I. Implication of interleukin-2 receptor antibody induction therapy in standard risk renal transplant in the tacrolimus era: a meta-analysis
- In your own words, summarise this article
- What are the weakness and strength of this study?
- Please reflect your practice if possible.
IL2 ra antibody has been authorized as induction therapy since 2000.
In comparission to thymocyte , IL2 ra does not cause infection and malignancy .
Many previous study , proves the efficacy of IL2ra in reducing acute rejection in standard risk patients ,in those who were on cyclosporine therapy .
Many study prove the more powerful effect of TACROLIMUS over the cyclosporine in reducing acute rejection .
This effect could be a result of
v Could be due to more potent immune suppressive effect of tacrolimus. Or
v Could be due to less nephrotoxic effect of tacrolimus .
Accordingly the incidence of acute rejection is about 10% in tacrolimus era in comparission to 50% previously in cyclosporine era
This meta analysis is conducted to assess the role of IL2ra in reducing acute rejection , graft and patient survival in standard risk patient who are on tacrolimus maintenance therapy .
In conclusion, IL-2R antibody induction therapy has no significant effect on the rate of rejection and patient or graft survival in standard-risk renal transplant recipients on tacrolimus-based maintenance immunotherapy
weakness
1. There is some degree of heterogeneity in risk stratification .
2. Short follow up period of one year .
3. The percentage of extended criteria donors in our analysis is low compared to the current set-up in clinical transplantation which is around 20–60% of deceased donor grafts .
Strength
the inclusion of several studies from different countries and thereby being less influenced by local findings, thus having higher statistical power to detect an effect.
in our practice
low immunological risk patient is treated by IL2ra induction .
Intermediate and high risk patient are treated by thymoglobulin induction .
unless there competitive indication, all patient receive tacrolimus as maintenance therapy
Basiliximab
Anti CD25 monoclonal antibodies.
Chimeric (75%) and human (25%) murine in orgin.
Adverse reactions :
Hypersensitivity reaction (<1%) , insomnia, tremor.
Headache, lack of infection of risk or cancer .
There is no increased risk for CMV infections and malignancies (12) .
Approach to induction therapy in high risk patients
•For patient with high immunological risk , recommended induction therapy with r-ATG thymoglobulin rather than an interleukin (IL)2 receptor antagonist (basiliximab). In patients who are unable to tolerate r-ATG thymoglobulin , as hypotensive, leukopenia and / or thrombocytopenic patients at time of transplant surgery the basiliximab is the alternative option.( this approach is consistent with the 2009 KDIGO clinical practice guidelines (13).
r-ATG Thymoglobulin versus Basiliximab
•The efficacy and safety of r-ATG Thymoglobulin versus Basiliximab in high risk patients was best assessed in a multicenter trial that randomly assigned 278 first deceased donor kidney transplant recipients to a five- day course of r-ATG Thymoglobulin or two doses of basiliximab . A ll patients received cyclosporine,mycophenolate mofetil and prednisone for maintenance immunosuppression and ganciclovir as antiviral prophylaxis (14).
r-ATG Thymoglobulin versus Basiliximab over an one year after surgery:
At one year , patients received r-ATG Thymoglobulin had low rates of acute rejection and acute rejection requiring antibody treatment .
Graft survival and serious adverse events were similar between the groups .
Patients who treated with r-ATG Thymoglobulin had higher rate of infection but a lower rate of cytomegalovirus (14).
r-ATG Thymoglobulin versus basiliximab over a five year after surgery:
At five years, rate of acute rejectiona nd acute rejections requiring antibody treatment remained lower among those treated with r-ATG Thymoglobulin compared with basiliximab.
Patients treated with r-ATG Thymoglobulin had a lower composite endpoint of acute rejection, graft loss and death at five years.
Incidence of malignancy didn’t differ(14).
Basiliximab
Anti CD25 monoclonal antibodies.
Chimeric (75%) and human (25%) murine in orgin.
Adverse reactions :
Hypersensitivity reaction (<1%) , insomnia, tremor.
Headache, lack of infection of risk or cancer .
There is no increased risk for CMV infections and malignancies (12) .
Approach to induction therapy in high risk patients
•For patient with high immunological risk , recommended induction therapy with r-ATG thymoglobulin rather than an interleukin (IL)2 receptor antagonist (basiliximab). In patients who are unable to tolerate r-ATG thymoglobulin , as hypotensive, leukopenia and / or thrombocytopenic patients at time of transplant surgery the basiliximab is the alternative option.( this approach is consistent with the 2009 KDIGO clinical practice guidelines (13).
r-ATG Thymoglobulin versus Basiliximab
•The efficacy and safety of r-ATG Thymoglobulin versus Basiliximab in high risk patients was best assessed in a multicenter trial that randomly assigned 278 first deceased donor kidney transplant recipients to a five- day course of r-ATG Thymoglobulin or two doses of basiliximab . A ll patients received cyclosporine,mycophenolate mofetil and prednisone for maintenance immunosuppression and ganciclovir as antiviral prophylaxis (14).
r-ATG Thymoglobulin versus Basiliximab over an one year after surgery:
At one year , patients received r-ATG Thymoglobulin had low rates of acute rejection and acute rejection requiring antibody treatment .
Graft survival and serious adverse events were similar between the groups .
Patients who treated with r-ATG Thymoglobulin had higher rate of infection but a lower rate of cytomegalovirus (14).
r-ATG Thymoglobulin versus basiliximab over a five year after surgery:
At five years, rate of acute rejectiona nd acute rejections requiring antibody treatment remained lower among those treated with r-ATG Thymoglobulin compared with basiliximab.
Patients treated with r-ATG Thymoglobulin had a lower composite endpoint of acute rejection, graft loss and death at five years.
Incidence of malignancy didn’t differ(14).
1.Article summary: This is a meta analysis of 7 papers which were all retrospective observational study except for one paper which was a prospective study. Unfortunately this metanalysis did not include even one RCT. The level of evidence is 1B.
The KDIGO guidelines in 2009 included IL2 receptor antagonists as induction agent in standard or low risk patients. This was based on metanalysis published previously with the use of cyclosporine based regimen with IL2 receptor blockers, who quoted a risk of reduction of acute rejection by 28% when basiliximab was used. The same was incorporated in the KDIGO guidelines. But this metanalysis reported the use of IL2 receptor blockade as induction agent in the tacrolimus era.
In the metanalysis included there was no difference reported in the overall patient survival or the graft survival when using IL2 receptor blockade as induction in standard risk or low risk group individuals. There was no difference in the rate of acute rejections also.
Strengths of the study are: they have included in the meta analysis many studies from different countries and different race and ethnic background. Studies included both living as well deceased donors.
Limitations of the study are short duration of follow up of 1 year and ECD not included in the studies
I would use Basiliximab for all standard risk or low risk transplants in my practice as per the KDIGO guidelines, the cost being the major hinderance in most of the cases. If there is a good HLA Match >50%, with no other risk factors for sensitization I will still go ahead with the transplant even if they are not affordable for Basiliximab as the above metanalysis did not show any difference in acute rejection or patient/graft survival
1- In your own words, summarise this article
1- no significant effect was noted for Basiliximab versus placebo, regarding acute rejection, graft survival and patient survival.
2- 3 of 7 studies reported no effect on creatinine or CMV activation.
3- 2 of 7 studies reported a lower risk of new-onset DM.
2- What are the weakness and strength of this study?
1- the short period of follow-up. it was only 1 year.
2- the percent of donors with extended criteria was low.
1- the included studies were from differrent countries, not a single country.
3- Please reflect your practice if possible.
This is a meta-analysis about induction therapy with IL-2 receptor antibody in tacrolimus-based triple immunosuppression therapy in standard risk renal TX versus no or placebo induction therapy. Four hundred and seventy papers were noticed but only 10 papers were included and finally seven papers were included for meta-analysis. Transplants with less than two HLA-DR mismatches, PRA>20% and no more than one TX were defined as standard-risk, acute rejection and patient and graft survival (for one year) were primary outcomes and variation is creatinine, NODAT and CMV infection were secondary outcomes. 29426 TX cases (62.3% male) were included. There was no difference in patients’ background variables. There was no difference between two groups in term of rate of rejection. After the removal of bias due to the risk of heterogeneity, overall risk was -0.02 that shows no difference in graft survival between two groups either. Three studies showed no difference in creatinine level or CMV infection between groups.
In conclusion there was no significant statistical benefit to use IL-2 receptor antibody as induction therapy in standard risk group. The strength of this study is including different countries studies which could be generalized in deferent populations. The weak points were relatively short-term follow-up and percentage of ECD in this study. In our center we don’t use IL-2 inhibitors as induction therapy in standard risk patients routinely due to inaccessibility. Comparing with those who used this drugs in past there was no difference between these two groups in our center either.
ABSTRACT
Interleukin-2 (IL-2) antagonist has been used as an induction therapy in many centers in calcineurin inhibitor sparing regimens. Tacrolimus has overwhelmingly replaced cyclosporine in the maintenance immunosuppressive protocols in many transplant centres.
The aim of our study and meta-analysis is to explore 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 aims included assessment of the effect of IL-2 induction therapy on creatinine change and the risk of cytomegalovirus (CMV) infection.
Methods.
We conducted a systematic review in different databases to identify studies and research work that assessed the effect of IL-2 antibody induction therapy on renal transplant outcomes. Inclusion criteria for our meta-analysis were all studies that compared IL-2 induction therapy with placebo or no induction therapy in standard-risk renal transplant recipients on tacrolimus-based maintenance immunosuppressive therapy.
Results.
Of the 470 articles found in different databases, 7 were included in the meta-analysis. Forest plot analysis for rate of rejection during the follow-up period post-transplant showed no significant difference between the groups. There was no evidence of heterogenicity between included studies (I2 ¼ 21.8%, P ¼ 0.27). The overall risk difference was 0.02 [95% confidence interval (CI) 0.05–0.01]. A random effects meta-analysis for patient and graft survival was performed using forest plot analysis and showed no significant effect of IL-2 receptor (IL-2R) antibody induction on patient or graft survival compared with placebo. The overall risk difference was 0.01 (95% CI 0.04–0.01) and 0.00 (95% CI 0.00–0.01), respectively.
Three of the included studies showed no effect of basiliximab on creatinine change, two showed no effect on risk of CMV infection and two showed less risk of post-transplant diabetes in the basiliximab group.
Conclusion.
IL-2R antibody induction therapy has no significant effect on the rate of rejection or patient or graft survival in standard-risk renal transplant recipients on tacrolimus-based maintenance immunotherapy. More randomized controlled studies are needed.
1. What are the weakness and strength of this study?
Weaknesses
1) Studies included in the meta analysis showed variations in assessment of the risk factors of acute rejection among both donors and recipients
2) Short period of follow up ( 1 year)
3) The percentage of donors included with extended criteria donors is low .
Strengths
A meta analysis studies were conducted in different countries which helps generalization and randomization of the population .
1. In your own words, summarise this article
This meta analysis was conducted in order to evaluate the impact of induction with IL2 R AB ( a nondepleting monoclonal antibody immunosuppressive agent) in standard risk kidney transplant sensitized recipients on tripple IS mentainance protocol ( Tacrolimus, steroids, MMf or azathioprine)
Its impact on reducing episodes of acute graft rejection , impact on graft and patient survival, and toxic side effects in the form of NOPTDM, rising serum creatinine and infection particularly CMV)
Selection of the studies included was based on certain Inclusion criteria , all case control studies with 2 groups of standard-risk renal transplant recipients , one receiving IL-2 induction therapy Vs placebo or no induare mentained on tripple IS mentainance protocol ( Tacrolimus, steroids, MMf or azathioprine)
Standard risk patients criteria as defined as less than two HLA mismatchon locus (HLA-DR) , panel reactive antibody (PRA) <20%, and not more than one previous KTx .
Numerous previous studies done in the era of cyclosporine IS mentainence protocols revealed the use of IL-2R antibody as induction therapy reduces the risk of acute rejection episodes[1].
However later studies showed that Tacrolimus based regimens are superior on cyclopsporins as a mentainence therapy as it provides abetter graft and patient survival , reducing episodes of acute rejections over the first ear post transplantation and chronic rejection five year post transplantation . [2).
Conclusion. No significant impact of IL-2R antibody induction therapy on the rate of rejection , patient or graft survival in standard-risk kidney Tx recipients mentainained on tacrolimus-based IS protocol. With much less toxic effects . more RCT needed .
1. What are the weakness and strength of this study?
Weaknesses
1) Studies included in the meta analysis showed variations in assessment of the risk factors of acute rejection among both donors and recipients including, degree of HLA mismatch, cold ischaemia time, ethnicity, PRA, presence of donor-specific antibodies, blood group incompatibility and previous failed transplants [3].
2) Short follow up duration ( one year)
3) The percentage of donors included with extended criteria donors is low [4].
Strengths
The studies included in this meta analysis were conducted in different countries which helps generalization of the population .
2. Please reflect your practice if possible.
induction with IL2 R AB for better outcome and less rate of Acute rejection episodes should be considered in:
· Patients of low to intermediate risk on cyclosporine immune suppression mentainence protocol would consider
· Patients receiving a graft from extended criteria donor or deceased donor with CNIs ( either tacrolimus or cyclosporine )as Is menainence
References:
(1) Vincenti F, Kirkman R, Light S et al. Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. Daclizumab Triple Therapy Study Group. N Engl J Med 1998; 338: 161–165
(2) Ekberg H, Tedesco-Silva H, Demirbas A et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007; 357: 2562–2575
(3) Kidney Disease: Improving Global Outcomes Transplant Work Group. KDIGO clinical practice guideline for the care of 598 | H. Ali et al. Downloaded from https://academic.oup.com/ckj/article/12/4/592/5289522 by guest on 10 September 2021 kidney transplant recipients. Am J Transplant 2009; 9(Suppl 3): S1–S155
(4) Tanriover B, Jaikaransingh V, MacConmara MP et al. Acute rejection rates and graft outcomes according to induction regimen among recipients of kidneys from deceased donors treated with tacrolimus and mycophenolate. Clin J Am Soc Nephrol 2016; 11: 1650–1661
In your own words, summarise this article؟
●Interleukin-2 receptor (IL-2R) antibody, a non-depleting immunosuppressive agent, has been authorized forinduction therapy since 2000, with the aim of reducing the risk of acute rejection and improving graft survival.
●Many studies have proved that the use of IL-2R antibody asinduction therapy reduces the risk of acute rejection episodes inrenal transplant patients on cyclosporine-based maintenance
immunotherapy.
●In this study there is comparison betweeninterleukin 2ab as induction in standard risk transplantation and others with no induction with Interleukin 2 ab .
●Standard risk for renal transplant was defined as less than twohuman leucocytic antigen DR (HLA-DR) mismatches, panel reactive antibody (PRA) <20% and recipients with no more thanone previous transplant.
● in this meta-analysis, seven studies were included for assessment of risk of acute rejection in the standard-risk populationwith IL-2R antibody induction versus placebo, five of them were
used in the meta-analysis for graft survival 1-year post-
transplant.
●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 as the former is better immunosuppression and low risk of nephrotoxicity.
●In conclusion, IL-2R antibody induction therapy has no
significant effect on the rate of rejection and patient or graft
survival in standard-risk renal transplant recipients on
tacrolimus-based maintenance immunotherapy.
●What are the weakness and strength of this study?
Strength .. There are several studies included
Weakness..
1.short follow up time only one year .
2. Percentage of extended criteria doner is low .
Implication of interleukin-2 receptor antibody induction therapy in standard risk renal transplant in the tacrolimus era: a meta-analysis
Studies have shown that the use of LR 2R antibody induction reduced the risk of acute rejection episodes in renal transplant recipient (RTR) on cyclosporin (CyA) based maintenance immunosuppression (IS). Tacrolimus has been replaced CyA in maintenance therapy in most of the country since Symphony trial as it showed lower risk of rejection. The change from tacrolimus to CyA has questioned the role of IL-2R antibody induction therapy.
This is systemic review class 1 evidences. The study conducted to evaluate the effect of IL-2R antibody induction on the rate of rejection and graft and patient survival in standard risk renal transplantation patient(less than 2 DR mismatches , PRA <20% and recipient < 1 previous transplant) as primary objective and effect of IL-2R induction therapy on creatinine change, NODAT and risk of CMV as secondary objective.
Total of 29426 RTR included in the study – 62.3% in induction group vs 62.9% in the no-induction group. Baseline characteristics are similar and maintenance therapy was triple therapy (steroids, CNI, MMF/AZA).
1. Forest plot analysis of the rate of rejection showed no significant differences between groups, risk difference is -0.06
· The highest weight by Gralla and Wiseman -24.9%
· Baek et al -17.81% ( I2 =72.3%)
When risk of bias is done using Galbraith plot- the risk differences is -0.02
So, IL2R induction has no impact on rejection rates.
2. Random effect meta-analysis for graft survival done using forest plot analysis showed no significant effect of IL-2R induction on graft survival vs Placebo.
· The greatest weight by Gralla and Wiseman-97.34% (I2-41.5%)
3. Forest plot analysis for patient survival 1 year post Transplant showed similar between the groups. The greatest weight by Gralla and wiseman – 50.16%
4. Only 3 articles (de Sandes-Freitas et al,Gavela Martinez et al.and Baek et al)evaluated the changes in creatinine – no differences in creatinine after one year
5. 2 studies (de Sandes-Freitas et al.and Baek et al) showed no differences in NODAT
6. Baek et al. – no significant difference in CMV risk
So, IL-2R antibody induction therapy has no significant effect on the rate of rejection and patient or graft survival in standard-risk renal transplant recipients on tacrolimus-based maintenance immunotherapy.
This a systematic review of 7 articles (6 retrospective observational studies and one prospective study) from 6 different countries.
Aims and objectives:
1- 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.
2- assessment of the effect of IL-2 induction therapy on creatinine change and the risk of cytomegalovirus (CMV) infection.
Level of evidence: 1B (all observational studies, no RCTs).
IL-2R antibody is a monoclonal antibody that inhibits T-cell proliferation was authorized in 2000 as induction agent in transplantation.
IL-2R antibody doesn’t increase the risk of infection and cancer when compared to T-cell depleting agents.
KDIGO 2009 guidelines recommended IL-2R antibody induction therapy as part of routine immunosuppressive protocols especially in low risk groups and maintenance IS by cyclosporine.
Tacrolimus has significantly reduced the incidence of rejection from 50% (3 decades ago) to 10 %.
Inclusion criteria:all studies that compared IL-2 induction therapy with placebo or no induction therapy in standard-risk renal transplant recipients.
Standard risk for renal transplant was defined:
1- less than two HLA-DR mismatches.
2- PRA<20%.
3- recipients with no more than one previous transplant.
Exclusion criteria:
1- Studies with no control group,
2- Studies that compared IL-2 induction therapy with other depleting or non-depleting antibodies, cyclosporine-based maintenance immunotherapy,
3- Studies with high-risk renal transplant recipients.
4- Studies with follow- up period <1year,
5- Studies performed on animals,
6- Studies for dual organ transplant.
7- Studies for organ transplant other than the kidneys.
8- Study language other than English.
Results:
1- IL-2R antagonist has no influence on rejection rates.
2- no significant effect of IL-2R antibody induction on graft survival compared with placebo.
3- 1-year patient survival post- transplant showed no significant different between both groups.
4- No difference in renal function between both groups at the 1-year follow-up.
5- No significant difference in the risk of CMV infection.
6- 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
7- Multi-center European study found similar results when they followed-up the patients for 5 years post-transplant.
8- no additional benefit of IL-2R antibody induction therapy in standard-risk patients in the tacrolimus era.
Limitations and Drawbacks:
1- A degree of heterogeneity among included studies when assessing the risk of acute rejection, while the studies were homogeneous when assessing graft survival.
2- Short follow-up period of 1 year.
3- Low percentage of extended criteria donors compared to the current set-up in transplantation which is around 20–60% of deceased donor grafts.
Strengths:
Higher statistical power because of including 7 studies from 6 countries so it will be less impacted by local findings.
In Practice:
IL-2R inhibitor (Basiliximab) is usually used in low risk patients.
ATG is usually used for high risk patients.
IL-2 receptor antibody is non depleting monoclonal antibody, bind IL-2 receptors leading to inhibition of T cell proliferation, used in induction to decrease risk of AR and to increase graft survival with lower risk of infection and cancer.
It was recommended using IL-2R antibody induction as part of routine immunosuppression in low risk transplant as studies showed that IL-2 R antibody induction is associated with lower risk of AR in patients with low immunological risk on cyclosporine based maintenance therapy.
Recently tacrolimus replaced cyclosporine in maintenance therapy.
Inclusion criteria:
All studies comparing IL-2R induction with the control group or with placebo.
exclusion criteria:
Studies with no control group, compared IL-2R antibody induction with other biological antibodies, cyclosporine based maintenance therapy, high risk patients, dual organ transplant and studies in language other than English.
Standard risk according to studies included was defined as < 2 HLA-DR mismatches, PRA <20%and patients with no more than one previous transplant
primary outcomes were number of AR, patient and graft survival one year post transplant.
secondary outcomes were change in creatinine, new onset diabetes post transplant and CMV infection.
7 articles were included in the meta analysis
AR was confirmed by renal biopsy in all included studies except one.
baseline characteristics of patients showed no significant differences
Maintenance therapy in all studies was steroid, CNI and mycophenolate or azathioprine
The metanalysis showed that IL-2R antibody had no additional benefit in standard risk patients on tacrolimus based maintenance therapy
Strength:
include studies from different centers so has high statistical power.
Studies included were homogenous when assessing graft survival
weakness:
short follow up period
low percentage of extended criteria donors in the studies included
studies were heterogenous when assessing risk of AR due to variability in defining standard risk recipients
studies in language other than English were excluded.
Interleukin-2 receptor (IL-2R) antibody is a monoclonal antibody agent that inhibit T-cell proliferation through binding to IL2R on the T-helper cell surface,it’s not associated with increase the risk of infection and cancer .
Many studies shows a lower risk of rejection in IL2R AB induction in cyclosporine-based ,CNIs inhibitors-sparing regimens compared with placebo in low immunological risk transplant recipients ,Tacrolimus-based maintenance IS.
This systemic review-meta-analysis study performed to explain the effect of IL2R antibody induction therapy on the rate of rejection and graft and patient survival in standard-risk renal transplant patients on tacrolimus-based maintenance immunosuppressant therapy with secondary aim included assessment of effect of IL2R induction on creatinine,NODAT and risk of CMV infection.
The inclusion criteria for this meta-analysis were all studies that compared IL2R induction therapy with placebo on no induction therapy in standard -risk renal transplant recipients
Standard risk mean less than two HLA DR mismatches ,PRA <20% and recipients with no more than one previous transplant.
Primary outcome were the number of acute rejection episodes
Patients survival
Graft survival 1-year post transplant
Secondary outcomes
Include creatinine changesNODAT
CMV infection
Of the total 470 paper from different databases
81 recipients,389 papers screened
379 excluded
10 papers included
3 papers excluded for short follow-up
7 papers included for this meta-analysis
Diagnosis of AR was proved by renal biopsy in all studies included in the meta analysis
Rate of rejection during the follow-up period post-transplantation showed No significance between IL2R induction and no-IL2R induction groups.
No effect of IL2R AB induction on graft survival
No significant effect of IL2R AB on patients survival 1 year post transplant.
No difference in renal function between both groups at 1 year follow up.
No significant difference in the risk of CMV infection between the 2 groups.
One study in this meta-analysis assess the risk of NODAT between the 2 groups
Strengths :
The inclusion of several studies from different countries make it less influenced by local findings compared with single-country studies and generalization of the population of studies.thus having higher statistical power to detect an effect.
Limitations:
Short follow up time (1 year )
Percentage of ECD is low
1-summary
IL 2 AB as induction therapy in standard risk renal transplant (PRA <20%,less than 2 previous transplant,DR mismatch<2)when using CNI specially TAC has no significant decrease the risk of acute rejection compared to placepo
in this meta analysis use of 7 studies from 470 ,5 of them follow the patient 1 year after transplantation found that about 14 patient in every 100 recepient in risk of acute rejection half of them need ttt to prevent one rejection
KDIGO recommend IL2 AB in as astandard induction in in low risk patient who on Tacrolimus as a maintenance immune suppressant
Symphony study show that the standard maintenance therapy include (TAC,MMF,Corticosteroid) less acute rejection and more graft survival 5 years also show that TAC more potent than cyclosporine may be due to less nephrotoxicity
Study show that no need for induction in low (standard) risk population and no need for IL2 AB
2-strenth of study
That it include a lot of studies from different countries and population
Weakness
Short follow up duration (1 year after transplantation)
This is a Systematic review of metanalysis, level 1B as there were no random controlled studies implicated.
Interlukin2 inhibitors are considered as non-depleting monoclonal antibodies that are used as an induction therapy in low, and standard immunological risk kidney transplant protocols with cyclosporine-based maintenance immunotherapy with lower rejection rate and favorable graft survival compared to placebo group and Tcell depleting agent like ATG with less side effects.
Tacrolimus replaced Cyclosporine due to its potent efficacy with less side effect with reducing the rejection rate significantly as compared to
cyclosporine.
The Primary target of the study was to determine the effect of IL2I induction in standard risk recipients with tacrolimus-based maintenance immunotherapy on the rate of acute rejection and patient survival.
The Secondary target was to assess the risk of induction with IL2I in standard risk on creatinine change, post-transplant diabetes risk and CMV infection risk .
This study showed that the use of IL2 I induction therapy in standard risk kidney transplantation with tacrolimus-based maintenance IS had no significant effect on the rate of rejection and graft or patient survival compared to placebo or no induction group.
Strengths of the study:
*The studies Included diverse populations from different countries thus the findings are not influenced by local population or centers.
*The studies were homogeneous when assessing graft survival.
Limitations:
*Lower percentage of extended donor criteria (EDC) in this meta-analysis.
*Variations in the definition of standard risk group among the studies and centers resulted in conflicting results in assessing the risk of acute rejection
*Short follow up of 12 months not enough to assess long-term outcome.
I Used Simulect as induction IS in living donor kidney transplant protocol with standard with favorable results in tacrolimus based IS , but ATG for high risk groups , while no induction for low risk groups .
This a systematic review .
Aims and objectives:
-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.
-assessment of the effect of IL-2 induction therapy on creatinine change and the risk of cytomegalovirus (CMV) infection.
Summary
IL-2R antibody is a monoclonal antibody that inhibits T-cell proliferation was authorized in 2000 as induction agent in transplantation.
KDIGO 2009 guidelines recommended IL-2R antibody induction therapy especially in low risk groups and maintenance Immunosuppression by cyclosporine.
Tacrolimus has significantly decreased the incidence of rejection from 50% to 10 %.
Standard risk for renal transplant was defined:
1- less than two HLA-DR mismatches.
2- PRA<20%.
3- recipients with no more than one previous transplant.
Results:
* IL-2R antagonist has no influence on rejection rates ,on graft survival compared with placebo.
* No significant difference in the risk of CMV infection.
*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
*no additional benefit of IL-2R antibody induction therapy in standard-risk patients in the tacrolimus era.
Limitations and Drawbacks:
*Short follow-up period of 1 year.
Strengths of study:
This article is a systematic review with level 1 of evidence, with meta-analysis of different databases such as PubMed and Embase.
Inclusion of several studies from different countries, that leads to elimination of the influence of local findings. Thus, it has higher statistical power to detect an effect.
Limitations of study:
Although 470 articles were found in different databases, 7 were included in the meta-analysis.
Too short period of follow up (1 year) for getting conclusion on graft survival.
The number of ECDs in this study was low, so could not evaluate if IL2R antibody induction therapy is beneficial in this setting.
Included studies for assessing the risk of acute rejection were heterogeneous due to variations in the definition of standard risk patients among different studies.
One of the main barriers to improving kidney transplant outcome is episodes of acute rejection, and for overcoming this problem, new immunosuppressive agents have developed such as IL-2 receptor antibody. It is a no-depleting immunosuppressive agent that inhibits T cell proliferation with less risk of cancer and infection than T-cell depletive immunotherapy.
Based on meta-analysis that had shown lower risk of rejection in IL-2R antibody induction therapy compared with placebo, and no advantage of T cell depleting agents over IL-2R antibody induction therapy with cyclosporine-base maintenance therapy, the KDIGO guideline recommends IL-2R antibody induction therapy as a part of routine immunosuppressive protocols.
In that meta-analysis, a 28% decrease in the risk of acute rejection with IL-2R antibody induction therapy was reported. In addition, the number needed to treat to prevent one rejection episode was seven patients.
Given that tacrolimus-based therapy has a lower risk of rejection compared with cyclosporine, the primary aim of this study is to explore the effect of IL-2R antibody induction therapy on allograft and patient survival in standard risk patients treated with tacrolimus-based therapy. Standard risk was defined as less than two HLA-DR mismatches, PRA<20%, and recipients with no more than one previous transplant.
The favorable long-term outcome of patients on tacrolimus maintenance therapy compared with those on cyclosporine therapy may be related to less nephrotoxic effect and more powerful immunosuppressive effect of tacrolimus compared with cyclosporine, leading to a lower rate of chronic rejection.
This meta-analysis illustrated no additional benefit of IL-2R antibody induction therapy in standard risk patients in the tacrolimus era. Although there were conflicting data about advantages of IL-2R antibody induction therapy in various studies.
This is a systematic review which assessed the consequences of induction with IL-2 antibody therapy on the outcomes in standard-risk kidney transplant recipients on tacrolimus based maintenance therapy . Standard risk was defined as less than two DR mismatches, PRA<20% and recipients with no more than one prior transplant. It has analyzed 470 articles and only 7 were assessed at the end (463 were excluded due to repetitions, unrelated or short follow-up period . The total number of patients analyzed was 29426. Primary outcomes were the number of acute rejection episodes and patient and graft survival 1-year post-transplant which were not different statistically .Secondary outcomes were creatinine changes, new onset diabetes after transplant (NODAT) and CMV infection which were also not different statistically between the groups .
The strengths
inclusion of several studies from different countries so higher statistical power
Limitations
· Short follow-up period only 1 year
· The proportion of ECD is low (these graft may benefit from IL-2R antibody induction to spare CNIs.
Please reflect your practice if possible.
we have stopped using IL-2 antibody as induction in standard and low risk patients in Sudan due to financial burden. there was no documented studies to assess the effect of this.We do not do protocol biopsies.
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.
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
welldone
IL2 receptor antagonist ( basliximab) is monoclonal Ab receptor that inhibits T-cell proliferation by binding to IL-2 receptors on T-helper cells. It is non T cell depleting so it does not increase the risk of infection or cancer and used as induction therapy .
According to meta analysis done 2010 , basliximab was recommended by KDIGO in all transplant patients with low Immunological risk , but the meta analysis included patients receiving cyclosporine .Tacrolimus has replaced cyclosporine, with the significant reduction in rejection rates , so the role of basiliximab in patients receiving tacrolimus was questionable .
The primary aim of meta-analysis is to explore the effect of IL-2R antibody induction therapy on the rate of rejection and graft and patient survival in standard-risk renal transplant patients on tacrolimus-based maintenance immunotherapy. Secondary aims to know the effects of IL-2 induction therapy on creatinine change, new-onset diabetes post-transplant (NODAT) and risk of cytomegalovirus (CMV) infection
The result showed the IL-2 receptor antibody induction therapy has no significant effect on the rate of rejection or graft survival in low Immunological risk patient compare to patient on tacrolimus-based maintenance immunotherapy.
What are the weakness and strength of this study?
Strengthes of the study include inclusion of 7 studied from different countries, so preventing results from being influenced by local circumstances of a single country, gaining more statistical power .
Weaknesses
Include too short period of follow up 1year .
Low percentage of extended criteria donors included in studies .
In our center we do not use IL2 receptor Ab in the standard-risk renal transplant recipients . IS protocols of common use in low – risk transplantation are TAC based MMF and prednisolone .
wellread thankyou for mentioning your center practice which is in agreement with the above coclusion.
Implication of interleukin-2 receptor antibody induction therapy in standard risk renal transplant in the tacrolimus era: a meta-analysis
early acute rejection have great impact on graft survival .biological antibody induction therapy(using depletion or non depleting) one of the best option to decrease ABPR risk of incidence. basliximab was recommended by KDIGO in all transplant patients with low Immunological risk based on meta-analysis done in cyclosporine era. the aim of this systematic review is to study the significance of basiliximab in preventing acute rejection in the era of tacrolimus. systematic review of 6 retrospective observational and one prospective studies showed no clinical or statistically significant of basiliximab induction in preventing acute rejection if the patient on tacrolimus based regimen
my center experience
basilixmab is signal 3 blocker in t cell stimulation and allograft recognition and so its expected to be of low clinical impact on incidence of acute rejection but we still use it specially in older recipient with low immunological risk to be able to keep the patient on low tac regimen and early steroids decrease to 5mg in first 3m
the weakness of this study is
1/no long term followup
2/no standardization of immunosuppressive regimens
3/ almost all data from retrospective studies
Please answer all the questions? Brief appraise the article with the appraisal template.
summarise this article
early acute rejection have great impact on graft survival .biological antibody induction therapy(using depletion or non depleting) one of the best option to decrease ABPR risk of incidence. basliximab was recommended by KDIGO in all transplant patients with low Immunological risk based on meta-analysis done in cyclosporine era. the aim of this systematic review is to study the significance of basiliximab in preventing acute rejection in the era of tacrolimus. systematic review of 6 retrospective observational and one prospective studies showed no clinical or statistically significant of basiliximab induction in preventing acute rejection if the patient on tacrolimus based regimen
What are the weakness and strength of this study?
1/no long term followup
2/no standardization of immunosuppressive regimens
3/ almost all data from retrospective studies
Please reflect your practice if possible
my center experience
basilixmab is signal 3 blocker in t cell stimulation and allograft recognition and so its expected to be of low clinical impact on incidence of acute rejection but we still use it specially in older recipient with low immunological risk to be able to keep the patient on low tac regimen and early steroids decrease to 5mg in first 3m
Acute rejection remains one of the obstacles facing better outcomes after renal transplantation.
IL2 receptor antagonist ( basliximab) is monoclonal Ab agained IL2 receptor on the surface of t helper cell , is non T cell depleting , used as induction therapy , and so is associated with lower risk of infections and malignancy post transplantation .
According to meta analysis done 2010 , basliximab was recommended by KDIGO in all transplant patients with low Immunological risk , but the meta analysis included patients receiving cyclosporin .
After tacrolimus has replaced cyclosporine, with the significant reduction in rejection rates with tacrolimus , the role of basiliximab in patients receiving tacrolimus was questionable
And this is the value of the current meta analysis that is studied role of basliximab in patients receiving tacrolimus, regarding rates of acute rejections.
This meta analysis included 7 articles, comparing IL2 R antagonist to placebo as induction therapy, in recepients receiving tacrolimus based IS .
This meta analysis concluded that there is no extra benefit of IL2 receptor antagonist, in tacrolumus era
Strengthes of the study include inclusion of 7 studied from different countries, thus preventing results from being influenced by local circumstances of a single country, gaining more statistical power .
Weaknesses include very short period of follow up 12months .
Proportion of extended criteria donors was low , comparable to actual status
At our center we use only ATG as induction therapy for high risk patients
For standard risk we don’t used basiliximab in tacrolimus based regimens
Induction therapy is almost always individualised among patients
How many registry based studies were included in the paper? What are your view about the report of funnel plots in the study?
1. In your own words, summarise this article
Implication of interleukin-2 receptor antibody induction therapy in standard risk renal transplant in the tacrolimus era: a meta-analysis
This is a meta-analysis done with the aim to find out effects of interleukin-2 receptor (IL-2R) antibody induction on low-risk kidney transplants on tacrolimus immunosuppression with respect to acute rejection, graft survival, as well as complications including CMV infection and post-transplant diabetes mellitus.
The meta-analysis was done after an online search of studies related to IL-2R antibody versus no induction in standard-risk (PRA<20%, <2 HLA DR mismatch and <2 prior transplants) kidney transplant recipients who were on Tacrolimus based maintenance immunosuppression. A total of 7 studies with a total pool of 29,426 patients were shortlisted. The analysis revealed:
1) There was no significant difference between the 2 groups with respect to acute rejection episodes.
2) There was no significant difference between the 2 groups with respect to graft survival and patient survival.
3) Three of the studies which analyzed effect on creatinine change showed similar results in both the groups.
4) Two of the studies compared risk of new onset diabetes in the two groups and found no difference.
5) One study compared CMV infection rates in the two groups and found that to be similar.
So, to summarize, there is no added benefit of IL-2R antibody induction use in standard-risk transplant recipients with Tacrolimus based maintenance immunosuppression with respect to graft and patient outcomes.
2. What are the weakness and strength of this study?
Weaknesses:
1) Although this study included 7 studies, but more than 97% of the patients in this analysis were covered by single study by Gralla and Wiseman (28686 patients out of total 29,426 patients). So, the results shown in this study would have undue weightage on the final analysis.
2) The follow-up in these studies was only 1 year, too short a period to assess the long-term effects. It is quite possible that the positive effects of IL-2R antibody induction could be visible later-on. Hence a longer follow-up would have been ideal to proclaim that IL-2R antibody induction has no significant benefit in this subgroup of patients.
3) The donor characteristics also have a role in graft prognosis. In the studies, pool of donors with extended criteria was low as compared to that seen in real-life transplants, hence the effects of IL-2R induction in such donors could not be analyzed.
4) The defining criteria for standard-risk recipient were not same in the studies.
Strengths:
1) The analysis involved a large number of patients, from different centers in different countries.
2) Detailed statistical analysis done.
3. Please reflect your practice if possible.
We have a living related transplant program. In our unit, all patients are on triple drug immunosuppression (tacrolimus. MMF and steroids). Earlier, we were not using induction therapy in low-risk transplant recipients (one haplotype match, no history of sensitization). But few years back, we compared our data (not published) in low-risk patients with no induction versus basiliximab versus low dose ATG (2 mg/kg) and there was significant reduction in acute rejection episodes with no significant increase in CMV infections in low dose ATG group. The outcomes were similar in basiliximab and no induction group.
Hence, nowadays we use low dose ATG induction in low-risk patients
Good analysis. Why did authors use random effect model despite heterogeneity being <25%. What are your comments.
I have tried to look into this aspect, but unable to come to any conclusion. One reason might be that by using random effect model, the heterogeneity goes out of the picture as it is based on the assumption that effects being seen in different studies are not identical but follow a distribution pattern, which is plotted in the funnel plot in which the observed outcomes are plotted horizontally and standard error is plotted vertically.
you are looking in right direction. With Low heterogeneity , authors should have chosen fixed model but heterogeneity is >25 in some outcomes, so random effect appears to be the right choice for those outcome analysis.
This is a meta-analysis study included 7 articles aimed first to study the effect of IL-2R antibody induction therapy on rejection rate and graft and patient survival in standard-risk renal transplant patients on tacrolimus-based maintenance immunotherapy ;
And it shows no significant effect on the rate of rejection or patient or graft survival in standard-risk renal transplant recipients on tacrolimus-based maintenance immunotherapy.
the second aim was the to study the effects of IL-2 induction therapy on creatinine change, new-onset diabetes post-transplant (NODAT) and risk of cytomegalovirus (CMV) infection.
no significant increase in CMV infection.
Strength points ;
inclusion of several studies from different countries and generalization of the population of studies, so having higher statistical.
Limitations points.
period of 1 year is too short to assess graft survival.
Low percentage of extended criteria donors
And in particular, this type of graft may benefit from IL-2R antibody induction use in order to spare CNIs.
The effect on CMV infection was studied only in one study .
There was no results on the creatinine chages.
The definition of standard-risk patients was not clear and uniform for all studies
In my paractice we don’t use basiliximab for standard-risk recipient
Answer all the questions. Why did authors exclude Wiland et al for analysis for risk of rejection 1-year post-transplant? any clues.
They were excluded as diagnosis of of acute rejection was confirmed by renal biopsy in all studies except for Wiland et al who didn’t mention this clearly
Primary aim of the meta-analysis is study is to explore 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 aims assessment of the effect of IL-2 induction therapy on creatinine change
and the risk of cytomegalovirus (CMV) infection.
Conclusion reached IL-2R antibody induction therapy has no significant effect on the
rate of rejection or patient or graft survival in standard-risk renal transplant recipients on
tacrolimus-based maintenance immunotherapy.
Strength:
Systemic review of large number of studies in different population.
Weakness:
Shor he percentage of extended criteria donors in our analysis is low.
one year time ,which won’t reflect late risk LAR ,CAN .
Its met analysis not RCT with inherited heterogeneity and publication bias.
Relation to practice:
IL2 used in low risk LRD patient, who are most of our center and ATG for high risk
patient.
Very brief answer. What is the level of evidence of this study?
-Interleukin-2 receptor (IL-2R) antibody, is a mono[1]clonal antibody acts by inhibiting T-cell proliferation through binding to IL-2 receptors on the T-helper cell surface. In comparison with T-cell depletive immunotherapy, IL-2 induction therapy does not increase the infection nor the cancer risk
(KDIGO) guidelines recommended the use of IL-2R antibody induction therapy as part of routine immunosuppressive protocols as a meta-analysis study demonstrated that there is no privilege of T cell depleting agents over IL2R antibody in induction of low immunogenic risk transplant naïve recipients with cyclosporine used as the main maintenance immunotherapy
The aim of the study is to assess the effect of IL-2R antibody induction therapy on rejection rate and graft and patient survival in standard-risk renal transplant patients on tacrolimus-based maintenance immunotherapy as well as the effects of IL-2 induction therapy on creatinine change, new-onset diabetes post-transplant (NODAT) and risk of cytomegalovirus (CMV) infection.
The study included all the studies that compared IL-2 induction therapy with placebo or no induction therapy in standard-risk renal transplant recipients and excluded studies with no control group, those that compared IL-2 induction therapy with other depleting or non-depleting antibodies, cyclosporine-based maintenance immunotherapy, high-risk renal transplant recipients, followup period less than 1 year
The meta-analysis showed no added benefit of IL-2R antibody induction therapy in standard-risk patients in the tacrolimus era
It was concluded that IL-2R antibody induction therapy has no significant effect on the rejection rate nor the patient or graft survival in standard-risk renal transplant recipients on tacrolimus-based maintenance immunotherapy.
-The strengths of the study is assessing multiple studies from different countries rather than a single country, thus having higher statistical power .
Limitations include the short follow up period of 1 year which is not enough to assess the graft survival and the low percentage of extended criteria donors compared to the current set-up in clinical transplantation
Would absence of RCT’s be a limitation of this Meta analysis?
Summary:
This systematic review is being undertaken in several databases in order to determine the influence of interleukin-2 (IL-2) on kidney transplant outcomes.
The study looked at whether IL-2 induction therapy was superior to placebo or no induction therapy among standard-risk kidney transplant recipients receiving tacrolimus-based maintenance immunosuppressive therapy. In the tacrolimus period, this meta-analysis found that induction treatment with an anti-IL-2R antibody had no extra benefit in patients at standard risk.
Weakness:
1-Short follow up 1 year.
2-low percentage of extended donor criteria, included in the study.
Strength:
1-the study includes varied people from different nations, the conclusions are not impacted by the local population or concentrations of populations.
2-To identify the impact, use sound statistical analysis.
Impact on my practice:
the induction therapy (Basiliximab)in low immunological risk patients, can be avoided in the presence of tacrolimus. at least during 1st-year post-transplantation, no more rejection attack.
What is the impact factor of the journal? How many registry based studies were in the article.
The impact factor in 2020 is ( 4.452)
470 articles were found in different databases, 7 were included in the meta-analysis.
Good. There was only 1 registry study in the analysis.
This study is meta-analysis of the effect of IL2 antagonist, as an induction agent , in low risk kidney transplantation recipients in the tacrolimus era.
Primary endpoints were acute rejection ang graft survival after 1 year.
Secondary endpoints were serum creatinine change and NODAT and CMV infection.
inclusion criteria :
The meta-analysis found no difference in acute rejection or graft survival between the two groups.
Strength of the study : it uses data from different centers.
Weakness of the study :
In our center we use basiliximab in low risk patients even if the CNI used was tacrolimus.
What were the results of analysis of secondary outcomes?
Study Summary
A meta-analysis study aimed at investigation of IL2 induction therapy on renal graft rejection and patient and graft survival in standard risk patients using tacrolimus as maintenance therapy. Second aim was exploring the effect of IL-2 on creatinine and CMV infection risk in same patients.
It was found that no significant beneficial impact on on risk of graft rejection and patient and graft survival with using of IL2 as induction therapy and tacrolimus in maintenance regimen. Additionally, no significant increase in CMV infection.
Strength of the study
generalization of population so having more statistical power being including several studies from different countries.
Weakness
Short period;1 year
Low percentage of extended criteria donors who could benefit from IL-2R Ab induction for CNI sparing.
Practically, Basiliximab is used in induction therapy for low risk patients ,while ATG is used in high risk ones.
what is the level of evidence of this study
1B,no RCT
Meta-analysis of systemic review study aimed to identify the effect of IL-2R Ab ( as induction) on AR & graft out-come among standard risk recipients (<2HLA-DR mismatch, PRA <20%, with-out or with one previous transplant) with Tac based regime. Second out-come was the effect of IL-2R Ab on creatinine change, NODAT, & risk of CMV infection.
IL-2RAb is a non depleting immunosuppressive agent, authorized as induction at 2000. It is not associated with increasing risk of infection or cancer when compared to depleting agents.
This review include all studies use IL-2RAb compared to placebo or not using induction in standard risk recipients. Exclusion criteria include:
This review was the first study assess the effect of IL-2RAb in Tac based maintenance regime ( previous studies were use CsA based regime). There are some heterogeneity between includes studies regarding risk of AR, which may be due to:
Strength of the study: using different studies from different countries leading to high statistical power in detecting an effect
Weakness of the study:
In summary the study conclude that there is no significant difference in graft & patient survival when used IL-2RAb as induction in tacrolimus based maintenance regime.
In our center we use IL-2RAb for low risk recipient & ATG for high risk recipients.
What is heterogeneity?
studies that analyzed together in systemic review will differ inevitably, this may be due to variability in in participant, intervention & outcomes, study design, & variability in in intervention effect.
Summary:
Systemic review with metanalysis, evidence level 1B (no single RCT in this meta-analysis).
Introduction:
Interlukin2 inhibitor (IL2) is one of the nondepleting monoclonal antibodies have been used since many years as an induction therapy in low, and standard immunological risk kidney transplant protocols with cyclosporine-based maintenance immunotherapy, with lower rejection rate and favorable graft survival compared placebo group and T-cell depleting agent like ATG with less side effects from evidence of many studies including one large meta-analysis of randomized control trial ,for that the kidney disease improving Global Outcomes(KDIGO) guidelines recommend IL-2R antibody induction therapy as part of routine immunosuppressive protocols in standard risk recipients.
Tacrolimus based maintenance IS replaced Cyclosporine since many years and widely used by many centers with proven its potent efficacy with less side effect with reducing the rejection rate significantly as compared to cyclosporine.
Aim of this study:
Primary end point: to determine the effect of IL2 induction IS in standard risk recipients with tacrolimus-based maintenance immunotherapy on the rate of acute rejection and on graft and patient survival.
Secondary endpoint: to assess the risk of induction with IL2 in standard risk recipient on creatinine change, post-transplant diabetes risk (PTDM), CMV infection risk
7 studies included from diverse populations all in retrospective design accept one study was prospective from Korea all with short fu (one year), majority have small sample size only one registry study have good number of more than 14000 with missing raw data for some patients characteristics which can affect the assessment of the rejection risk .
This study concludes that the use of IL2 monoclonal antibodies induction therapy in standard risk kidney transplantation with tacrolimus-based maintenance IS has no significant effect on the rate of rejection and graft or patient survival compared to placebo or no induction group.
Strength of the study:
the studies Includes diverse populations from different countries (Europe, US , ASIA ),so the findings not influenced by local population or centers.
Use good statistical analysis to detect the effect.
the studies were homogeneous when assessing graft survival.
Limitations:
1-variation in the definition of standard risk group among the studies and centers resulted in heterogenicity and conflicting results in assessing the risk of acute rejection
2-Short follow up of 12 months not enough to assess long-term outcome.
3- including lower percentage of extended donor criteria (EDC) in this meta-analysis.
Please reflect your practice if possible:
I have been used basiliximab monoclonal AB as induction IS in local livingdonor kidney transplant protocol with low and standard immunological risk since many years ago with favorable results in both cyclosporine-based maintenance IS and later tacrolimus based IS , but currently I’m working in center using ATG as Induction IS for both low and high immunological risk with modification of the ATG dosing , as we don’t have access to IL2 ab -basiliximab .
Excellent! very well done
The implication of interleukin-2 receptor antibody induction therapy in standard risk renal transplant in the tacrolimus era: a meta-analysis
This systemic review study used different databases to identify researches from different countries that assess the impact of IL-2 anti-body induction therapy on renal transplant. It includes all studies that compared IL-2 induction therapy with placebo or no induction therapy in renal recipients on tacrolimus-bases maintenance immunosuppression and are standard risk recipients. 7 studies have been included from 470 studies reviewed.
Many immunosuppressive protocols have been intended with the goal to prevent graft rejection.
Interleukin-2 receptor (IL-2R) antibody, is a monoclonal, non-depleting agent, that inhibits T-cell proliferation by binding to IL-2 receptors on T-helper cells. It does not increase the risk of infection or cancer.
A meta-analysis done in 2010, that assessed the outcome of IL-2 induction compared with placebo as well, compared with T-cell depletive induction therapy in low immunologic risk recipients on cyclosporine as the main maintenance therapy. This cohort showed a lower risk of rejection in the IL-2 group. It also showed no excellence of T-cell-depletive agents over IL-2R antibody agents. Based on this result the KDIGO guidelines recommend IL-2R antibody induction as part of routine immunosuppressive protocols.
In the Tacrolimus era, as it replaced cyclosporine as maintenance immunosuppressive therapy in many transplant centres.
The change to tacrolimus as maintenance immunotherapy with an obvious decline in the rate of rejection episodes put the use of IL-2R antibody as induction therapy in doubt. Raising the question of the significance of IL-2R antibody induction in the tacrolimus era and whether it adds any benefits in lowering the rejection risk in standard risk recipients.
Definition standard risk recipient:
It was defined as:
· less than two HLA-DR mismatches.
· Panel reactive antibody (PRA) < 20%
· Recipients with no more than one previous transplant.
Studies compared the long-term outcomes of renal transplants using tacrolimus and cyclosporine as maintenance immunotherapy. Most showed better outcomes with tacrolimus therapy. This advantage of tacrolimus over cyclosporine could be explained by the lower nephrotoxic effect of the tacrolimus, and its powerful immunosuppressive effect compared with cyclosporine. These advantages of the tacrolimus raised questions about the IL-2R antibody induction therapy whether it adds boons in reducing rejection risk in tacrolimus based therapy.
In previous studies, there were conflicting data about the actual benefit of IL-2R antibody induction therapy in the standard-risk population.
The present meta-analysis showed no additional benefit of IL-2R antibody induction therapy in standard-risk patients using tacrolimus as a maintenance therapy
Good. Please comment on funnel plots. What do they indicate?
Summary of article ;
Since many centre today use tacrolimus as maintenance immunotherapy and most of the previous studies have compared long-term outcomes of renal transplant using cyclosporine and tacrolimus as maintenance immunotherapy. questions about the validity of the results of this meta-analysis were raised . Also the better outcomes of patients on tacrolimus maintenance therapy and fewer nephrotoxic effects raised concerns aboutthe need and the benefit of induction therapy in the standard risk population. It could also be related to the more powerful immunosuppressive effect of tacrolimus compared with cyclosporine, ending in a lower rate of chronic rejection. The better outcomes of patients on tacrolimus maintenance therapy and fewer nephrotoxic effects raised concerns about the need and the benefit of induction therapy in the standard risk population. In previous studies there were conflicting data about the actual benefit of IL-2R antibody induction therapy in the standard-risk population.
The aim of this study and meta-analysis is to;
– explore 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 aims included assessment of the effect of IL-2 induction therapy on creatinine change and the risk of cytomegalovirus (CMV) infection.
This systemic review is conducted in different data base to assess the effect of IL-2 on renal transplant outcomes . It compared IL-2 induction therapy with placebo or no induction therapy in standard –risk renal transplant recipient on tacrolimus-based maintenance immunosuppressive therapy . this meta-analysis showed no additional benefit of IL-2R antibody induction therapy in standard-risk patients in the tacrolimus era.
The strengths of our study are ;
The inclusion of several studies from different countries and thereby being less influenced by local findings compared with single-country studies and generalization of the population of studies, thus having higher statistical power to detect an effect.
Weakness of the study ;
The follow-up period of 1 year is too short to draw definitive conclusions on graft survival. The percentage of extended criteria donors in our analysis is low compared to the current set-up in clinical transplantation which is around 20–60% of deceased donor grafts .
My practice ;
We use IL2 inhibitor for low risk group of patient . the maintenance protocol usually tacrolimus based .
Good, what model of analysis did authors use, random or fixed effect model and WHY?
thanks prof
A random effects meta-analysis for patient and graft survival was performed using forest plot.
-IL-2 receptor antibody is a monoclonal nondepleting antibody when compared with T cell depletive immunotherapy, it does not increase the risk of infection or cancer.
-IL-2 receptor antibody inhibits T cell proliferation.
-Inclusion criteria for this study were all studies that compared IL-2 induction therapy with placebo or no induction therapy in standard-risk renal transplant recipients.
-All studies were tacrolimus-based maintenance immunotherapy.
-Standard risk for renal transplant was defined as less than two HLA-DR mismatches, PRA ˂20 %, and recipient with no more than one previous transplant.
-470 articles were found in different databases but seven articles were included in this meta-analysis.
-29426 patients were included in the meta-analysis and there were no significant differences between baseline characteristics of the patient included in the IL-2R antibody induction group and noninduction group.
-The primary aim of this study is to assess the risk of acute rejection in the standard risk population with IL-2R antibody induction versus placebo in tacrolimus–based maintenance immunosuppression.
-Some studies showed a decreased risk of acute rejection in those receiving IL-2R antibody induction so KDIGO guidelines recommended IL-2R antibody induction as standard induction therapy in low-risk renal transplant patients.
-The Symphony study showed better graft survival and less risk of acute rejection at 1-year follow-up in patients receiving tacrolimus compared with those receiving cyclosporine.
-This meta-analysis showed no additional benefit of IL-2R antibody induction therapy regarding rate of rejection and graft or patient survival in the standard-risk patient in tacrolimus–based maintenance immunosuppressive therapy.
Strength of study:
inclusion of several studies from different countries and thereby less influence by local findings.
Limitation of the study :
1. Short follow-up period.
2. Low percentage of extended criteria donors included in studies.
3. the Small number of studies included in this meta-analysis.
-In my practice, we use Basiliximab in the low-risk recipient and tacrolimus -based maintenance immunosuppressive therapy.
Good . Please comment on the metaanalysis findings on the secondary outcomes.
Summary of the Article:
This systemic review and meta-analysis article studied the effect of IL-2 induction in standard-risk kidney transplant recipients with the following main out-come:rejection rate, patient and graft survival. Secondary outcome were: change in serum creatinine ,NODAT and risk of CMV infection.
IL-2R antibody,is a mono-clonal antibody inhibits T-cell proliferation.Many studies proved it’s effectiveness as induction therapy in reducing the risk of acute rejection in combination with CsA(1).
The meta-analysis showed no superiority for T-Cell depleting agents over IL-2R Antibody in induction therapy in addition to it’s effect in lowering the risk of rejection, that’s why being recommended by KDIGO 2009 Guidelines as part of immunosuppressive protocols.
The use of TAC as maintenance mmunotherapy was associated with remarkable decline rate of rejection(from 50% to 10%) in comparison to CsA based immunotherapy(2) and this lead to enquire about the additional value of IL-2R antibody. This meta-analysis found no additional benefit in the use of IL-2R antibody in standard-risk patients in the presence of Tacrolimus which proved to be with fewer nephrotoxic effects.
Only 2 studies in the meta analysis assessing the risk of NODAT and one study to address the risk of CMV infection which wasn’t significant. From the studies included in the meta-analysis there were conflicting data about the effect of IL-2R antibody on the rate of rejection,aptient and graft survival in the standard-risk RT-recipients. The meta-analysis conclusion was the absence of significant effect on the main outcome.
Limitations:
The strengths of this study:
In practice of transplantation in centres where I’m working or used to work in, we don’t use IL-2R antibody induction in the standard-risk renal transplant recipients.IS protocols of common use in standard -risk transplantation are TAC based or CsA based Immunosuppression.
Referrences:
1.Nashan B, Moore R, Amlot P et al. Randomised trial of basilix- imab versus placebo for control of acute cellular rejection in renal allograft recipients. Lancet 1997; 350: 1193–1198.
2.Meier-Kriesche HU, Schold JD, Srinivas TR et al. Lack of im- provement in renal allograft survival despite a marked de- crease in acute rejection rates over the most recent era. Am J Transplant 2004; 4: 378–383
Excellent.
IL2 receptor antagonist ( Basiliximab) was found to decrease the risk of rejection by 27% in cyclosporine era in standard risk transplant recipients ( < 2HLA DR mismatches, not more than 2 previous transplant, PRA< 20 %)
Later on tacrolimus was used instade of cyclosporine by most of transplant centers, tacrolimus is more potent and less nephrotoxic than cyclosporine
Although IL2 receptor antagonist does not increase the rate of infection and malignancy but the benefit is doubtful in tacrolinus era
This study which is a meta analysis including 7 studies found no benefit of IL2 receptor antagonist in tacrolimus era regarding rate of acute rejection and graft survival in standard risk patients.
Strength of this study
– It is a meta analysis including studies from different countries.
Weakness of this study
– Short follow up period, 1 y is not sufficient to have accurate conclusion
– Low percent of extended criteria donors included in these studies
In my practice
– We were dealing with low risk living related donors so we use basiliximab in induction and ATG was only used in acute celluler rejection.
How many registry based studies were there. How do they affect analysis?
Before this article has been published, many studies have proved that the use of IL-2R antibody as induction therapy followed by Cyclosporine based maintenance therapy reduces the risk of acute rejection episodes.
This paper reviewed studies demonstrating the efficacy of tacrolimus based maintenance therapy , preceded by induction therapy using IL-2R antibodies.
This review included 7 studies using this regimen in standard risk patients defined as less than two HLA-DR mismatches, PRA <20% and recipients with no more than one previous transplant.
The primary aim of this study was to address the effect of IL-2 antibody induction therapy on the rate of rejection and graft survival in standard risk patients.
Secondary aim was to assess the effect of IL-2 induction on creatinine change and the risk of CMV infection.
Results
IL-2 induction therapy in the tacrolimus based maintenance immunosuppression has no significant effect on the rate of rejection or patient or graft survival in standard-risk renal transplant. No significant difference in the risk of CMV infection.
Strengths
Inclusion of several studies from different countries
Weaknesses
The follow-up period of 1 year is too short to draw definitive conclusions on graft survival
The definition of standard risk in this review included mismatches at HLA DR antigen only, but not –B, -A.
Most of the results were concluded from one study with the highest number of patients, where the remaining studies account for a minority number of patients.
In my practice
Patients who are compatible with definition of low risk for rejection are given Basiliximab as induction therapy whereas high risk patients receive r-ATG.
Good, please comment on evidence of this study.
Summary:
Meta-analysis study to show impact of IL-2 monoclonal antibody as induction therapy on graft outcome and survival in the standard risk renal allograft recipients. In addition, its impact on incidence of post-transplant CMV infection.
These patients received cyclosporine free regimen (Tacrolimus based regimen).
IL-2 monoclonal antibody basiliximab is non depleting monoclonal antibody used in induction of immunosuppression to prevent acute rejection and improve graft outcome. It prevents T cell proliferation by binding to IL-2 receptor on the surface of T cell. No increase in the risk of malignancy and infection with its use as compared to depleting antibodies.
It is used as induction therapy in the standard risk patients either cyclosporine based or tacrolimus based regimens.
Tacrolimus based regimen is associated with decreased risk of rejection from 50 % (with cyclosporine based regimen) to 10 % with tacrolimus based regimen, so, the study of effect of induction with basiliximab versus no induction is of value in the standard risk recipient receiving tacrolimus.
Criteria of Standard risk patients:
1- cPRA is less than 20%
2- 1 previous transplant or no previous transplant
3- Less than 2 HLA-DR mismatch
In the cyclosporine based regimen, Authors showed that the risk of acute rejection episodes decreased by 14% in the recipient take induction by IL-2 antagonist versus the recipient with no induction. Basiliximab is considered an induction agent in the standard risk patients as per KIDIGO guidelines.
As regard comparison between cyclosporine and tacrolimus , tacrolimus has more potent immunosuppressive effect over cyclosporine and has less nephrotoxic effects , and associated with better graft outcome than cyclosporine.
The study showed no additional benefit of using basiliximab as induction therapy in the patient on tacrolimus based regimen. Some other studies showed additional benefit of basiliximab induction in tacrolimus based regimen as regard graft outcome.
Strengths:
The meta-analysis includes studies from different centers from different countries not limited to local area, that make data generalized.
Weakness:
Short period of follow up of outcome.
Small numbers of study justify inclusion criteria
Need more clinical trials to prove long term effect of basiliximab on graft outcome in tacrlimus based regimen
Some other factors affect incidence of rejection like age of donor and recipient, ABO match and HLA mismatch, ethnicity, level of DSA.
In my practice, we always use basiliximab as induction therapy in standard risk patients either in cyclosporine based or tacrolimus based regimen. We not use induction at all in 000 mismatch only.
very good. Please comment on heterogeneity and how does it affect the analysis.
A meta analysis that aimed to assess the effect of IL-2 antibody induction on transplant outcomes.
IL-2 receptor antibody , a non depleting agent authorized for induction therapy since 2000, it is a monoclonal antibody that inhibit T cell proliferation through binding to IL-2 receptors on T cell surface. This agent does not increase the risk of infection or malignancy.
The primary aim of this study was to explore the effect of IL-2 antibody induction therapy on the rate of rejection and graft survival in standard risk patients.
Secondary aim was the assessment of the effect of IL-2 induction on creatinine change, PTDM, and the risk of CMV infection
How a standard risk patient was defined?
Based on patients characteristics on most of the studies included:
Inclusion Criteria:
All studies that compared IL-2 induction with placebo or no induction in standard risk patients
Exclusion Criteria:
Ethical approval was not required as all of the studies included were published.
A total of 470 studies were identified in this field but only seven studies were included after exclusion of the other studies. Five of these studies were used in the meta analysis for graft survival. This was the first meta analysis to be conducted in the Tac era.
Only 3 studies compared the changes in creatinine level.
Two studies assessed the risk of PTDM.
Only one study assessed the risk of CMV infection.
Findings:
IL-2 induction has on significant effect on the risk of rejection or patient and graft survival in standard risk patients in the Tac era.
No significant difference in the risk of CMV infection.
Strength of the study:
inclusion of several studies from different countries and generalization of the population of the studies thus having higher statistical power.
Limitations of the study:
In our practice we give Basiliximab induction for low risk patients( non sensitized, DSA negative, live related donor, first transplant), while ATG induction is reserved for high risk patients.
Very nice, you are the only student , who has commented on ethical approval till now.
thank you
In your own words, summarise this article
Basiliximab is a monoclonal antibody agent that inhibits T-cell proliferation through binding to IL-2 receptors on the T-helper cell surface. Compared with T-cell depletive immunotherapy, IL-2 induction therapy does not increase the risk of infection or risk of cancer .
In this meta-analysis, seven studies were included for assessment of risk of acute rejection in the standard-risk population with IL-2R antibody induction versus placebo.
Based on patients characteristics on most of the studies included:
The risk factors for acute rejection include-
the age of the recipient and donor
degree of HLA mismatch
cold ischaemia time
ethnicity
PRA
presence of donor-specific antibodies
blood group incompatibility
previous failed transplants
Conclusion-This meta analysis showed that IL-2R antibody induction therapy has no significant effect on the rate of rejection and patient or graft survival in standard-risk renal transplant recipients on tacrolimus-based maintenance immunotherapy.
What are the weakness and strength of this study?
Strengths-
First meta analysis done with tacrolimus as maintenance.
The inclusion of several studies from different countries and thereby being less influenced by local findings compared with single-country studies and generalization of the population of studies, thus having higher statistical power to detect an effect.
Limitations –
The follow-up period of 1 year is too short to draw definitive conclusions on graft survival.
The percentage of extended criteria donors in the analysis was low compared to the current set-up in clinical transplantation which is around 20–60% of deceased donors.
Please reflect your practice if possible.
Basiliximab is used as induction in deceased donor.
Live related – no induction.