulin versus basiliximab induction in obese (BMI greater than 30) and non-obese patients, follow up for almost 4 years.
Graft survival was better in Thymoglobulin group both in obese and non-obese patients. There was no difference in patient and graft survival between obese and non-obese recipients who received Thymoglobulin.
Paediatric recipients:
Khositseth et al. (2005) presented a retrospective single-centre study that compared Thymoglobulin with ATGAM, patient and graft survival were similar between both groups, but the incidence of acute rejection was higher in ATGAM group.
Elderly recipients:
Laftavi et al. (2011) studied the effect of low-dose induction therapy with Thymoglobulin in 45 patients older than 65 years, as compared with another 45 patients younger than 65 years.
They concluded that this induction protocol was safe and effective in this age group with a three-year patient and graft survival comparable to that observed in younger age recipients.
Human immunodeficiency virus (HIV) positive recipients:The use of Thymoglobulin in this special population was not associated with increased risk of progression to AIDS or death. However, it was associated with marked CD4+ T-cell and total lymphocyte depletion, this increased risk of severe infection requiring hospitalization.
In light of these data, it is advisable to restrict the use of Thymoglobulin to patients at high immunological risk of rejection, with close monitoring of lymphocytic count.
How do you define high-risk patients in your centre (you can refer to the national and international guidelines)?
high-risk patient is defined as someone with presence of one or more of the risk factors including:
1- Increased HLA mismatch
2- DSA presence, MFI>3000.
3- Blood group/ ABO incompatibility
4- Older donor age>65 year and younger recipient
5- High PRA>80%.
6- African-American race
7- Increased cold ischemia time> 24hours
8- History of prior transplant.
How would you manage high risk-patients in your centre (you can refer to the national and international guidelines)?
Management of high-risk patients in our unit involves:
A- Pre-transplant work-up.
B- If crossmatch positive, desensitization using plasmapheresis and IVIG.
C- Immunological risk assessment:
C1- Low risk: induction with basiliximab
C2- High risk: induction with ATG or Alemtuzumab.
D- Maintenance immunosuppression:
D1- CNIs: Tacrolimus vs Ciclosporin
D2- MMF
D3- Steroids
Follow up.
In your own words, summarise this article
Induction is to cause tolerance and to avoid acute rejection .
The degree of immunosuppression in renal transplant and type of drugs depending on risk of rejection , in other words high risk individuals need potent immunosuppression ..
there is no optimum universally accepted protocol in this group of patients .
biological agents commonly used which are save and effective in preventing rejections and improving graft survival .
biological ab are divided into
depleting agent
============
rATG alemmtuzmab .
non depleting
==========
basilixmab .
they help in preventing acute rejection in addition giving a chance of reducing the dose of immune suppressant post operatively and even withdrawal or avoidance of some of them .
although there is controversy regarding the optimum induction therapy but generally it classified in to two main category
conventional drug therapy
used in low immunological risk patients
uses initial high dose of CNI, anti metabolite ,steroid .
advantages
cheap, less risk of infection ,easy to monitor )
Disadvantages
not suitable in high risk patients
higher doses causes side effects
high immunological risk individuals
depleting ab plus low dose immune suppressants .
advantages
potent medication
allow to use low dose or even to a avoid some is medication .
disadvantages
expensive
high infection risk
complex prescription and monitoring
high immunological risk individuals :
1) High panel reactive antibody (PRA).
2) Increased number of HLA mismatch.
3) Old aged donor.
4) Afro-American ethnicity.
5) Prolonged cold ischemia time.
6) The presence of donor-specific antibody (DSA).
7) ABO-incompatible transplantation.
rATG
rATG is the drug of choice in high risk patients
SIDE EFFECTS
anaphylaxis ,cytokine release syndrome , serum sickness , flue like illness
thrombocytopenia , leukopenia
infection , PTLPD .
Comparing Thymoglobulin versus ATGAM
Acute rejection , graft survival , cmv infection is better with rATG tham ATGAM .
Brokhof et al. They concluded that induction with ATG was not only associated with the lower incidence of de novo donor-specific antibodies, but it also associated with a decrease in the antibody-mediated rejection when compared
with basiliximab at three years follow-up
In the other hand , a meta-analysis compared IL-2 receptor antibodies versus ATG found that there was no difference in graft survival or clinically diagnosed acute rejection between both induction modalities at any time point, however, ATG had a lower incidence of biopsy-proven acute rejection (BPAR) at one year but at the cost of increased adverse effects including ( malignancy increase in CMV disease . ATG patients had significantly more adverse reactions to drug administration like fever, cytokine release syndrome and more leukopenia .
Comparing Thymoglobulin to Alemtuzumab:
Alemtuzumab is a humanized monoclonal antibody targeting
CD52, which is present on almost all B and T lymphocytes, natural killer cells, macrophages and some granulocytes. Alemtuzumab induces marked lymphocyte depletion via antibody dependent cell lysis, an effect that will persist for several months .
in one study ,With a median follow-up of 2 years, patients and graft survival
were similar for both group ( alemtuzmab ) as well as incidence of infection
and malignancy, but the incidence of BPAR was higher in Thymoglobulin group
In the high-risk group, there was no difference in the incidence
of acute rejection between patients who received Alemtuzumab
and their comparative group who received thymoglobulin
With a median follow-up of 2 years, patients and graft survival
were similar for both groups as well as incidence of infection
and malignancy, but the incidence of BPAR was higher in
Thymoglobulin group after a follow-up for three years.
Dosing Regimen of Thymoglobulin
in one study comparing total high ( 5mg /kg ) dose with lower( 4.5 mg/kg ) dose
the lower dose is associated with less cost with same effect .
different doses ( 1-6mg/kg ) with different duration ( 1-10 days ) .
but most accepted regimen 1.5 mg/kg 3-5 days .
Thymoglobulin in Special Populations:
obesity : – there is no difference in patient and graft survival between obese and non obese patients .
Conclusions
1. There is no ideal induction protocol. Rather there are
different approaches based on risk stratification of each
patient.
2. Antibody induction therapy proved to be safe and efficient,
with an excellent patient and graft survival, especially in highrisk
transplantation.
3. Thymoglobulin (rATG) is more potent and provide a
therapeutic advantage over other biological antibodies used
in induction therapy, yet it’s optimum dose and regimen is
uncertain.
4. Thymoglobulin has a markedly heterogeneous cell receptors
target antigens, which explain the potent lymphocytic
depletive action of this agent, this may be used in the induction
of tolerance protocols in the future
How do you define high-risk patients in your centre (you can refer to the national and international guidelines)?
high HLA mismatch
ABO incompatibilty
poasitive DSA .
high PRA .
Afroamerican ethnicity
old age donor
prolonged ischemic time .
How would you manage high risk-patients in your centre (you can refer to the national and international guidelines)?
high risk patient treatment include
1- assessment of patient for the need of desensitiztion .( by plasmaphresis, IVIG , +_ rituximab )
2- methyl prednisolone (500- 1000 mg ) at 6.00 oclock to changed to oral dose of 1mg/kg to be tapered tp atarget of 5mg /day by month three .
3- mmf tab 2 gm per day
4- tacrolimus at adose of 0.1 mg/kg divided in two dose to target atrouph level 8-10 ng/ml
Induction therapy is used to prevent acute rejection and even to decrease the incidence of DGF. There are different types of induction therapy in renal transplantation. Although induction therapy is equivalent to biologic agent administration in the majority of protocols but high dose conventional drugs is another option only for low- risk patients. Those with high PRA, high HLA mismatch, presence of DSA ABO- incompatible, black, old age and prolonged cold ischemic time are considered high-risk. Induction therapy in high risk group is performed with administration of biologic agents in form of monoclonal or polyclonal antibodies. Another classification of these antibodies are lymphocyte depleting and lymphocyte non-depleting agents. Monoclonal Abs are against a single receptor such as basiliximab for CD25 of 1L2 receptor or alemtuzxmab against CD25.While polyclonal Abs such as thymoglobulin are against a variety of receptor, adhesion molecules and trafficking molecules. Thymoglobulin is prepared by rabbit immunization with human thymocytes and is the most prevalent Ab which is used in high -risk transplants and is useful preventing kidney damage by ischemic -repercussion .Thymoglobulin is a potent polyclonal antibody that deplete T cell through different mechanisms like CDC ,ADCC, phagocytosis and apoptosis and can create adverse reactions. So it needs premedication before administration. On the other hand expansion of T regs by this antibody help for better long-term outcome. Alemtuzxmab is another lymphocytes -depleting agent and is a human monoclonal antibody against CD52 present in B and T cell, NK cells, macrophages and granulocytes. Comparing alemtuzxmab with thymoglobulin induction, there were no difference between them in terms of patient and graft survival among kidney -pancreas TX. In opelzs study many benefits of using antibody induction in high risk group and no benefit in low risk group. In tacrolimus immunosuppression regimes benefits of using basiliximab in low – risk group is not completely obvious. In Stanford University protocol for induction of tolerance mixed chimerism by combined kidney and HSCT was performed and Thymoglobulin induction was used. Comparing two different doses of thymoglobulin as induction therapy showed no difference in term of BPAR, graft function and survival.
Thymoglobulin is a good option in steroid minimization protocols in children. Low dose Thymoglobulin induction is used as on option in elderly recipients. Biologic antibodies were associated with lower HR for patient’s death in HCV positive patients but more infection in HIV positive recipient.
Our center protocol:
a) Use Thymoglobulin® if T-cell depleting antibody (TDAs) is indicated.
1. Indications of antibody induction (High risk individuals)
i. Positive PRA (>0%) at the time of transplantation
ii. History of previous transplantation
iii. Donor’s age >50 years
iv. Extended criteria donor (ECD)
v. Cold ischemia time > 6 hours
vi. Delayed graft function (DGF) (As defined in the previous
chapter)
2. Three different dosing regimes are used:
i. A single dose of 4.5 mgr/kg
ii. Three daily doses of 1.5 mgr/kg (Total dose of 4.5
mgr/kg)
iii. Three daily doses of 2 mgr/kg (Total dose of 6 mgr/kg)
3. Premedication
i. Acetaminophen 650 mg PO, 30 minutes prior to first and
second treatment. This may be continued throughout the
treatment.
ii. Methylprednisolone 40-60 mg IV, 30 minutes before the
first (and possibly second) treatment.
iii. Diphenhydramine 25-50mg PO, 30 minutes before the
first treatment.
4. Administration
i. The preferred rout of administration is through a central
vein.
ii. When Thymoglobulin is administered through a
peripheral vein, concomitant use of heparin and
hydrocortisone in an infusion solution of 0.9% sodium
chloride may minimize the potential for superficial
thrombophlebitis and deep vein thrombosis.
iii. Set the flow rate to deliver the dose over a minimum of 6
hours for the first dose and over at least 4 hours for
subsequent doses.
5. Thymoglobulin® dose adjustment would be done according to
white blood cell (WBC) and platelet (PLT) count:
2
i. An initial WBC >2000/ mm2 and PLT > 75000/mm2 is
required to start treatment.
ii. The Thymoglobulin® dose is reduced to half if WBC is
between 2000 and 3000/mm2, or a platelet count is
between 50,000 to 100,000/mm2 in daily evaluations.
iii. The Thymoglobulin® is held if WBC is less than
2000/mm2, or a platelet count is less than 50,000/ mm2 in
daily evaluations.
This articles demonstrate the need for induction therapies as they lower incidences of acute rejections and allowes the use of lower doses or even omission of one of maintenance agents with its side effects .
According to KDIGO 2009 recommendations, low/ standard risk patients don’t require induction,
High risk patients should receive induction treatment
Induction agents may be classified monoclonal ( targeting single T cell receptor) or polyclonal ( targeting more than one receptor )
Also they are classified into depleting / non depleting
examples include : thymoglobulin , ATG Alemtuzumab , OKT3 , basiliximab , daclizumab
Common side effects of these antibodies include anaphylaxis, leucopenia , thrombocytopenia.
Comparing thymo to ATG , studies revealed less acute rejections, better graft survival up to 10 years follow up
Comparing thymoglobulin to basiliximab, studies showed no difference regarding patient and graft survival , but less acute rejections more infections in the thymoglobulin group
Considering the above-mentioned studies,
Thymoglobulin remains the best choice to be used whenever
Comparing thymoglobulin to alemtuzumab , results were similar regarding patient and graft survival , Incidence of infections and malignancy
But incidence of biopsy proven acute rejections were higher in thymoglobulin group .
Thymoglobulin also has a role in induction of tolerance post transplantation
Studies proved that no difference regarding efficiency of the drug, between high (>5 mg/kg ) and lower doses.
The most widely accepted dose of thymoglobulin is 1.5 mg / kg for 3 to 5 days .
Lastly thymoglobulin proved to be effective in different patients populations obese, pediatric and elderly
high-risk kidney transplantation are :
PRA >80%
DSAs with MFI > 3000
Patients with autoimmune illnesses
2nd transplantation
The high risk patients are subjected to ordinary CDC cross match and virtual Cross match ,
If DSAs are proved to exist with significant MFI , Desensitization is applied which includes 4 sessions of plasma exchanges followed by IV IG , to be repeated according to the responses, then to use one of the depleting antibodies ( ATG ) as induction agents.
Post transplant, virtual Cross match follow up is done once / twice per year
There’s different protocol in use for induction therapy, which include both:
Conventional drugs:
Initial high doses of CNI + antimetabolite + steroids, indicated Low immunological risk
transplantation.
Depleting or non-depleting biological antibodies + lower doses of conventional
drugs, in high immunological risk transplantation.
Many studies shown biological agent use in induction therapy is associate with better
graft function and low AR, with better survival.
High-risk transplantation:
1) High panel reactive antibody (PRA).
2) Increased number of HLA mismatch.
3) Old aged donor.
4) Afro-American ethnicity.
5) Prolonged cold ischemia time.
6) The presence of donor-specific antibody (DSA).
7) ABO-incompatible transplantation.
Antibody Induction either:
Monoclonal (e.g. basiliximab).
Polyclonal ATG.
Another classification of biological agent:
Lymphocyte-depleting:
Anti-thymocyte globulin, rabbit.( Thymoglobulin®).
Anti-thymocyte globulin, equine (At gam®).
Alemtuzumab (Campath®).
Muromonab-CD3 (OKT3, Orthoclone®).
Lymphocyte non-depleting:
Daclizumab
Basiliximab (Simulect®).
Advantage:
Thymoglobulin is a potent agent that is useful in preventing ischemia-reperfusion injury.
Action:
Exact mechanisms unknown; broadly targets and eliminates preactivated, non-cycling
memory lymphocytes; alters T-lymphocyte activation, homing, and cytotoxic function.
Side Effect:
Cytokine release syndrome (fever, shivering, myalgia, and headache), hypertension,
anemia, leukopenia, thrombocytopenia, increased risk of infection.
Comparing Thymoglobulin versus ATGAM:
Thymoglobulin:
Lower incidence of acute rejection.
Better one-year graft survival.
Lower incidence of CMV disease.
Comparing Thymoglobulin with Basiliximab:
Thymoglobulin group :
Had lower incidence of acute rejection.
Lower cytomegalovirus (CMV) disease.
Infectious complications were lower in basiliximab group.
ATG patients had significantly more adverse reactions to drug administration like fever,
cytokine release syndrome and more leukopenia.
Comparing Thymoglobulin to Alemtuzumab:
Patients and graft survival were similar for both groups as well as incidence of infection
and malignancy, but the incidence of BPAR was higher in Thymoglobulin group.
Dosing Regimen of Thymoglobulin:
Thymoglobulin at a dose of 1.5 mg/kg for three to five days, is in agreement with the
international practice.
Thymoglobulin in Special Populations:
Obesity:
Thymoglobulin graft survival was better in Obese.
Pediatric recipients:
Thymoglobulin to allow steroid free maintenance immune suppression in pediatric
patient.
Elderly recipients:
Induction protocol was safe and effective in this age group with a three-year patient and
graft survival.
Hepatitis C virus-seropositive (HCV+) recipients:
HCV+ transplant recipients have improved survival in comparison to those who remained
on dialysis.
Among HVC+ recipients, induction with biological antibodies was associated with
decreased hazard ratio (HR) for patient deathز
Human immunodeficiency virus (HIV) positive recipients:
The use of Thymoglobulin in this special population was not associated with increased
risk of progression to acquired immunodeficiency syndrome (AIDS) or death,
However, it was associated with marked CD4+ T-cell and total lymphocyte depletion, this
increased risk of severe infection requiring hospitalization , In light of these data, it is
advisable to restrict the use of Thymoglobulin to patients at high immunological risk of
rejection, with close monitoring of lymphocytic count.
How do you define high-risk patients in your center (you can refer to the national and international guidelines)?
High-risk patients according to KDIGO guideline:
1- Number of HLA mismatchز
2-Younger recipient ageز
3.-Old donor ageز
4.-ABO incompatibilityز
5-PRA˃0ز
6-DSA
7-African –American originز
8-Cold Ischemia more than 24 hز
9- Retransplant.
10-Delayed onset of graft functionز
11-Cold ischemia time greater than 24 hoursز
In our center:
we use basiliximab ,as most of our patient is low risk (LRD).
Maintenance immunosuppression: Tacrolimus, MMF, steroid.
High-risk patients defined as those with high PAR, increased number of HLA mismatches, prolonged cold ischemia, those with DSA, ABO-incompatible transplant, etc need high dose induction therapy especially with depleting agents (preferably: rATG, or maybe Almetuzumab) followed by high dose maintenance therapy. historically used agents were OKT3, ATGAM (depleting) now replaced by rabbit ATG (Thymoglobulin). although exact mechanisms are not well known, rATG broadly targets and eliminates preactivated, non-cycling memory lymphocytes, alters T- lymphocyte activation and cytotoxic function. alemtuzumab targets CD52 primarily found on T cells but also B cells. So it is depleting with wide spectrum. contrary to it is Basiliximab (chimeric murine monoclonal antibody ) against CD25 IL2 receptor. As ist it is not depleting, it is preferred in non-high risk patients. non-depleting agents are not used in rejection.
In centers I know, high-risk patients are pretreated with 1.5mg/kg rATG for 5 days in addition to pulse steroid 500 mg intraoperatively with targeted tacrolimus level of 11-15 especially in first 3 months, in addition to standard dose MMF and steroid maintatinance ..
Induction therapy includes all immune suppression drugs that are given in the perioperative period, but it has been commonly used to describe the use of biologic antibodies .
In 2009, Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group has suggested using one of the lymphocytes depleting agents in high-risk transplantation which include one or more of the following 7 factors
High panel reactive antibody (PRA).
ABO-incompatible transplantation
The presence of donor-specific antibody (DSA).
Increased number of HLA mismatch.
Old aged donor.
Afro-American ethnicity.
Prolonged cold ischemia time.
My center experience:
we do living donation only and we have no experience in transplantation in ABO- incompatible groups:
Presence of DSA (even low MFI)
3 or more mismatches
Glomerular disease is the 1ry kidney disease
Sensitized patients with high PRA
Antibody Induction in High-Risk Renal Transplant Patients
Depleting: causes cell lysis by complement dependent or non-complement dependent mechanisms causing cytokine storm and flue like symptoms
examples include ATG and Campath
Non depleting: it cause Rs blockade
Example: Basiliximab
Center experience:
In our center we use ATG each vial contain 100mg and we used to give 1st dose of 100mg intraoperative preceeded by 250-500mg methylprednisolone and total induction dose is 3mg/kg divided on 1st few days postoperative with close follow up of the cell count.
rATG for high risk group as prescribed before 3mg/kg induction total while basilixmab for intermediate risk patient but if not we proceed for low immunological risk with no biological induction.
Role of Thymoglobulin in Tolerance Induction Protocol:
Thymoglobulin is also thought to selectively increase expansion of Treg cells (CD4+CD25+Foxp3+ T cells), which attracts great attention due to its role in long-term immunomodulation.
Stanford University had a leading study about induction of tolerance using post-transplant conditioning The patients were given combined kidney and enriched CD34+ hematopoietic cell transplants to achieve mixed chimerism The recipients received induction therapy in the form of Thymoglobulin and successfully 75% achieved tolerance with no immunosuppressive medications for more than 5 years
Dosing Regimen of Thymoglobulin:
there is no total agreement on dosing of ATG or dividing protocols multiple studies discussed Thymoglobulin at the dose of 5 mg/kg or higher (5.2 ± 0.2 mg/kg, n = 138) while the other group received a cumulative dose lower than 5 mg/kg (4.5 ± 0.6 mg/kg, n = 123) like Pennington et al. (2015) and Agha et al. (2002) which showed no difference
Thymoglobulin in Special Populations:
Pediatric recipients: safe and effective to decrease dose or stop steroids which enhance growth and decrease risk of fracture according to Khositseth et al. (2005) study.
Obesity : safe and effective to decrease dose of steroids according to Patel et al. (2011) study
Elderly recipient: safe and effective according to Laftavi et al. (2011) study
In my center
Induction by biological antibody rATG cumulative dose 3mg/kg divided over 1st 3 days after follow up of cbc .1st dose given intraoperative after pulse methyleprednisolone 500mg
tacrolimus: started 2 days pre-transplant 0.1mg/kg then upgrade to 0.15mg/kg just postoperative with follow up of trough level and adjust dose to keep it around 8-10 1st 3m post-transplant.
MMF: starts 2 days pre-transplant with dose 500mg every 8 hrs and to be upgraded to 1gm twice daily day 4 .
Hand in hand with gradual tapering of steroids 25 mg daily till 80 mg are reached then oral prednisolone is started along with gradual tapering till 20-30 mg per day and then tapering accordingly; Individualization accodingly is the Key .
-Acute rejection and delayed graft function(DGF) are important complications that affect long-term graft survival.
-Induction drugs are biological antibodies against different immune system targets given in the immediate perioperative period.
-Induction therapy reduces the incidence of acute rejection, lowers the dose of maintenance immunosuppression, and sometimes assists in the development of tolerance.
-DGF is associated with male gender, black race, prolonged waiting time in dialysis, degree of HLA mismatch, old age donor, and use of expanded criteria donors.
-High immunological risk recipients are :
1. High PRA.
2. Increased number of HLA mismatches.
3. Old age donor.
4. Prolonged cold ischemia time.
5. Afro-American ethnicity.
6. Presence of DSA.
7. ABO-incompatible transplantation.
-Antibodies used in induction are either lymphocyte -depleting eg . ATG, Alemtuzumab, and OKT3, or non-lymphocyte-depleting eg. basiliximab, and daclizumab.
–ATG inhibits T lymphocytes, naïve and activated B cells, and bone marrow resident plasma cells and increases expansion of Treg cells. It prevents ischemic perfusion injury.
-It is prepared by immunization of rabbit (rATG) or horse( ATGAM) with human thymocytes.
-ATG induces T-cell depletion by complement-dependent cytotoxicity, antibody dependant cell-mediated cytotoxicity, opsonization, phagocytosis and apoptosis.
-Side effects of ATG:
1-Leukopenia and thrombocytopenia.
2-Anaphylaxis.
3-Flu-like symptoms.
4-cytokine release syndrome and serum sickness.
5-Infection.
6-Post-transplant lymphoproliferative disease.
-It needs a daily check of white blood cells and platelet.
-Comparing thymoglobulin versus ATGAM:
– Study showed that thymoglobulin has a lower incidence of acute rejection, better one-year graft survival, lower incidence of CMV but more leukopenia than ATGAM.
-ATG is associated with high mean serum creatinine and lower eGFR than ATGAM.
Comparing ATG with basiliximab
-Study showed that no significant difference in patient and graft survival but thymoglobulin had a lower incidence of acute rejection and CMV.
-There is no difference in graft survival but ATG had more adverse reactions to drug administration.
-ATG induction is associated with a lower incidence of DSA and a decrease with antibody-mediated rejection when compared with basiliximab at three years follow-up.
Comparing thymoglobulin to alemtuzumab
-It is a lymphocyte-depleting, humanized monoclonal antibody.
-A study showed that patient and graft survival, the incidence of infection, and malignancy were similar in both groups with a median follow-up of 2 years.
-No difference in the incidence of acute rejection after follow-up for 3 years between the ATG group and alemtuzumab group.
Role of thymoglobulin in tolerance induction protocol
-Tolerance is a well-functioning graft without any histological signs of rejection, while the recipient is not any immunosuppression drugs for at least one year.
-One study used combined kidney and hematopoietic cell transplant and recipients received ATG induction therapy and total lymphoid irradiation. Majority of recipients (75%) achieved tolerance for 5 years.
The dosing regimen of thymoglobulin :
1.5mg/kg for 3-5 days,
Thymoglobulin in special population:
-ATG can be used in obese recipients, pediatrics recipient HCV +ve recipient, and HIV +ve recipients with monitoring of lymphocyte count.
-There is no consensus protocol for ATG induction therapy.
High-risk patients according to KDIGO guideline:
1. Number of HLA mismatch
2. Younger recipient age
3. Old donor age
4. ABO incompatibility
5.PRA˃0
6. DSA
7. African –American origin
8. Cold Ischemia more than 24 h
9. Retransplant
In my center:
high-risk recipient: induction with ATG
Maintenance immunosuppression: Tacrolimus, MMF, steroid.
Induction therapy include immunosuppression given in perioperative period including conventional drugs and the more commonly used antibody induction.
Antibodies used are either monoclonal as basiliximab and polyclonal as ATG, also classified into lymphocyte depleting and non-depleting antibodies
ATG induce T-cell depletion through various mechanisms and selectively increase Treg cells
Side effects include cytokine release storm, leucopenia, thrombocytopenia and increased risk of infection and PTLD
Thymoglobulin versus ATGAM
A study showed that thymoglobulin was better as had lower incidence of AR and decreased incidence of CMV infection with the same graft survival at 1 and 10 years.
Thymoglobulin versus basiliximab
It was shown that thymoglobulin had decreased incidence of AR and graft loss at 1 year and 5 years but basiliximb had less infectious complications.
A meta analysis showed that ATG had lower incidence of BPAR but more cytokine release syndrome and leucopenia
Another study showed that ATG had lower incidence of De novo DSA and lower incidence of AMR in moderate sensitized patients at 3 year follow up
Thymoglobulin versus alemtuzumab
A study showed that patient and graft survival were the same with similar incidence of infection and malignancy
Role of thymoglobulin in tolerance induction:
In a study about induction of tolerance, the patients were given kidney and enriched CD34+ hematopoietic cell transplant with thymoglobulin induction and total lymphoid irradiation, 75% of HLA matched recipients stoppped immunosuppression for 5 years without kidney graft loss or graft versus host disease.
Dosing regimen of thymoglobulin:
Studies showed that low and high cumulative dose of thymoglobulin have the same graft and patient survival so lower doses can be used to decrease the cost
patients who received thymoglobulin for three days had the same patient and graft survival as those who were given thymoglobulin for 7 days.
Thymoglobulin in special population:
obese recipients: Thymoglobulin was associated with better graft survival in both obese and non obese patients than basiliximab
Pediatric recipients: Induction with thymoglobulin with steroid minimization leads to stable graft function, better linear growth and normal bone density.
Elderly recipients: induction with thymoglobulin was safe with graft survival comparable to that in younger recipients
HCV positive recipients: induction with biological antibodies was associated with decreased risk of death
HIV positive recipients: The use of thymoglobulin wasn’t associated with progression to AIDS or death but was associated with increased risk of infection requiring hospitalization due to total lymphocytes depletion.
High immunological risk patients are those have DSA, increased number of HLA mismatches, previous transplantation, multiple pregnancies, old age donor and young age recipient.
management:
If crossmatch is positive, desensitization with plasmapheresis and IVIG
if crossmatch is negative, induction with ATG then triple maintenance therapy using Tacrolimus, MMF and steroids
The main aim of kidney transplantation management is the improvement in graft and patient survival. Induction therapy has been developed to decrease acute rejection and DGF that affects long-term survival. It allows lower doses of maintenance therapy.
Conventional drugs that are used for induction, consist of initial high doses of CNI, antimetabolite, and steroids. Their indication is low immunological risk transplantation.
Their advantages: they are cheap with less risk of infection, and the probability of easier monitoring.
Their disadvantages are: not suitable in high-risk cases, and higher doses of drugs mean more adverse effects.
Antibody induction drugs consist of depleting or non-depleting biological antibodies that are used with lower doses of conventional drugs for induction therapy. Their indication is high immunological risk transplantation.
Their advantages: they are potent and effective immunosuppression and allow lower doses of maintenance immunosuppression.
Their disadvantages: they are expensive with a higher risk of infection, and they need complex prescriptions and monitoring.
Biologic antibodies that are use as induction therapy can be categorized into depletive (ATG, and Alemtuzumab) and non-depletive antibodies (Basiliximab). Based on results of various studies, induction of immunosuppression by biologic antibodies is superior to conventional immunosuppressive drugs.
In 2009, KDIGO has suggested using one the lymphocyte depleting agents in high-risk transplantation.
High risk immunologic transplantation is defined as the presence of one or more of the following factors:
High panel reactive antibody (PRA).
Increased number of HLA mismatch.
Old aged donor.
Afro-American ethnicity.
Prolonged cold ischemia time.
The presence of donor-specific antibody (DSA)
ABO-incompatible transplantation
In another classification, antibodies used in induction protocols are either monoclonal (Basiliximab, Doclizumab, Alemtuzumab, and Muromonab-CD3), which are targeted to a single cell surface receptor or polyclonal (ATG), which is directed against various receptors, adhesion molecules, cell trafficking molecules, and other pathway mediators.
ATG is a depleting agent and a polyclonal antibody contains antibodies that affect T cells and a wide range of other immune system cells such as B cells and Plasma cells. It is in two forms: either rabbit (rATG or Thymoglobulin) or horse (ATGAM).
ATG is useful in preventing ischemia reperfusion injury.
It exerts its effect by T cell depletion through different mechanisms such as complement dependent toxicity and antibody dependent cell mediated cytotoxicity. It also selectively leads to increased expansion of Treg cells.
Its adverse effects range from serious events such as anaphylaxis, cytokine release syndrome, and serum sickness syndrome to less emergent leukopenia, thrombocytopenia, flu-like symptoms, and increased risk of infection and PTLD.
Thymoglobulin vs ATGAM
Lower incidence of acute rejection and better short-term graft survival and similar long-term patient and graft survival with thymoglobulin compared with ATGAM.
Thymoglobulin vs Basiliximab
Induction therapy with thymoglobulin has been associated with lower incidence of acute rejection (ABMR), lower incidence of de novo DSA (especially in high risk kidney transplantation), more adverse reactions, and higher incidence of infection (such as CMV infection) and malignancy compared with Basiliximab.
Thymoglobulin vs Alemtuzumab
Alemtuzumab is a monoclonal antibody directed against CD52 on all B cells, T cells, NK cells, macrophages, and some granulocytes. It induces marked lymphocyte depletion.
It has been reported that Alemtuzumab in comparison to thymoglobulin has similar graft and patient survival, incidence of acute rejection as well as incidence of infection and malignancy.
It has been reported that Alemtuzumab in comparison to Basiliximab, has a lower incidence of acute rejection. Clear benefit of induction antibody therapy has been shown in high-risk transplants. Basiliximab is ideal for patients with low immunologic risk.
Role of thymoglobulin in tolerance induction therapy
In protocols that tolerance achieve by eliminating alloreactive immune cells and potentiating mixed chimerism, induction therapy by thymoglobulin has been used with good outcomes.
Dosing regimen of Thymoglobulin
There are several studies that compare different doses and various duration of thymoglobulin therapy with approximately similar outcomes, although, the more typical regimen is 1.5 mg/kg for 3-5 days.
Thymoglobulin in special populations
Obese recipients: thymoglobulin induction therapy was associated with similar graft and patient survival in obese and non-obese recipients.
Pediatric recipients: thymoglobulin compared with ATGAM was associated with lower incidence of acute rejection and similar graft and patient survival.
In addition, thymoglobulin induction and steroid minimization were related to favorable outcome regarding linear growth, graft survival, and normal bone density.
Elderly recipients: kidney transplantation in patients older than 60 years old is associated with higher risk of post-transplant complications, mortality and morbidity. Low dose thymoglobulin induction therapy can be useful with good outcome in this group.
HCV+ recipients: Among HVC+ recipients, induction with biological antibodies was associated with decreased hazard ratio (HR) for patient death.
HIV+ recipients: although use of thymoglobulin was not associated with progression to AIDS, since it was associated with profound lymphocyte depletion and increased risk of infection, its use is restricted to patients at high immunological risk of rejection.
In our center, patients with one or more HLA mismatches, younger recipients and older donor age, PRA greater than 0 percent, DGF, second or more transplant, candidates for deceased donor kidney transplantation are considered as high risk and receive rATG at a dose of 1.5 mg/kg for 3-5 days with a maximum cumulative dose of 6 mg/kg along with steroids, tacrolimus and MMF.
1-The Summary:
The main challenge of transplantation is occurrence of acute rejection which leads to graft loss and negative impact on long term of graft survival. With the era of using induction with biological antibodies, the rate of acute rejection and DGF are decreasing. Also, their use in the perioperative period has the advantage of lowering the doses of maintenance immune suppression and allows complete withdrawal of some of these agents and their associated side effects like steroid withdrawal strategy. It also can help the promising strategies to induce tolerance of the recipient immune system to the transplanted graft, which if therapeutically achieved, will be considered a revolutionary step in the transplantation immunology.
Induction agents are classified as:
1-Lymphocyte Depleting agents as ATG and alemtuzumab (Campath)(anti CD 52 monoclonal antibody): increase the risk of infection and risk of cancer and decrease risk of rejection.
Adverse effects of ATG, it ranges from serious events like anaphylaxis, cytokine release syndrome and serum sickness, to more tolerable leukopenia, thrombocytopenia, flu-like symptoms and increased risk of infection. It is also can increased incidence of post-transplant lymphoproliferative disease (PTLD).
2-Non-Lymphocyte Depleting agents as monoclonal antibody against CD25 IL-2 receptor: Basiliximab (Simulect): no increase in the risk of infection or risk of cancer.
-Choice of induction immunotherapy agent is depending on stratification of immunological risk.
Delayed graft function (DGF) is a clinical diagnosis that describes the failure of the renal allograft to function immediately post-transplantation. Another definition of DGF is the need for at least one dialysis treatment in the first week after kidney transplantation (But dialysis can be needed for management of volume overload or hyperkalaemia). Development of DGF is associated with recipient factors like male gender, black race, prolonged waiting time on dialysis and the degree of HLA mismatch. Donor factors contribute to the development of DGF such as prolonged warm and cold ischemia time, an old age donor and use of Expanded Criteria Donors (ECD).
Role of Thymoglobulin in Tolerance Induction Protocol:Tolerance means a well-functioning graft without any histological signs of rejection, while the recipient (who is immune competent) is not on any immunosuppression drugs for at least one year.
The patients were given combined kidney and enriched CD34+ hematopoietic cell transplants to achieve mixed chimerism. The recipients received induction therapy in the form of Thymoglobulin (1.5 mg/kg/day) for five days starting intraoperatively and total lymphoid irradiation for ten days.
How do you define high-risk patients in your centre?
HLA mismatch at HLA DR, Deceased donor, second and third renal transplant,previous transplant rejection due to ABMR,DSAs
International guidelines: High immunological risk for rejection:
one or more of the following:
One or more human leukocyte antigen (HLA) mismatches
Younger recipient and older donor age
African American ethnicity
Panel reactive antibody (PRA) greater than 0 percent
Presence of a donor-specific antibody (DSA)
Blood group incompatibility
Delayed onset of graft function
Cold ischemia time greater than 24 hours
How would you manage high risk-patients in your centre?
Induction with ATG with 4 doses at 1.5 mg/kg days 0,1,2 and 5
Using Alemtuzumab (20 mg/day on Days 0 and 4) for induction in case of intolerability to ATG
References:
Chandraker A, Sayegh MH, Singh AK. Core Concepts in Renal Transplantation. Springer, 2012.
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9 Suppl 3:S1.
Webster AC, Ruster LP, McGee R et al. Interleukin 2 receptor antagonists for kidney transplant recipients. Cochrane Database Syst Rev 2010; 1: CD003897
Induction was aimed to decrease the risk of acute rejection and delayed graft function. Further more they provide a chance for reduction of immune suppressant drugs and induction of tolerance . up to now no ideal induction protocol was approved . Induction with biological antibodies is safe and effective with better patient and graft survival. There are two types : depletive (ATG and Alemtuzumab) and non-depletive antibodies ( Basiliximab). This review assessed ATG in high risk recipients ( High PRA , high number of HLA mismatch, Old aged donor, Afro-American ethnicity, Prolonged cold ischemia time, DSA presence and ABO-incompatibility).
Comparing Thymoglobulin versus ATGAM
Thymoglobulin is associated with lower incidence of : acute rejection , ten year acute rejection and CMV disease . But it causes more leukopenia, higher mean serum creatinine and lower eGFR .
There were no differences in patient survival and graft function at 12 months and 10 years and PTLD .
Comparing Thymoglobulin with Basiliximab
Thymoglobulin is associated with lower incidence of one-year acute rejection and CMV , five years acute rejection, graft loss or death , biopsy-proven one year acute rejection . But it has more adverse effects(malignancy and CMV disease ), drug reactions ( fever, cytokine release syndrome ) and leukopenia . In sensitized recipients with positive DSAs negative FCX at the time of transplantation, ATG was associated with lower incidence of de novo DSA and AMR at three years follow-up.
At one-year follow-up, there was no significant difference in patient survival ,graft survival and clinically diagnosed acute rejection
Comparing Thymoglobulin to Alemtuzumab:
After 2 years, patients survival ,graft survival, incidence of infection and malignancy were similar but the incidence of BPAR was higher in Thymoglobulin group. After three years , the high-risk group has no difference in the incidence of acute rejection between patients who received Alemtuzumab and those received Thymoglobulin .
Role of Thymoglobulin in Tolerance Induction Protocol:
Thymoglobulin (1.5mg/kg/day) for five days starting intraoperatively and total lymphoid irradiation for ten days ended, in 75% of HLA matched recipients ,with complete withdrawal of immune suppression medications for up to 5 years without evidence of suffered from graft versus host disease or kidney graft loss
Dosing Regimen of Thymoglobulin:
The incidence of BPAR was similar if the dose is less or more than 5 mg/kg or duration of 3 or 7 days . Patient survival, graft survival and graft function were similar at 12 months of follow-up.
So lower doses of Thymoglobulin were preferred to reduce the cost
Thymoglobulin in Special Populations:
Recipient obesity: graft survival was better in Thymoglobulin group in obese patients
Paediatric recipients: less acute rejection and a chance for steroid minimization
Elderly recipients: > 60 years safe and effective in this age with a three-year patient and graft survival comparablto that observed in younger age recipients
HCV seropositive recipients: decreased hazard ratio (HR) for patient death
(HIV) positive recipients: is associated with marked CD4+ T-cell and total lymphocyte depletion, this increased risk of severe infection requiring hospitalization
1. How do you define high-risk patients in your centre ?
Presence of any of the following criteria indicates high immunological risk:
• Second transplants.
• Child to mother or husband to wife transplants.
• Donors with two HLA-DR mismatches.
• Weak DSAs (cumulative MFI < 2000) with negative FCXM.
• Positive B-cell CDC-XM (current or historic).
• Positive historic T-cell CDC-XM.
2. How would you manage high risk-patients in your centre ?
The aim of induction therapy is to improve graft survival ,to decrease acute rejection and DGF .DGF is associated with recipient factors like male gender, black race, prolonged waiting time on dialysis and the degree of HLA mismatch . Donor factor such as prolonged warm and cold ischaemia time, an old age donor and use of Expanded Criteria Donors (ECD) .
Many RCT and meta-analysis studies showed superiority in the use of biologic agents in induction therapy over the use of conventional Immunosuppression drugs
. In 2009 KDIGO guidelines suggested using one of the lymphocytes depleting agents in high risk transplantation.
Biological antibodies acting as induction agents can be either monoclonal {including Alemtuzumab, OKT3, Interleukin 2 receptor antibodies (Basiliximab and Daclizumab)} or polyclonal (ATG – Thymoglobulin and ATGAM). OKT3 is no longer used . ATG acts on pre-activated non-cycling memory T lymphocytes leading to T cell depletion by complement mediated and antibody dependent cytotoxicity.
Thymoglobulin has been compared with other induction agents.
Thymoglobulin is associated with better graft survival and lower acute rejection rates, but lower eGFR and higher creatinine levels as compared to ATGAM use.
Thymoglobulin compare with basiliximab is associated with lower acute rejection but the graft and patient survival are the same
Thymoglobulin, when compared with Alemtuzumab, had similar patient and graft survival but increased biopsy proven acute rejection. Alemtuzumab has been shown to be associated with lower acute rejection as compared to basiliximab use.
Thymoglobulin in Special Populations: In obese patient the effect of Thymoglobulin in long term graft survival and outcome is same as in none obese patient .
Paediatric recipients: the effect of Thymoglobulin is better in growth ,bone density and improved cardiovascular risk with low incidence of infection . Also in elderly age more than 65y the outcome is good .
Hepatitis C virus-seropositive (HCV+) and (HIV) patient :
Use of Thymoglobulin was not associated with increased risk of progression to (AIDS) or death . However, it was associated with marked CD4+ T-cell and total lymphocyte depletion, this increased risk of severe infection requiring hospitalization , so the advice is to restrict the use of Thymoglobulin to patients at high immunological risk of rejection, with close monitoring of lymphocytic count .
How do you define high-risk patients in your centre (you can refer to the national and international guidelines)?
Local guideline
–Presence of any of following criteria indicate high immunological risk ;
-second transplant
-child to mother or husband to wife transplant .
-Donor with 2 HLA-DR mismatches
-weak DSA(cumulative MFI less than 2000) with negative FCMX .
-Positive B-cell CDC-XM (current or historical ).
-positive historic T-cell CDC-XM .
How would you manage high risk-patients in your centre (you can refer to the national and international guidelines)? In our practice we use ATG as induction therapy with methylprednisilone ,low dose of TAC and MMF.
1-The Summary:
Implication of interleukin-2 receptor antibody induction therapy in standard risk renal transplant in the tacrolimus era:
The aim of this meta-analysis is to determine the effect of IL-2 induction therapy on the rate of rejection and patient and graft survival in standard-risk renal transplant patients with tacrolimus based maintenance immunotherapy. Secondary assessment of the effect of IL-2 induction therapy on creatinine change and the risk of cytomegalovirus (CMV) infection.
The main challenge of transplantation is occurrence of acute rejection which leads to graft loss and negative impact on long term of graft survival. With the era of strong induction therapy the rate of acute rejection and DGF are decreasing.
Many induction agents are available and classified as:
1-Lymphocyte Depleting agents as ATG and alemtuzumab (Campath)(anti CD 52 monoclonal antibody): increase the risk of infection and risk of cancer and decrease risk of rejection.
2-Non-Lymphocyte Depleting agents as IL-2 receptor antibody Basiliximab (Simulect): no increase in the risk of infection or risk of cancer.
-Choice of induction immunotherapy agent is depending on stratification of immunological risk of acute rejection
– Standard risk for renal transplant was defined as less than two human leucocytic antigen DR (HLA-DR) mismatches, panel reactive antibody (PRA) <20% and recipients with no more than one previous transplant.
Webster et al. conducted a large meta-analysis that included studies with cyclosporine-based maintenance immunosuppression. The meta-analysis reported a decrease in the risk of acute rejection of 28% in those receiving IL-2R antibody induction therapies, The KDIGO guidelines, based on results of this meta-analysis, recommend IL-2R antibody induction as standard induction therapy in low-risk renal transplant patients.
Another meta-analysis concluded that in patients at low immunological risk, with more than one-third of the patients having no previous transplants. It showed a lower risk of rejection in IL-2R antibody induction compared with placebo. It also showed no privilege of T-cell-depleting agents over IL-2R antibody induction therapy in these patients at low immunological risk.
The Symphony study showed better graft survival and less risk of acute rejection events at 1-year follow up post-transplant in patients receiving tacrolimus compared with those receiving cyclosporine.
In the current meta-analysis they concluded that no additional benefit of IL-2R antibody induction therapy in standard-risk patients in the tacrolimus era regarding rejection rate.
How do you define high-risk patients in your centre?
HLA mismatch at HLA DR, Deceased donor, second and third renal transplant,previous transplant rejection due to ABMR,DSAs
International guidelines: High immunological risk for rejection:
one or more of the following:
One or more human leukocyte antigen (HLA) mismatches
Younger recipient and older donor age
African American ethnicity
Panel reactive antibody (PRA) greater than 0 percent
Presence of a donor-specific antibody (DSA)
Blood group incompatibility
Delayed onset of graft function
Cold ischemia time greater than 24 hours
How would you manage high risk-patients in your centre?
Induction with ATG with 4 doses at 1.5 mg/kg days 0,1,2 and 5
Using Alemtuzumab for induction in case of intolerability to ATG
References:
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9 Suppl 3:S1.
Webster AC, Ruster LP, McGee R et al. Interleukin 2 receptor antagonists for kidney transplant recipients. Cochrane Database Syst Rev 2010; 1: CD003897
Sorry it is a wrong contribution y mistake
1- The summary
Induction therapy is effective in reducing the acute rejection rate, and also reducing the incidence of delayed graft rejection through allowing the use of lower doses of maintenance immune suppression and enhancing development of tolerance in transplantation.
At 2009 KDIGO recommended using lymphocyte depleting agents in high immunological risk patients which are those with high PRA , those with high number of HLA mismatch, Old aged donor, Afro-American ethnicity ,prolonged cold ischemia time, the presence of d DSA and ABO-incompatible transplantation.
Antibody Induction in High-Risk Renal Transplant Patients
is divided into depleting and non depleting agents where
Depleting include
-OKT3 which was withdrawn due to its side effects
– ATG which has antibodies directed against T cells ,B cells and plasma cells ,its side ffects includes cytokine release syndrome, leucopenia and thrombocytopenia, increasing infection risk and associated with PLTD
Comparing ATG to basiliximab ATG provides lower rejection risk while basiliximab provides lower infection risk
Comparing ATG to Alemtuzumab showed no difference regarding rejection and infection risk
-Alemtuzumab as monoclonal antibody against CD 52 with sam side effects as ATG
Non depleting agents include
Basiliximab ,and Daclizumab which are monoclonal antibody against CD25 IL-2 receptor with same side effects as ATG but less infection risk
Role of Thymoglobulin in Tolerance Induction Protocol
A study was done in Stanford university aimed at inducing tolerance to 38 renal transplant recipient with enriched CD34+ hematopoietic cell transplants to achieve mixed chimerism.
Thymoglobulin was given as induction therapy with lymphoid irradiation for 10 days ,75% of HLA matched recipients stopped immunosuppression for 5 y without experiencing graft rejection
Concerning the ATG dose , multiple studies concluded that lower doses are cost effective and efficient.
Thymoglobulin at a dose of 1.5 mg/kg for three to five days is internationaly agreed dose.
Thymoglobulin in Special Populations
Astudy relevaled that lower doses of thymoglobulin given to obese and non obese patients is associated with better graft survival if compared to basiliximab
Another study concluded that Thymoglobulin induction and steroid minimization regimens in paediartic group was associated with acceptable effects on linear growth, graft function, cardiovascular risk and bone density with no episodes of EBV or CMV infection
Thymoglobulin used in induction therapy given to elderly group of renal transplant recipients showed favourable 3 y graft survival outcome
HCV +ve recipients reciving biological therapy had less death risk
Also using thymoglobulin in HIV +ve well controlled recipents did not increase risk of death nor AIDS flurring but increased infection risk
The author Protocol for Induction Therapy In High-Risk Cases
on the transplantation day 500 mg intravenous (IV) prednisolone is given at 6 am , then intraoperative infusion of 1.5 mg/ kg Thymoglobulin which will be given daily for 4 more days
Day 1 the patient will recive
0.05 mg/kg Tacrolimus twice daily adjusted to achieve a trough level of 7 to 10 ng/ml,
500 mg (MMF) twice daily and
oral prednisolone 1 mg/kg once daily (maximum 60 mg per day) that will be decreased by 5 mg every 3 days till reaching 20 mg daily then tapering will be more slowly over weeks to reach 10 mg final maintenance steroid dose.
WBCs and platelet counts are monitored and thymoglobulin and MMF doses are manged accordingly.
2- High risk patients
patients who currently have or have a history of PRA > 20% or retransplant.
older age recipents , deceased donor, higher number of HLA mismatches, and high risk for cytomegalovirus disease as in donor positive and recipient negative cases; and immunosuppressive therapy including cyclosporin A (compared with tacrolimus) (1)
3- Most of the immunosuppressive regimes use long-term triple immunosuppression with Tacrolimus, Prednisolone and Mycophenolate mofetil. Maintenance immunosuppression without corticosteroids is usually only considered if the induction agent is a lymphocyte depleting antibody such as anti-thymocyte globulin (ATG) or Alemtuzumab (Campath).(2)
Reference
1- Cippa E P .etal Risk Stratification for Rejection and Infection after Kidney Transplantation .CJASN 2015, 10 (12) 2213-2220
2- Phanish MK et al. Immunological risk stratification and tailored minimisation of immunosuppression in renal transplant recipients. BMC Nephrology volume 21, Article number: 92 (2020)
In your own words, summaries this article
Antibody Induction in High-Risk Renal Transplant Patients
Antibodies used in induction protocols, are either ;
-monoclonal(e.g. basiliximab), which is targeted to a single cell surface receptor .
– polyclonal ATG, which is directed against many different cell receptors .
Another common classification of biological antibodies is to
divide them into depleting and non-depleting antibodies .
May be chimeric or humanized .
ATG is a depleting agent with profound immune suppressant activity. It contains antibodies that will not only affect T-cells but also it will have an impact on a broad range of other immune system cells e.g. naive and activated B cells together with bone marrow resident plasma cells . It is prepared by immunization of an animal with human thymocytes . The animal is either rabbit (in this case it will be named rATG or Thymoglobulin), or horse (called ATGAM) .
Thymoglobulin is a potent agent that is useful in preventing ischemia-reperfusion injury .It is thought to induce T-cell depletion through variable mechanisms, including complement dependant cytotoxicity, antibody dependant cell mediated cytotoxicity, opsonisation and phagocytosis by macrophages and induction of apoptosis. Thymoglobulin is also thought to selectively increase expansion of Treg cells(CD4+CD25+Foxp3+ T cells), which attracts great attention due to its role in long-term immune modulation .
This potent drug has well recognized adverse effects that are mostly due to the animal origin of antithymocyte immunoglobulin, it ranges from serious events like anaphylaxis, cytokine release syndrome and serum sickness, to more tolerable leucopenia , thrombocytopenia, flu-like symptoms and increased risk of infection. It is also accused for the increased incidence of post-transplant lymph proliferative disease (PTLD) .
Dosing Regimen of Thymoglobulin:
There are several studies that analyzed different dosing strategies of Thymoglobulin (from 1 to 6 mg/kg per dose) and for various durations (ranged from 1 to 10 days), however, the more typical regimen is 1.5 mg/kg for three to five days .
Comparing Thymoglobulin versus ATGAM ;
Thymoglobulin is associated with lower incidence of acute rejection . while
both drugs are associated with similar graft survival , Thymoglobulin is associated with better one-year graft survival . leucopenia is seen more with thymoglobulin . Based on risk for rejection and graft survival Thymoglobulin as the anti thymocyte globulin of choice is justifiable and appropriate .
Comparing Thymoglobulin with Basiliximab;
Induction with ATG was not only associated with the lower incidence of de novo donor-specific antibodies, but it also associated with a decrease in the antibody-mediated rejection when compared with basiliximab.
Comparing Thymoglobulin to Alemtuzumab:
Alemtuzumab is a humanized monoclonal antibody targeting
CD52, which is present on almost all B and T lymphocytes, as
well as natural killer cells, macrophages and some granulocytes
.Alemtuzumab induces marked lymphocyte depletion
via antibody dependant cell lysis , an effect that will persist for
several months .
Both drugs are associated with similar patient and graft survival as well as incidence of infection and malignancy .
Thymoglobulin in Special Populations:
Recipient obesity:
obesity is a challenging problem in renal transplant recipients that is associated with increased morbidity, mortality and graft loss . In spite of these facts, kidney transplantation offers a survival benefit as compared to dialysis in obese patients . Thymoglobulin versus basiliximab induction in obese (body mass index (BMI) greater than 30) and non-obese patients. At a mean follow-up of 47.4 ± 10 months, graft survival was better in Thymoglobulin group both in obese (90.3% versus 63.6%, P < .05) and non-obese patients (88.7% versus 68.2%, P < .05). There was no difference in patient and graft survival between obese and non-obese recipients who received Thymoglobulin.
Hepatitis C virus-seropositive (HCV+) and (HIV) recipients:
Use of Thymoglobulin in this special population was not associated with increased risk of progression to acquired immunodeficiency syndrome (AIDS) or death . However, it was associated with marked CD4+ T-cell and total lymphocyte depletion, this increased risk of severe infection requiring hospitalization . In light of these data, it is advisable to restrict the use of Thymoglobulin to patients at high immunological risk of rejection, with close monitoring of lymphocytic count .
How do you define high-risk patients in your centre (you can refer to the national and international guidelines)?
The national protocol ;
Presence of any of following criteria indicate high immunological risk ;
-second transplant
-child to mother or husband to wife transplant .
Donor with 2 HLA-DR mismatches
-weak DSA(cumulative MFI less than 2000) with negative FCMX .
-Positive B-cell CDC-XM (current or historical ).
-positive historic T-cell CDC-XM .
Presence of any of the following criteria is considered contra indication to transplant ;
-positive T-cell CDC-XM(current)
– positive FCXM accompanied by DSAs or repeat HLA mismatches .
-positive FCXM when DSAs or repeat HLA mismatches cannot be excluded .
How would you manage high risk-patients in your centre (you can refer to the national and international guidelines)?
The national protocol
induction ; methylprednisolone 500 mg and ATG (1.5 mg /kg / 4 doses )
maintenance ; tacolimus , MMF and prednisolone .
target tacrolimus trough level are ;
8 – 10 ng/ml in the first month
6 -8 ng/ml in the second to six months
4 -6 ng/ml after the sixth month
In case of ATG induction reduce tacrolimus dose or delay its initiation .
Summary of the Article
This is a review article, studying ATG as induction agent and it’s outcome in immune suppression post-transplant.
The long term out come of graft survival and patient survival is largely dependent on the complications in the early transplant period such as acute rejection and delayed graft function. Induction therapy aims at prevention and lowering of early transplant rejection beside improving graft function and survival.
Many RCT and meta-analysis studies showed superiority in the use of biologic agents in induction therapy over the use of conventional Immunosuppression drugs(1). In 2009 KDIGO guidelines suggested using one of the lymphocytes depleting agents in high risk transplantation.
High imunologic risk of rejection can be expected in the followings:
Commonly used induction agents can be categorized as follows:
According to lymphocyte depletion effect
According to clonality
ATG
In favor of its use
Adverse events mostly due to the animal form of ATG but not rATG.
ATG as induction agent
Brennan et al. (1999); rATG vs ATGAM
Thymoglobulin vs Basiliximab
According to large prospective multi-centre trial(3):
Thymoglobulin vs Alemtuzumab
Farney et al 2009 study(4):
Thymoglobulin in Tolerance Induction
Stanford University study:
Thymoglobulin: Dosing Regimen
several studies analysed different dosing strategies of Thymoglobulin
Thymoglobulin in Special Populations:
How do you define high-risk patients in your centre (you can refer to the national and international guidelines)?
We are dealing with living donation in all centres of transplant in my country.
We are coinciding the KDIGO GUIDELINES in definition of high risk transplant :
How would you manage high risk-patients in your centre (you can refer to the national and international guidelines)?
I will follow the following steps in managing high risk KTR:
Referrences:
1.Szczech LA, Berlin JA, Aradhye S et al. Effect of anti- lymphocyte induction therapy on renal allograft survival: a meta-analysis. J Am Soc Nephrol. 1997, 8(11): 1771-1777.
2.Hardinger KL, Rhee S, Buchanan P et al. A prospective, randomized, double-blinded comparison of thymoglobulin versus Atgam for induction immunosuppressive therapy: 10- year results. Transplantation. 2008, 86(7): 947-952.
3.Turner N. Oxford Textbook of Clinical Nephrology. Fourth edition, Oxford University Press, 2016.
4.Farney AC, Doares W, Rogers J et al. A randomized trial of alemtuzumab versus antithymocyte globulin induction in renal and pancreas transplantation. Transplantation. 2009, 88(6): 810-819.
5.Kahan BD. Individuality: the barrier to optimal immunosuppression. Nat Rev Immunol. 2003, 3: 831-838.
6.Laftavi MR, Patel S, Soliman MR et al. Low-Dose Thymoglobulin Use in Elderly Renal Transplant Recipients Is Safe and Effective Induction Therapy. Transplantation Proc eedings. 2011, 43(2): 466-468.
7.Luan FL, Schaubel DE, Zhang H. Impact of immunosuppressive regimen on survival of kidney transplant recipients with hepatitis C. Transplantation. 2008; 85(11): 1601–1606.
8.Andress L, Gupta A, Siddiqi N et al. Rabbit anti-thymocyte globulin induction in renal transplantation: review of the literature. Transplant Research and Risk Management. 2014, 6: 9-21.
why would you not prefer campath over ATG?
1. In your own words, summarise this article
Induction with Thymoglobulin in High-Risk Renal Transplant Patients; Beauty and the Beast
Kidney transplant is the treatment of choice in end stage renal disease and immunosuppression is the backbone of transplant patient management. Immunosuppression used in the perioperative period, usually biologic antibodies, is known as induction therapy and it has been shown to be helpful in reducing both delayed graft function (DGF) and acute rejection episodes. Use of lymphocyte depleting agents have been recommended in high-risk patients (with high PRA, increased HLA mismatch, icreased donor age, afro-american ethnicity, increased cold ischemia time, ABO incompatible transplant, or elevated DSA).
Biological antibodies acting as induction agents can be either monoclonal {including Alemtuzumab, OKT3, Interleukin 2 receptor antibodies (Basiliximab and Daclizumab)} or polyclonal (ATG – Thymoglobulin and ATGAM). OKT3 is no longer available. ATG acts on pre-activated non-cycling memory T lymphocytes leading to T cell depletion by complement mediated and antibody dependent cytotoxicity.
Thymoglobulin has been compared with other induction agents.
Thymoglobulin has been found to be associated with better graft survival and lower acute rejection rates, but lower eGFR and higher creatinine levels as compared to ATGAM use.
Thymoglobulin use is associated with lower acute rejection but similar graft and patient survival when compared with basiliximab use. This has been prominent especially in high-risk group.
Thymoglobulin, when compared with Alemtuzumab, had similar patient and graft survival but increased biopsy proven acute rejection. Alemtuzumab has been shown to be associated with lower acute rejection as compared to basiliximab use.
Thymoglobulin has been used in tolerance induction protocol, in conjunction with CD34+ hematopoietic cell transplants to achieve mixed chimerism.
There is no consensus on dosing regime of Thymoglobulin, ranging from 1-6 mg/kg/dose for 1 to 10 days, but the usual dose used is 1.5 mg.kg/day for 3-5 days.
Thymoglobulin use has been shown to be safe and effective in special population groups like elderly, children, HIV positive and HCV positive patients.
The protocol used by the authors for high-risk patients involved induction therapy in form of Thymoglobulin at dose 1.5mg/kg starting from the day of transplant for 3 to 7 days with maintenance immunosuppression in form of tacrolimus, MMF and steroids.
2. How do you define high-risk patients in your centre (you can refer to the national and international guidelines)?
In our unit, a high-risk patient is defined as someone with presence of one or more of the risk factors including:
1) Increased HLA mismatch
2) DSA presence
3) Blood group/ ABO incompatibility
4) Older donor age and younger recipient
5) High PRA
6) African-American race
7) Increased cold ischemia time
8) History of prior transplant.
3. How would you manage high risk-patients in your centre (you can refer to the national and international guidelines
Management of high-risk patients in our unit involves:
1) Pre-transplant evaluation: detailed history especially regarding sensitization events and pre-transplant investigations including single antigen bead assay for quantification of DSAs.
2) Desensitization: If crossmatch positive, desensitization using plasmapheresis and IVIG.
3) Induction therapy: Injection Thymoglobulin at 1 mg/kg/day for 3 days. Alemtuzumab is not available.
4) Maintenance immunosuppression:
Tacrolimus: 0.06 mg/kg twice a day, started 2 days prior to transplant. Target trough levels: 9-10 ng/ml
MMF: 1000 mg twice a day, started 2 days prior to transplant
Steroids: Prednisolone 1 mg/kg/day 3 days, then 20 mg/day, tapered over 3 months to 5 mg/day.
5) Post-transplant regular, close follow-up with monitoring of DSA levels and protocol biopsy in patients with DSA.
nice
Introduction
improving long-term patient and graft survival is the goal of transplantation.
Acute rejection and delayed graft function (DGF) are the major risk that affect long-term graft survival .
The risk of acute rejection is highest in the early post-transplant period, so induction therapy was developed to decrease the incidence of acute rejection and allow using lower doses of maintenance therapy .
There is no standard protocol for induction immunosuppression and different protocols exist according to different centers experience.
Induction therapies are classified into biologic antibodies and conventional induction.
large number studies have shown that biologic antibodies was superior conventional immune suppression drugs alone, as it offers better graft survival and lower incidence of acute rejection and DGF.
2009, Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group has suggested using one of the lymphocytes depleting agents in high-risk transplantation. High immunologic risk of acute rejection can be anticipated in the presence of one or more of the following factors :
•High panel reactive antibody (PRA).
•Increased number of HLA mismatch.
•Old aged donor.
•Afro-American ethnicity.
•Prolonged cold ischemia time.
•The presence of donor-specific antibody (DSA).
Another classification of Induction therapy is either depleting or non depleting
Antibodies used in induction protocols, are either monoclonal (e.g. basiliximab), which is targeted to a single cell surface receptor as, or polyclonal ATG.
Antithymocyte globulin;
ATG is a depleting agent with profound immune suppressant activity.
It is prepared by immunization of an animal with human thymocytes. The animal is either rabbit so named rATG or Thymoglobulin, or horse so called ATGAM
Role of ATG
•contains antibodies affect T-cells.
•Affect a broad range of other immune system cells e.g. naive and activated B cells together with bone marrow resident plasma cells . •useful in preventing ischemia-reperfusion injury.
Mechanisms of action of ATG:
induce T-cell depletion throug different mechanisms;
1 complement dependant cytotoxicity.
2 antibody dependant cell mediated cytotoxicity,
3 opsonisation and phagocytosis by macrophages .
4 induction of apoptosis .
5 Thymoglobulin is also thought to selectively increase expansion of Treg cells (CD4+CD25+Foxp3+ T cells), which attracts great attention due to its role in tolerance.
ADVERSE effects of ATG;
-Serious adverse effects :
anaphylaxis
cytokine release syndrome.
serum sickness.
increased incidence of PTLD.
Premedication to decrease this side effects include use corticosteroids, diphenhydramine, and acetaminophen just before Thymoglobulin administration .
-MORE tolerable:
leukopenia, thrombocytopenia, flu-like symptoms and increased risk of infection. leukopenia and thrombocytopenia can be aggravated by the concomitant use of mycophenolate mofetil and valganciclovir, Daily check of the white blood cell and platelets is recommended.
Comparing Thymoglobulin versus ATGAM
study on two transplant groups who had induction by ATG And
ATGAM showed
Thymoglobulin group had
•lower incidence of acute rejection.
• better one-year graft survival .
•Thymoglobulin group had more leukopenia
•lower incidence of CMV disease
• ten year the incidence of acute rejection was lower in Thymoglobulin group , while patient and graft survival were similar in both groups.
•And There were no differences in patient survival and graft function at 12 months
And none of both groups patients develop PTLD .
•mean serum creatinine was higher and eGFR was lower in the Thymoglobulin group.
Comparing Thymoglobulin with Basiliximab;
At one-year follow-up, there was no significant difference in patient and graft survival, however, Thymoglobulin group had lower incidence of acute rejection and cytomegalovirus (CMV) disease .
infectious complications were lower in basiliximab group .
Five years of follow-up, Thymoglobulin group showed lower incidence of acute rejection, graft loss or death.
ATG was associated with lower de novoDSA, and with decrease in the AMR when compared with basiliximab at three years follow-up.
there for Thymoglobulin remains the best choice with high-risk kidney transplantation .
Comparing Thymoglobulin to Alemtuzumab:
Alemtuzumab is a humanized monoclonal antibody targeting CD5
•median follow-up of 2 years, patients and graft survival were similar for both induction protocols
•incidence of infection and malignancy were the same.
• incidence of BPAR was higher in Thymoglobulin group.
Role of Thymoglobulin in Tolerance Induction Protocol:
Tolerance can be defined as a well-functioning graft without any histological signs of rejection, while the recipient (who is immune competent) is not on any immunosuppression drugs for at least one year .
Stanford University had a leading study about induction of tolerance patients were given combined kidney and enriched CD34+ hematopoietic cell transplants to achieve mixed chimerism The recipients received induction therapy in the form of Thymoglobulin and successfully 75% achieved tolerance with no immunosuppressive medications for more than 5 years
Dosing Regimen of Thymoglobulin:many studies recommended Thymoglobulin 5 mg/kg or higher (5.2 ± 0.2 mg/kg, n = 138) while the other group received a cumulative dose lower than 5 mg/kg (4.5 ± 0.6 mg/kg, n = 123) .
Some studies showed no difference between both protocols.
Thymoglobulin in Special Populations:
1 Obesity and paediatric : it is safe and effective and allow decrease dose of steroids and avoid its sideeffects.
2 Elderly recipients: safe and effective .
IN my paractice we use ATG for induction Therapy in High-Risk Cases:
ATG at a dose 1.5mg/kg for 3 days with daily follow up of CBC .
First dose given intraoperative after pulse methyleprednisolone 500mg.
tacrolimus: started 2 days pre-transplant 0.1mg/kg then adjusted to keep trough level 7-10 in the first 3 months post-transplant.
MMF: started 2 days pre-transplant with dose 1gm twice daily
In Conclusion:
There is no standard protocol, instead, there are different protocols according to patients is.
Biological agents are proved to be effective in reducing acute rejection
Thymoglobulin is a potent agent used in induction more in high-risk patients.
The goal of a transplant physician is to enhance graft survival.
Acute rejection and delayed graft function are the primary transplant survival factors.
Induction treatment reduces the chance of graft rejection, permits lower immunosuppressive dosages, and may help establish tolerance.
The optimal induction protocol is debated. The use of biologic antibodies in induction regimens outperformed the use of traditional immunosuppressive drugs alone in several randomized trials and meta-analyses
Induction treatment also reduced the incidence of delayed graft function.
ATG, Alemtuzumab, OKT3 are all lymphocyte depleting antibodies used in induction treatment ( Daclizumab, Basiliximab).
Oncologists recommend lymphocyte depletion medicines for high-risk patients with one or more of the following:
-One or more mismatches in the human leukocyte antigen (HLA) are present.
-Age differences between the receiver and the donor
-Ethnicity of African-American descent (in the United States)
-The presence of a positive panel reactive antibody (PRA) larger than 0 per cent
-A donor-specific antibody was found to be present (DSA)
-Incompatibility between blood groups
-The beginning of graft function is delayed.
-The duration of cold ischemia is higher than 24 hours.
Induction treatment in the high-risk category should be started using lymphocyte-depleting drugs rather than interleukin (IL) 2 receptor antibodies, according to the KDIGO.
In conclusion,
there is no standardized induction protocol, and patient risk identification is based on choice and dose. AB induction has been shown to have a favourable short and long-term graft and patient survival profile, particularly in patients at high immunological risk. ATG is one of the most potent induction therapies in both low and high immunological risk, with no consensus on the total cumulative dose. ATG can also enhance immune tolerance.
our immunological high-risk patients:
-We have paired exchange programme, if they agree we put them on paired exchange.
we also transplant the HLA mismatch, after explaining the risk. In addition, We transplant patients with DSA(up to MFI 3000 as long as the cross-match is negative). The remaining, we are referring them to a higher centre.
Induction with Thymoglobulin in High-Risk Renal Transplant Patients; Beauty and
the Beast
Induction therapy was developed to decrease the incidence of acute rejection in the early post-transplant period. Induction therapy allows low maintenance immunosuppression and may assist in the development of tolerance.
Still, there is debate concerning the optimal induction protocol. Many protocols worked out based on local expertise and available resources.
Induction drugs are revealed to that given in the perioperative period, yet it mainly refers to the biologic antibodies used in the immediate perioperative period. Many studies have shown that using biologic agents in induction was better than conventional immune suppression drugs alone in regard to graft survival and lower incidence of rejection. In addition, induction therapy was proved to decrease the incidence of Delayed graft function (DGF).
DGF is defined as the failure of the graft to function immediately post-transplantation. Recipient and donor factors associated with DGF.
Recipient factors are:
· Male gender
· Black race
· Prolonged waiting time on dialysis
· Degree of HLA mismatch.
Donor factors are
· prolonged warm and cold ischaemia time.
· an old age donor.
· use of Expanded Criteria Donors (ECD).
In 2009, KDIGO has suggested using lymphocytes depleting agents in high-risk recipients.
The presence of one or more of the following factors put the recipient at high risk of acute rejection:
1. High PRA
2. High HLA mismatch
3. Older donor
4. Afro-American ethnicity
5. Prolonged cold ischemia time.
6. Positive DSA
7. ABO-incompatible transplantation.
The biological agents are classified as monoclonal (e.g. basiliximab) or polyclonal (ATG) antibodies according to their ability to block single or multiple receptors. Another classification divides them into depleting and non-depleting agents.
· OKT3 (Anti-CD3antibody) is a monoclonal depleting agent, has serious side effects therefore it was withdrawn by the manufacturer.
· ATG is a depleting agent with profound immune suppressant activity. It affects T-cells and many other immune cells, e.g. naive, activated B cells and bone marrow resident plasma cells.
ATG is either rATG or Thymoglobulin (rabbit origen) or ATGAM (horse origen).
Thymoglobulin is a potent agent that can prevent ischemia-reperfusion injury. And it selectively increases the expansion of Treg cells (CD4+CD25+FoxP3+Tcells), which has a role in long-term immunomodulation. ATG cause T-cell depletion in many different ways like complement-dependent cytotoxicity etc.
Adverse effects of ATG:
anaphylaxis, cytokine release syndrome, serum sickness, leukopenia, thrombocytopenia, flu-like syndrome, and increased risk of infection and post-transplant lymphoproliferative disease (PTLD). MMF and others can aggravate leukopenia and thrombocytopenia.
Comparing Thymoglobulin versus ATGAM
· Lower incidence of acute rejection with r ATG
· Better graft survival at one year which equalizes at 10 yrs
· More leukopenia
· Lower incidence of CMV
· Higher creatinine
· Lower e GFR
Comparing Thymoglobulin with Basiliximab:
Many comparable studies have shown that thymoglobulin is the best choice to be used in high-risk kidney transplantation. as it has a lower rejection rate, although it has a higher infection rate and malignancy rate.
Comparing Thymoglobulin to Alemtuzumab:
The monoclonal antibody of human origin, acting on CD52, which is present on B and T lymphocytes. it causes T-cell depletion via antibody-dependent cell lysis.
Alemtuzumab has the same efficacy as thymoglobulin if not better when conceder BPAR that was higher in thymoglobulin group especially in high-risk patients. it better than Basiliximab in low-risk patients as it has lower BPAR.
Antibody induction proved to be beneficial in high-risk patients, but it adds no advantage in low-risk patients. instead, it increases the risk of infection.
Role of Thymoglobulin in Tolerance Induction Protocol:
Stanford University had a leading study about the induction of tolerance. Thymoglobulin was the induction agent in this study in which the patient achieve tolerance with no immunosuppression for 5 years with good graft function.
Dosing of thymoglobulin:
the typical regimen is 1.5 mg/kg for three to five days
lower
the cumulative dose of Thymoglobulin provides a chance for cost
saving without compromising the efficacy of the drug
Thymoglobulin in Special Populations:
· Obese patients BMI > 30, thymoglobulin shows better graft survival than Basiliximab.
· Paediatric patients: thymoglobulin induction allow minimization of steroid or steroid-free regime which allow better linear growth, normal bone density, and improvement in cardiovascular risk
· Elderly recipient: these patients are at high risk, and they are expected to have more postoperative complications. Induction with thymoglobulin with a dose of about 3 mg/kg is safe and effective in a study carried by Laftavi et al. 2011.
Conclusion:
There is no standard protocol, instead, there are different protocols that can accept different patients according to their risk stratification.
Biological agents are proved to be effective in reducing acute rejection
Thymoglobulin is a potent agent used in induction more in high-risk patients. Yet, its optimal dose and regime are not standardized.
Summary:
Introduction
——————————
Induction immunotherapy refer to the different types of polyclonal depleting agent like ATG or monoclonal depleting alemtuzumab and nondepleting monoclonal antibodies, usually given intra-operative or immediate post operative time of transplantation in order to suppress the immune system with lowering the acute rejection rate and DGF in early post-transplant period with good evidence from randomized control trails and meta-analysis,inductionagents alsoallowed touse lower doses of maintenance immunosuppressive therapy and together will have superior effect on both graft and patient survival.
Antibody Induction in High-Risk Renal Transplant Patients:
1-Monoclonal nondepleting chimeric AB like basiliximab, Daclizumab anti CD25 1L2 receptor inhibitors, lead to T-cell in-activation, preferred in low immunological risk with less side effects .
2-Monoclonal depleting AB like alemtuzumab ( campath H ) Humanized monoclonal antibody against CD52, target immature and mature lymphocytes both T-B cells, NK cells , macrophage and leads to AB mediated cell lysis,
OKT3 (Anti-CD3 antibody) is a chimeric depletive monoclonal antibody removed from the market due to its serious adverse effects.
3-Polyclonal rATG AB which have T Cell depleting effect by multiple mechanisms , direct depleting effect on multiple receptors on CD3-TCR pathway including D25, CD28, CD40, CD80, and CD86), CD2, CD45. antibody dependent cell mediated cytotoxicity, opsonization and phagocytosis by macrophages and induction of apoptosis, also can enhance tolerance by increase expansion of Treg cells (CD4+CD25+Foxp3+ T cells).
rATG IS recommended for use in high immunological risk candidates with good benefits in term of lower rejection rate and better graft survival and the KDIGO guideline recommended its use in high immunological risk patients since 2009 and in the updated version in 2020.
Worldwide there is no agreement about the total cumulative ATG dose based on the literature review , in this study they use lower cumulative dose of Thymoglobulin of 1.5mg /kg /for 3-5 days provides less cost with good efficacy and lower side effects in comparison to high cumulative dose , with close monitoring with FBC and lymphocyte percentage count for spacing of the dose when WBC < 2000 and platelet count < 75000 , with CMV and PJP prophylaxis .
we use same protocal in our centre as well .
Comparing ATG with other induction AB
Many studies including meta-analysis of 18 RCT and some prospective studies most of them confirm the efficacy of the ATG as induction in high immunological risk with lower rejection rate and comparable graft and patent survival in short term and long-term FU with more cost and higher side effects including more CMV infection and malignancy rate in some studies compared with monoclonal AB basiliximab and alemtuzumab.
Monoclonal biological AB in the era of tacrolimus maintenance IS is preferred induction choice in low and standard immunological risk with favorable graft and patient survival rate.
High immunological risk including one or more of the following
Previous kidney transplantation
PRA > 20
Higher HLA mismatch
Young recipient and old donor ECD
Black race
DSA Dn or performed AHL DSA
Abo incompatibility
Longer Cold ischemic time
our local protocal for high risk group almost same but not including the cold ischemic time or black race .
Thymoglobulin in Special Populations:
Obesity: In general obesity with BMI > 30 associated with higher morbidity and mortality post transplantation however the studies reported no difference in patient and graft survival between obese and non-obese recipients who received Thymoglobulin as induction IS
Elderly patients Safe in elderly patients with similar patient and graft survival outcome in comparison to young recipient
HIV recipients: preferred ATG induction to be restricted for high immunological risk as its associated with marked T- cell depletion with lymphopenia and put them at risk of severe infection requiring hospital admission.
This study Conclusion:
-Till date no standardized induction protocol
– Choice and dose based patient risk identification ,
– AB induction confirm its effectiveness and safety profile with favorable short and long-term graft and patient survival especiallyin high immunological risk
-ATG is one of the most potent induction therapy in both low and high immunological risk with noconsensus about total cumulative dose, can enhance immune tolerance .
please answer all the questions
It is important to find an appropriate immunosuppression regime to improve graft & patient survival & to decrease AR rate. Because the risk of AR is highest in early post transplant period, The induction therapy developed to reduce this risk.Several studies prove that induction therapy can reduce the risk of DGF in addition to decreasing AR rate.
KDIGO classifies renal transplant reception according to their immunological risk into high & low risk recipient. High risk mean presence one or more of the following:
Induction protocol include depleting Ab ( rATG, eATG, OKT3, Alemtuzumab) & non depleting Ab ( daclizumab & basiliximab). rATG induce its action through: complement dependent cytotoxicity, Ab- dependent cell mediated cytotoxicity, & opsonization & phagocytosis.
rATG is effective in prevention of ischemia-perfusion injury & it increase expansion of Treg cells which may had a role in long-term immuno modulation.
rATG can reduce AR rate, low rate of CMV infection when compared with eATG, but long-term graft & patient survival are equal in both agents. And when compared with basiliximab , it was associated with lower rate of AR & de novo DSA but higher cost with increasing risk of cancer & CMV infection.
Graft survival , rate of infection & malignancy were similar in rATG & alemtuzumab, but rate of AR was higher with rATG. Using of rATG in post transplantation conditioning during induction of tolerance was associated with high rate of immunosuppression withdrawal up to 5-year without increase the risk of AR. rATG improve graft survival in obese, non obese recipients, pediatric & old age recipients.HCV+ve & HIV +ve recipients use induction with biological Abs show decreased hazard ratio of death, no risk of progression to AIDS, but there is increase risk of sever infection.
The study conclude:
High risk patient in our center are : high PRA, presence of DSA, & high HLA mismatch. ABO-incompatible donors are not accepted. The induction by ATG with maintenance CNI,MMF, & steroid
Immunological High risk renal allograft recipient are the recipient has one or more of the following criteria:
1- cPRA more than 20%
2- presence of DSA
3- more HLA mismatch
4- old age donor
5- ABO incompatibility
6- African American ethnicity
7- Prolonged ischemic time
Powerful induction is very important in these group to improve graft and patient outcome and decrease incidence of acute rejection and DGF.
ATG antithyomcye globulin is depleting polyclonal antibody used in induction of immunosuppression especially in high risk group patients, it was prepared by injection of rabbit (rATG) or horse (ATGAM) by human lymphocytes and formation of antibodies.
Its exact mechanism is unknown but it deplete T cells and also B cell lines.
Has important side effect like cytokine storm or cytokine release syndrome manifested as fever, myalgia, difficult breathing…etc. and it can be prevented by premedications given like steroid, paracetamol, antihistamincs.
It is powerful immunosuppression medication allows the decrease in the doses of conventional immunosuppression.
Can be used also in the treatment of acute cellular rejection.
Thymoglobulin is better than ATGAM in reducing incidence of acute rejection hence better graft outcome.
Basiliximab is IL-2 receptor antagonist used in induction , but in comparison to use of ATG especially in moderate or high risk patients , ATG is associated with more decrease in DSA and hence decrease incidence of antibody mediated rejection so better graft outcome and survival, also ATG is associated with more side effects than basiliximab like infection and PTLD and cytokine storm , and it is expensive than basiliximab.
Alemtuzumab is monoclonal antibody directed against CD52 receptor which is present on T and B lymphocytes, and also on natural killer and macrophage cells so it cause marked depletion of lymphocytes. The incidence of acute rejection with thympglobulin is the same with alemtuzumab in high risk patients, but in low risk patients; alemtuzumab is associated with lower incidence of biopsy proven acute rejection BPAR than basiliximab.
As regard dosing of ATG, its lower cumulative dose is associated with cost saving benefit and decrease incidence of complications without affecting its immunosuppressive efficacy and this is proved by protocol biopsy.
The usual dose of ATG 1-6 mg/kg/dose, and duration from 1-10 days , but the typical used regimen is 1.5 mg/kg/dose for 3-5 days.
There is no difference of the use of ATG in obese and non-obese recipients as regard graft outcome.
In my center : high risk patients are the patients with previous transplantation, multiple blood transfusions, multiple pregnancies, presence of DSA, PRA more than 20%.
In my center , if cross match positive the management include plasmapheresis sessions with IVIg after the session in alternate daily base with hemodialysis for 2 weeks then will repeat cross match if still positive will continue plasmapheresis and IVIg , if becomes negative will proceed to transplantation with induction of ATG started intraoperative with dose 3 mg/kg at day 0 intraoperative and of course preceded by methylprednisolone from 500-1000 mg , paracetamol iv, and antihistaminc , ATG given infusion in infusion pump in central line over 6 hours. The dose after day 0 is 1.5 mg/kg/dose for 3-7 days postoperative , we may start MMF before operation and will add tacrolimus from day 1. The patient is followed up closely as regard urine output and renal function.
The benefit of using induction therapy
Induction can be done by either depleting (ATG, ATGAM, OKT3, Alemtuzumab) or non-depleting antibodies (Basiliximab).
Depleting antilymphocyte antibodies are antibodies that kill bound T lymphocytes, 2 types exists :
A- Polyclonal antibodies: antibodies produced to many hematopoietic antigens (CD2, 3, 4,8, 18) raised from animals (rabbit, horse), immunized with human lymphocytes, lymphoblasts or thymocytes.
2 preparations are available :
1. Anti-thymocyte globulin (ATGAM) derived from horse
2. rATG-thymoglobulin derived from rabbit
B- Monoclonal antibodies: are antibodies produced to specific TCR include :
1. OKT3 – OKT3 (Muronab-CD3)
2. Alemtuzumab (Campath-1H) – humanized panlymphocytic (both B and T cells) anti-CD52 antibody .
rATG (thyroglobulin)
Indications for use in transplantation
1- Induction therapy
2- Acute rejection treatment
3- Induction of tolerance when used in a dose of 1.5 mg /kg for 5 days in combination with total lymphoid irradiation for 10 days, this leads to withdrawal of immunosuppressive medications for 5 years without occurrence of rejection used for induction for high-risk patients and for treatment of acute TCMR
Side effects include
Dose
Comparison between induction therapies
ATG safety in special transplant recipients
Immunosuppression protocol recommended by this study
1- Corticosteroids start Intraoperatively in a dose of 500 mg methylprednisolone then from day-1 prednisolone is given in a dose of 60 mg PO for 3 days then taper 5 mg every 3 days till reaching 20 mg, then tapered 5 mg every week till reach 10 mg and continue on 10 mg
2- ATG is given intraoperatively in a dose of 1.5 mg/kg in the central line and continued for another 3-5 days
3- Tacrolimus started from day 1 in a dose of 0.05 mg/kg twice daily to achieve a trough of 7-10 ng/m;
4- MMF started in a dose of 500 mg twice daily from day 1
5- Daily CBC is done if WBCS < 2000 microL or platelets < 75000microL the next dose of ATG is skipped and MMF temporary stopped till WBCS became > 3000/microL and platelet count > 100,000/microL.
How do you define high-risk patients in your center (you can refer to the national and international guidelines)?
I prefer to use this immunological risk stratification in ABO compatible living donor transplant recipients since ABO-incompatible has different protocol and deceased donor transplantation risk of DGF is included in risk stratification
A- Highest risk = transplantation is contraindicated
• Positive CDC due to DSA
• Positive FCM due to DSA with MCS> 250 or RIS 17 or more
B- Very high-risk = require desensitization, induction using ATG or alemtuzumab, maintenance using triple therapy, fu protocol
– Antigens of MFI of < 5000 are week antigens and take 2 points in relative intensity score (RIS)
– Antigens of MFI of 5000-10000 are moderately strong antigens and take 5 points in RIS
– Antigens of MFI of > 10000 are strong antigens and take 10 points in RIS
– Antigens of MFI of >15000 are unacceptable antigens, this mean if there is DSA to this antigen there will be a very high probability of ABMR and graft failure, thus this donor should be excluded.
C– High risk= possible desensitization, induction mandatory using ATG, maintenance using triple therapy, fu protocol
Negative cross-match + one of the following
D- Intermediate-risk = induction using ATG or basiliximab, maintenance triple therapy, follow up
Negative cross-match + no DSA+ one of the following :
E– low risk= induction therapy using basiliximab, maintenance triple therapy, fu
F- lowest risk = HLA identical 000 mismatch
How would you manage high risk-patients in your center (you can refer to the national and international guidelines)?
All patients I dealt with were low-risk patients with living related donors, But I will manage high-risk patients as follow :
I have a question here …
Are high cPRA and re-transplantation by themselves sufficient to render the patient high risk and eligible for ATG even if there is a perfect HLA match?
Some recommend desensitization in patients with negative crossmatch but positive Luminex for DSA (PLNC) patients.
Others recommend the use of Alemtuzumab on the day of transplantation together with IVIG 1-2 weeks later on in induction for HLA incompatible recipients after desensitization
What is the applicability of both protocols? … Thanks a lot
Others recommend desensitization if cPRA> 80% (some have lower threshold > 30%) or if the patient is seeking re-transplantation regardless of DSA, or crossmatch
Dear D. Sherif Yusuf; thank you for the extensive summary
Induction is not desensitization
Induction with Thymoglobulin in High-Risk Renal Transplant Patients; Beauty and the Beast
The term induction therapy include all immune suppression drugs that are given in the perioperative period, but it has been commonly used to describe the use of biologic antibodies
In 2009, Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group has suggested using one of the lymphocytes depleting agents in high-risk transplantation which include one or more of the following 7 factors
1) High panel reactive antibody (PRA).
2) ABO-incompatible transplantation
3) The presence of donor-specific antibody (DSA).
4) Increased number of HLA mismatch.
5) Old aged donor.
6) Afro-American ethnicity.
7) Prolonged cold ischemia time.
My center experience
We used to give induction in the presence one or more of the following factors as we do living donation only and we have no experience in transplantation against blood group
HIGH RISK GROUP
1. More than 3/6 mismatch
2. Glomerular disease is the 1ry kidney disease
3. Sensitized patients with high PRA
4. Presence of DSA (even low MFI)
5. Young aged recipient
Antibody Induction in High-Risk Renal Transplant Patients
Multiple classifications of biological antibodies
1. Monoclonal vs polyclonal
Polyclonal antibody: manufactured by injection of different antigenic peptide in a host then different (polyclonal)b cell will respond and form multiple antibodies ex, rATG(THYMOGLOBULIN) and eATG (ATGAM).
Adv. Cheap in production with high affinity and resist to antigenic modification
Monoclonal antibody: manufacture by injection of specific antigenic peptide in a host then specific (monoclonal)b cell will respond and form specific antibodies
Ex basiliximab (semulect),daclizumab (zenapex) and almutuzumab (campath)
Adv. very specific but expensive, low affinity and vulnerable to antigenic modification
Depleting: cause cell lysis by complement dependent or non-complement dependent mechanisms causing lymphopenia cytokine storm and flue like symptoms
Ex ATG, campth
Non depleting: it cause Rs blockage without causing cell lysis
Ex simulect
MY CENTER EXPERIENCE
In our center we GRAFLON which is rATG in concentration 20mg/ml (each vial 5ml contain 100mg) and we used to give 1st dose of 100mg intraoperative proceeded by 250-500mg methylprednisolone and total induction dose is 3mg/kg divided on 1st few days postoperative after follow-up of cbc.
Comparing Thymoglobulin versus ATGAM
multiple studies discussed this item like Brennan et al. (1999) study which showed superiority of rATG in 10 years graft survival and biopsy proven acute rejection and inducing of tolerance
Comparing Thymoglobulin with Basiliximab
Multiple studies addressed this issue like Brokhof et al. (2014) which shower superiority of rATG in high risk patients but no difference in low risk patient in patients and graft survival but lower incidence of acute rejection
MY CENTER EXPERIENCE
rATG for high risk group as prescribed before 3mg/kg induction divided starting from d0 intraoperative
basilixmab for low risk patient if the patients eligible for low steroids or rapid withdrawal of steroids regimens but if not we proceed for low immunological risk with no biological induction.
Comparing Thymoglobulin to Alemtuzumab:
Farney and his colleagues in 2009 and Opelz et al. (2016) showed no difference in both patient and graft survival in both groups
our center experience we only use rATG we don’t have campth in our center
Role of Thymoglobulin in Tolerance Induction Protocol:
Thymoglobulin is also thought to selectively increase expansion of Treg cells (CD4+CD25+Foxp3+ T cells), which attracts great attention due to its role in long-term immunomodulation.
Stanford University had a leading study about induction of tolerance using post-transplant conditioning The patients were given combined kidney and enriched CD34+ hematopoietic cell transplants to achieve mixed chimerism The recipients received induction therapy in the form of Thymoglobulin and successfully 75% achieved tolerance with no immunosuppressive medications for more than 5 years
Dosing Regimen of Thymoglobulin:
there is no total agreement on dosing of ATG or dividing protocols multiple studies discussed Thymoglobulin at the dose of 5 mg/kg or higher (5.2 ± 0.2 mg/kg, n = 138) while the other group received a cumulative dose lower than 5 mg/kg (4.5 ± 0.6 mg/kg, n = 123) likebPennington et al. (2015) and Agha et al. (2002) which showed no difference
MY CENTER EXPERIENCE
we give total cumulative dose 3mg/kg divided after follow up of cbc starting from day0 intraoperative.
Thymoglobulin in Special Populations:
1. Obesity….safe and effective to decrease dose of steroids according to Patel et al. (2011) study
2. Paediatric recipients…safe and effective to decrease dose or stop steroids which enhance growth and decrease risk of fracture according to Khositseth et al. (2005) study.
3. Elderly recipients…. safe and effective according to Laftavi et al. (2011) study
Our Protocol for Induction Therapy in High-Risk Cases:
induction by biological antibody rATG cumulative dose 3mg/kg divided over 1st 3 days after follow up of cbc .1st dose given intraoperative after pulse methyleprednisolone 500mg
tacrolimus: started 2 days pre-transplant 0.1mg/kg then upgrade to 0.15mg/kg just postoperative with follow up of trough level and adjust dose to keep it around 7-10 1st 3m post-transplant.
MMF: started 2 days pre-transplant with dose 500mg tid and to be upgraded to 1gm bid d+4 after improvement of patient’s bowel movement.
Well done; thank you for mentioning your unit experience
Immunosuppressive induction therapy in high risk kidney transplant recipients is either monoclonal (basiliximab or Daclizumab), or polyclonal ( ATG, Alemtezumab, Muromunab) and also divided into depleting and non-depleting antibodies.
Comparing Thymoglobulin versus ATGAM
There is lower incidence of acute rejection and better one-year graft survival with Thymoglobulin.
No differences in patient survival and graft function at 12 months
ATG versus Basiliximab:
The use of ATG was associated with lower incidence of acute rejection at 1 year ,lower graft loss, or death at 5 year follow up.
The incidence of de novo DSA was lower. Patients in the Basiliximab group have lower infectious complications.
ATG was associated with more adverse reactions like fever, cytokine release syndrome and more leukopenia.
ATG versus Alemtuzumab:
There is no difference in acute rejection rate. No difference in patients and graft survival in both groups as well as incidence of infection and malignancy, but the incidence of BPAR was higher in Thymoglobulin group
Role of Thymoglobulin in Tolerance Induction Protocol
Study by Stanford university included 38 living kidney transplant candidates. The patients were given combined kidney and enriched CD34+ hematopoietic cell transplants to achieve mixed chimerism. The recipients received thymoglobulin as induction therapy. HLA matched recipients achieved complete withdrawal of immune suppression medications for up to 5 years without evidence of rejection or recurrence of renal disease.
Dosing Regimen of Thymoglobulin
Different dosing regimens of thymoglobulins have been used in different centers, but the widely acceptable international protocol is dosing of 1.5 mg/kg for three to five days.
The use of ATG in special populationswas also addressed.
-In obese recipients, the studies demonstrated no difference in terms of patient and graft survival comparing to non-obese patients who received thymoglobulin.
-In pediatric patients: the use of thymoglobulins in induction allowed for avoidance or minimization in immunosuppression that can effect on growth and development.
-The use of thymoglobulins in Hepatitis C positive patients was associated with decrease mortality.
-In HIV positive patients, the use of Thymoglobulin was not associated with increased risk of progression to acquired immunodeficiency syndrome or death, however , there was increase in infection risk and hospitalization due to with marked CD4 and lymphocyte depletion.
-The use of low dose ATG in elderly population was safe and effective with 3 year patient and graft survival comparable to young patients.
How do you define high-risk patients in your centre (you can refer to the national and international guidelines)?
The risk of rejection depends upon the results of the immunologic evaluation which consists of 4 components:
· ABO compatibility
· HLA typing and matching
· Serum screening for DSA
· Crossmatching results
According to 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines, risk factors for acute rejection include one or more of the following:
●One or more human leukocyte antigen (HLA) mismatches
●Younger recipient and older donor age
●African-American ethnicity (in the United States)
●Panel reactive antibody (PRA) greater than 0 percent
●Presence of a donor-specific antibody (DSA)
●Blood group incompatibility
●Delayed onset of graft function
●Cold ischemia time greater than 24 hours
2009 KDIGO guidelines suggest the use of lymphocyte-depleting agents rather than interleukin (IL) 2 receptor antibodies in the high risk group as induction therapy.
The main of transplant physician is to improve the long term survival of the graft. Acute rejection and delayed graft function are the main factors that affect graft survival.
Induction therapy reduced the risk of graft rejection and allows the use of decreasing doses of immunosuppression and may assist in the development of tolerance.
There is controversy regarding the optimum induction regimen. Large number of randomized studies and meta analysis showed that the use of biologic antibodies in induction protocols was superior to the use of conventional immunosuppressive medications alone.
Also, induction therapy proved to be effective in reducing the rate of delayed graft function.
Antibodies used in induction therapy are either monoclonal eg. Basiliximab or polyclonal such as ATG, also can be classified to either lymphocyte depleting( ATG, eATG, Atgam, Alemtuzumab, OKT3) or non depleting drugs( Daclizumab, Basiliximab).
In 2009, KDIGO guidelines suggested using lymphocyte depleting agents for high risk patients who have one or more of the followings:
Comparison between different induction agents
ATG versus ATGAM:
ATG was better as it’s use associated with:
ATG versus Basiliximab:
The use of ATG was associated with lower incidence of acute rejection at 1 year follow up and CMV disease, lower rate of rejection, graft loss, or death at 5 year follow up, also lower incidence of de novo DSA,while infectious complications were lower in Basiliximab group.
ATG has more adverse reactions like fever, cytokine release syndrome and more leukopenia.
ATG versus Alemtuzumab:
no difference in acute rejection rate.
Role of ATG in induction of tolerance:
in a study at Stanford University, 38 kidney transplant candidates received ATG induction ( 1.5 mg/kg/day) for five days starting intraoperatively to a total of 10 days. about 75% of HLA matched recipients achieved complete withdrawal of IS for 5 years without evidence of rejection or recurrence of renal disease.
Dosing of ATG:
There are different dosing strategies ( 1-6 mg/kg per dose) and for various durations (1-10 days), the more typical regimen is 1.5 mg/kg for 3-5 days.
Use of ATG in special populations:
In our center patients who are sensitized, positive XM, DSA positive, high cPRA, had previous transplant are considered as high risk patients,,, we do not transplant through incompatible blood group and we do not have deceased donor program. we transplant them when XM is negative and we use induction with ATG and maintenance therapy with Tac, MMF and gradually tapered doses of steroids. They will require follow up to DSA level.
Well done
In your own words, summarise this article
Acute rejection and delayed graft function (DGF) affect long-term graft survival.
Induction therapy is used to decrease the incidence of acute rejection.
High immunological risk comprises of-
1) High panel reactive antibody (PRA).
2) Increased number of HLA mismatch.
3) Old aged donor.
4) Afro-American ethnicity.
5) Prolonged cold ischemia time.
6) The presence of donor-specific antibody (DSA).
7) ABO-incompatible transplantation.
Antibody Induction in High-Risk Renal Transplant Patients
Either monoclonal (e.g. basiliximab), which is targeted to a single cell surface receptor or polyclonal ATG, which is directed against many different cell receptors , adhesion molecules and cell trafficking molecules and other pathways mediators.
ATG is a depleting agent. It affects T cells, naive and activated B cells ,bone marrow resident plasma cells.It can be prepared from rabbit(thymoglobulin) or horse(ATGAM). It induces T-cell depletion through complement dependant cytotoxicity,antibody dependant cell mediated cytotoxicity, opsonisation and phagocytosis by macrophages and induction of apoptosis. Thymoglobulin is also thought to selectively increase expansion of Treg cells (CD4+CD25+Foxp3+ T cells). Side effect includes anaphylaxis, cytokine release syndrome and serum sickness,leukopenia, thrombocytopenia, flu-like symptoms and increased risk of infection,PTLD.
Comparing Thymoglobulin versus ATGAM
Brennan et al. (1999) had a leading study that demonstrates lower incidence of acute rejection and better one-year graft survival with Thymoglobulin. Thymoglobulin group had more leukopenia, lower incidence of CMV disease. There were no differences in patient survival and graft function at 12 months; none of both groups’ patients develop PTLD . At ten year follow up of the same group, the incidence of acute rejection was lower in Thymoglobulin group , while patient and graft survival were similar in both groups.
Comparing Thymoglobulin with Basiliximab
At one-year follow-up, there was no significant difference in patient and graft survival, however, Thymoglobulin group had lower incidence of acute rejection and cytomegalovirus (CMV) disease , while infectious complications were lower in basiliximab group .After five years of follow-up, Thymoglobulin group had maintained efficacy in the form of a lower incidence of development of acute rejection, graft loss or death.
Comparing Thymoglobulin to Alemtuzumab
In a prospective study, patients were randomly assigned to receive Alemtuzumab, basiliximab or Thymoglobulin according to their immunological risk .In the high-risk group, there was no difference in the incidence of acute rejection between patients who received Alemtuzumab and their comparative group who received Thymoglobulin after a follow-up for three years. While in the low-risk group, there was a therapeutic advantage of Alemtuzumab over basiliximab in the form of lower BPAR at three years follow-up.
Dosing Regimen of Thymoglobulin:
Thymoglobulin is used at a dose of 1.5 mg/kg for three to five days.
How do you define high-risk patients in your centre (you can refer to the national and international guidelines)?
In my residency
High risk-
Previous transplant
FCXM positive, CDC negative
ATG used as induction
Deceased donor – Basiliximab used
Live related donor- no induction used
In all three maintenance with tacrolimus, MMF, prednisolone
How would you manage high risk-patients in your centre (you can refer to the national and international guidelines)?
High immunologic risk –
(1) historical crossmatch positivity (complement‑dependent cytotoxicity, flow or Luminex crossmatch)
(2) nil match for HLA A and B antigens
(3) second or more transplant
ATG induction to be used