V. Eculizumab and Splenectomy as Salvage Therapy for Severe Antibody-Mediated Rejection After HLAY-incompatible Kidney Transplantation
This study suggested that for patients manifesting early severe AMR, splenectomy plus eculizumab may provide an effective intervention for rescuing and preserving allograft function.
- Summarise the methodology and the conclusion of this study in your own words.
- What is the mechanism of action of this drug?
- What are the side effects of therapy?
- Will you change your management of AMR based on this study?
Summary
-It is a retrospective study of a prospective database that was done by the Johns Hopkins Institutional Review Board.
– 267 HLA-incompatible kidney transplants are involved in the study,24 patients experienced early severe AMR, 14 of whom received splenectomy alone as salvage therapy,5 received eculizumab alone and 5 received a combination of splenectomy
and eculizumab.
-Patients have performed DSA and are desensitized.
– Antibody-mediated rejection was diagnosed at a median of 6 days after transplantation.
-Of the 14 splenectomy-alone patients, 4 lost their grafts at ˂ 1-year. 4- eculizumab-alone patients experienced graft loss at a median of 95 days.
-One-year death-censored graft survival was 77.9% in the splenectomy-alone group, 30.0% in the eculizumab-alone group, and 100.0% in the combination treatment group.
– In the splenectomy group at 6 months, there were 3 graft losses and 1 patient did not have a biopsy.
-There were 2 immediate graft losses in the eculizumab-alone group. In the combination group, there were no graft losses or missing data.
-In the splenectomy group, there were 4 graft losses after 1-year post-transplant.
-Conclusion: splenectomy is effective at graft salvage in refractory AMR but long-term graft survival is poor due to transplant glomerulopathy.
What is the mechanism of action of this drug?
-It is a humanized monoclonal antibody that binds complement protein C5, preventing cleavage into C5a and C5b that is required for membrane attack complex formation and cell lysis.
What are the side effects of the therapy?
-Infections
-Headache ,Back pain ,Nausea ,Cough ,Fatigue ,Hypertension ,Headache ,Diarrhea ,Anemia ,Vomiting .
Will you change your management of AMR based on this study?
No, I will not change my management of AMR based on this study, because it needs more studies with big sample sizes and from different centers in the world.
This is a retrospective analysis of a prospective database which undergoes
annual review by the Johns Hopkins Institutional Review Board. All patients were treated with a standardized treatment protocol. An Investigational New Drug application for off-label compassionate use of eculizumab
was initially approved by the Food and Drug Administration for the indication of severe AMR in 2004.
Eculizumab, sold under the brand name Soliris among others, is a medication used to treat paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and neuromyelitis optica. In people with PNH, it reduces both the destruction of red blood cells and need for blood transfusion, but does not appear to affect the risk of death.[1] Eculizumab was the first drug approved for each of its uses, and its approval was granted based on small trials.[2][3][4][5] It is given in a clinic by intravenous (IV) infusion.
Common adverse effects (occurring in between 1% and 10% of people who take the drug) include infections (pneumonia, upper respiratory tract infection, colds, and urinary tract infection), loss of white blood cells, loss of red blood cells, anaphylactic reaction, hypersensitivity reaction, loss of appetite, mood changes like depression and anxiety, a sense of tingling or numbness, blurred vision, vertigo, ringing in the ears, heart palpitations, high blood pressure, low blood pressure, vascular damage, peritonitis, constipation, upset stomach, swollen belly, itchy skin, increased sweating, blotches from small bleeds under the skin and skin redness, hives, muscle spasms, bone pain, back pain, neck pain, swollen joints, kidney damage, painful urination, spontaneous erections, general edema, chest pain, weakness, pain at the infusion site, and elevated transaminases.[7]
References
Martí-Carvajal, AJ; Anand, V; Cardona, AF; Solà, I (30 October 2014). “Eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria”. The Cochrane Database of Systematic Reviews. 10 (10): CD010340. doi:10.1002/14651858.CD010340.pub2. PMID 25356860.
^ a b c Commissioner, Office of the (27 June 2019). “FDA approves first treatment for neuromyelitis optica spectrum disorder, a rare autoimmune disease of the central nervous system”. FDA. FDA. Retrieved 28 June 2019.
^ a b c Russell P Rother, Scott A Rollins, Christopher F Mojcik et al. (2007). “Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria”. Nat Biotechnol. 25 (11): 1256–1264. doi:10.1038/nbt1344. PMID 17989688. S2CID 22732675.
^ a b c d Andrew Dmytrijuk, Kathy Robie-Suh, Martin H. Cohen, Dwaine Rieves, Karen Weiss, Richard Pazdur (2008). “FDA report eculizumab (Soliris) for the treatment of patients with paroxysmal nocturnal hemoglobinuria”. The Oncologist. 13 (9): 993–1000. doi:10.1634/theoncologist.2008-0086. PMID 18784156.
^ a b c Keating, GM (December 2013). “Eculizumab: a review of its use in atypical haemolytic uraemic syndrome”. Drugs. 73 (18): 2053–66. doi:10.1007/s40265-013-
0147-7. PMID 24249647. S2CID 36682579.
his study suggested that for patients manifesting early severe AMR, splenectomy plus eculizumab may provide an effective intervention for rescuing and preserving allograft function.
total number of 267 HLA-incompatible living donor highly sensitized with DSA ABs all have been recieved desinsatization protocal prior to kidney transplants, 24 patients developed oliguric early severe AMR (9.0%), not responsive to standard AMR rejection protocal so they divided in three groups for salvage therapy. 14patients received splenectomy alone , Five received eculizumab alone and five received a combination of splenectomy and eculizumab, majorty were females with white ethinicity , induction IS was mainly dacluzumab in splenectomy group while ATG was used in the another two groups
the study conculde that the combination of spleenectomy and eculuzemab assocaited with better outcome and less transplant glomerulopathy compared to other two groups in one year FU
eculuzemab is humanized monoclonal AB act as anti C5 complement which bind to protien C5 and prevent the cleavage into C5a and C5b The latter is required for membrane attack complex formation and cell lysis and inhibit the alterantive complement pathway activaion, its effective anticomplement therapy and FDA approved its use for complement mediated TMA and atypical HUS , PNH , but still the evidince limited regarding its use as slavage anticomplement therapy in AMR ( case series and report only ) .
bleeding , thrombosis , surgical wound infection,other nfections like bacterial , UTI pnemonia , viral and with eculuzemab like meningococcal infection thats why a per protocal meningococacl vaccination should eb given two weeks prior to the use of medicine , and ciprofloxacin prophylaxis for twow eeks if avccination give in less than two weeks from its use
no will not change my currnet practise based on weak evdince ,small retrospective design with use of very expensive drug Like eculuzemab
In this study , 267 patients who had Living donor transplants, who had DSAs , were reviewed
24 only of them developed sever early AMR , all of them were treated with standard treatment PP,IVIG and mabthera
14 of them were treated with splenectomy and eculizumab, 5 was treated with splenectomy alone , 5 was treated with eculizumab alone
Aim of this study was to identify possible graft salvage after sever AMR , using splenectomy and eculizumab
They found that graft loss was the least with both splenectomy and eculizumab, compared to either treatment alone .
Eculizumab is anticomplement protein C5 , that blocks formation of terminal complement attack complex .
Side effects include headache, high blood pressure, diarrhea, nasopharyngitis
It may rarly predispose to serious meningococcal meningitis.
Regarding our practical life , the drug is not available because of financial reasons .
Q1: Twenty -four patients with pre-transplant desensitization who had AMR soon after transplantation were divided in three groups for rescue therapy of AMR in addition to plasmapheresis, IVIG +/- rituximab: splenectomy, eculizumab and a combination of both. Combination therapy with splenectomy and eculizumab showed the best result with 100% saving the graft and the least cg score on protocol biopsy. Because of removing eculizumab by plasmapheresis, 600 mg must be administer after each session. They concluded that rescue therapy with eculizumab and splenectomy together may be effective for graft preservation.
Q2: Eculizumab is a humanized monoclonal antibody again C5 component of complement system and inhibits production of C5a and C5b and eventually inhibits formation of MAC complex by alternative complement pathway. So it is an effective treatment in complement -associated diseases and prevents micro vascular damage.
Q3: The common side effects in the study patients were: UTI, pneumonia, CMV viremia, bacteremia, sepsis, soft tissue or skin or surgical site and C.difficil infections. Most common known side effects of eculizumab includes: Throat irritation, UTI, back pain, myalgia, fever, headache, cough, nausea, vomiting, anemia and high BP.
Q4: This study is only a small retrospective one not RCT with sufficient cases. In addition, the price of eculizumab especially with high dose administration that performed in this study, is very high and expensive. So, I will wait for large randomized RCTs before changing AMR management. In selected refractory cases with enough resources this treatment may be considered.
Summarise the methodology and the conclusion of this study in your own words.
This is a retrospective analysis of 267 patients received live donor kidney transplantation at Johns Hopkins
All patients had DSA before desensitization. Some of them was ABO incompatibile with their live donor, and one patient was ABO incompatibile with his donor and had a stronge positive endothelial cross-match.
24 patients had Severe, oliguric AMR developed in the first month which was defined as sudden, early renal dysfunction with oliguria (urine output falling by more than 50% in 24 hr) and a 50% rise in serum creatinine, increase in DSA and histology consistent with AMR
rejection was treated with PP and IVIg until DSA MFI WAS below 5000or until AMR resolved on follow-up biopsy. Corticosteroids were also used to treat AMR.
patients received splenectomy alone, eculizumab alone , or both splenectomy and eculizumab.
Splenectomy was performed emergently as soon as the diagnosis of this AMR phenotype was confirmed.
4 of 14 splenectomy-alone patients experienced graft loss (median=320 days), compared to four of five eculizumab-alone patients with graft failure (median=95 days).
Protocol kidney biopsies were done at 6 months and at one year post transplantation.
No patients treated with splenectomy plus eculizumab experienced graft loss. There was more chronic glomerulopathy in the splenectomy alone and eculizumab-alone groups at 1 year, whereas splenectomy plus eculizumab patients had almost no transplant glomerulopathy.
Conclusion
For desensitized patients who experienced early severe AMR, splenectomy plus eculizumab may provide an effective intervention for rescuing and preserving allograft function together with plasma exchange and IVIG
What is the mechanism of action of this drug?
Eculizumab is a monoclonal antibody that binds complement protein C5, preventing cleavage into C5a and C5b.
C5b is required for membrane attack complex formation and cell lysis so it provides protection against antibody mediated injury to the vascular endothelium, preventing activation of the cascade that leads to irreversible microvascular damage. Blocking acute complement-mediated injury might allow time for DSA removal with aggressive PP.
What are the side effects of therapy?
side effects of eculizumab
Hypertension, headache,fever, insomnia ,hypokalemia, diarrhea, abdominal pain, leukopenia, peripheral edema,cough, nasopharyngitis, and venous thromboembolism
Splenectomy might be associated with
bleeding, esophagitis, GIT bleeding, increased infection with G+ve, G-ve diplococci, surgical wound infection( UTI, pneumonia, CMV).
Will you change your management of AMR based on this study?
This protocol although seems to be effective but needs to be studied in larger randomized studies and for longer time
With consideration of the cost of eculizumab
1. Summarise the methodology and the conclusion of this study in your own words.
This study is to evaluate the best treatment for recalcitrant ABMR. This is a retrospective analysis of a prospective database involving 24 highly sensitized renal transplant recipients with severe oliguria and AMR presenting within 3 weeks of post-transplant. The patients received Plasmapheresis and IVIG with or without anti-CD 20 therapy. 14 patients undergone splenectomy, 5 patients received eculizumab and 5 patients received combination of splenectomy and eculizumab. Protocol kidney biopsies were done at 6 months and at one year post transplantation. Graft loss was seen in 4 out of 14 in splenectomy group and 4 out of 5 in eculizumab group. There was 100% graft survival in combined group. Transplant glomerulopathy at 6 months and 12 months was seen in 2 patients and 5 patients in splenectomy group and 2 patients and one patient in eculizumab group. None of the combined group patients developed TG at 6 months while one patient developed TG at 1 year.
Combination of splenectomy and eculizumab with Plasmaphereis and IVIG is useful in treating AMR and preventing graft loss. Splenectomy removes antibody-generating cells and Eculizumab prevents endothelial damage by preventing MAC formation. Plasmapheresis removes remaining antibodies present in the peripheral blood circulation.But the risk of removal eculizumab during Plasmapheresis may risk of wasting the meds, which is costly.
2. What is the mechanism of action of this drug?
Eculizumab is a humanized monoclonal antibody.It binds to the C5, inhibiting its cleavage, hence preventing formation of C5a and C5b which important for generation of MAC, which prevents cell lysis.This provides protection from endothelial injury and micro vascular damage
3. What are the side effects of therapy?
The side-effects of Eculizumab include hypertension, peripheral oedema, headache, insomnia, fatigue, dizziness, hypokalemia, diarrhoea, abdominal pain, anaemia, leukopenia, infections (UTI, bacterial infections, surgical site infection, C. difficle infection), cough, nasopharyngitis, fever and venous thromboembolism,
4. Will you change your management of AMR based on this study?
1) This is not RCT
2) Eculizumab is expensive
3) Small size study
But its interesting to see 100% graft survival in combined therapy of Eculizimab and splenectomy
I would love to try this method when recalcitrant ABMR happens in my center
1. summarize the methodology and the conclusion of this study in your own
words.
Incompatible live donor kidney transplantation is associated with AMR) and subsequent
transplant glomerulopathy. For patients with severe, oliguria AMR, graft loss is inevitable
without timely intervention.
The study reviewed center experience in rescuing kidney allografts with this severe AMR
phenotype by using splenectomy alone, Eculizumab alone, or splenectomy plus
Eculizumab, in addition to plasmapheresis.
At a median follow-up of 533 days, 4 of 14 splenectomy-alone patients experienced graft
loss , compared to four of five Eculizumab-alone patients with graft failure
No patients treated with splenectomy plus Eculizumab experienced graft loss.
There was more chronic glomerulopathy in the splenectomy alone and Eculizumab-alone
groups at 1 year, whereas splenectomy plus Eculizumab patients had almost no
transplant glomerulopathy.
Conclusion. Study suggest that for patients manifesting early severe AMR, splenectomy
plus Eculizumab may provide an effective intervention for rescuing and preserving
allograft function.
2. What is the mechanism of action of this drug?
Eculizumab is a humanized monoclonal antibody that binds complement protein C5,
preventing cleavages into C5a and C5b. The latter is required for membrane attack
complex formation and cell lysis
3. What are the side effects of therapy?
Hypertension.
Infection.
Diarrhea.
Headache.
Leukopenia.
Anemia.
4. Will you change your management of AMR based on this study?
In patient with AR refractory to standard treatment it worth trial of his protocol.
Summarise the methodology and the conclusion of this study in your own words.
This a retrospective study.
267 renal transplant recipients with HLA incompatible transplants with DSA undergoing desensitization where reviewed during the first 3 weeks post-transplant. They received Plasma exchange, IVIG,+/- Rituximab.
24 patients developed oliguria, rising creatinine, high DSA, and early anti-body mediated rejection (ABMR).
These 24 patients were divided into 3 groups, first group (10 patients) treated with splenectomy, second group (5 patients) was treated with Eculizumab, third group (5 patients) was treated splenectomy and Eculizumab.
Median follow up was 533 days, follow up included transplant biopsy at 6, 12 months, monitor of graft function tests.
Results:
1- Splenectomy group: 4/14 had graft loss, 1- year patient survival 79%.
2- Eculizumab group: 4/5 had graft loss, 1-year patient survival 30%.
3- Combined group: no graft loss, 1- year patient survival 100%.
What is the mechanism of action of this drug?
Eculizumab is a humanized monoclonal antibody that binds complement protein C5, preventing cleavage into C5a and C5b. The latter is required for membrane attack complex formation and cell lysis
What are the side effects of therapy?
Eculizumab side effect: Hypertension, headache, fatigue, hypokalemia, diarrhea, abdominal pain, leukopenia, peripheral edema.
Splenectomy complications: bleeding, VTE, erosive gastritis, esophagitis, GIT bleeding, increased infection with G+ve, G-ve diplococci, surgical wound infection.
Other infections: UTI, pneumonia, CMV, C.difficle.
Will you change your management of AMR based on this study?
I will not change my management of AMR because this is a retrospective study with small number of cases using the most expensive medication worldwide.
1. This study is a retrospective analysis of a prospective database reviewed the results of experiences on some cases manifesting early severe oliguric AMR who were treated in different ways (splenectomy, eculizumab, and splenectomy plus eculizumab) in addition to standard therapy. Among 267 patients who had undergone desensitization, 24 patients presented with this phenotype.
2. Rescue splenectomy has been described as salvage therapy for patients with this phenotype who are refractory to standard therapy. Newly formed plasma blasts migrate to the spleen, and splenectomy can result in a rapid reduction in DSA production.
Eculizumab is a humanized monoclonal antibody that binds to the complement protein C5, preventing cleavage into C5a and C5b. The latter is required for membrane attack complex formation and cell lysis. Blocking acute complement-mediated injury might allow time for DSA removal with aggressive PP.
3. Noninfectious complications consisted of postoperative bleeding, venous thromboembolic events, fascial dehiscence, erosive gastritis or esophagitis, gastrointestinal bleeding, and perinephric fluid collection. Infectious complications included urinary tract infection, pneumonia, CMV viremia, bacteremia or sepsis, skin or soft tissue infection and surgical site infection, and C. difficile infection.
Bleeding and clotting were the most common noninfectious complications. Infectious complications, especially surgical site and blood stream infections, occurred at a high rate.
4. Results of this study don’t change my management of ABMR. For enter a treatment to practice, we need more studies with a higher level of evidence, I mean well-designed randomized clinical trials.
Summary:
This is a review of the 267 cases who received live donor RTx, who had detectable DSA before desensitization. The patient received plasma exchange , IVIg and steroids then were divided into 3 groups according to salvage therapy ; splenectomy, eculizumab or both.
Splenectomy plus eculizumab patients had no graft loss and almost no transplant glomerulopathy at 1 year.
Mechanism of action of this drug: Eculizumab is a monoclonal antibody that targets complement protein C5
Side effects: bacterial , viral infections , bleeding and clotting complications.
These lines need more dependable studies with large numbers , randomized studies , availability and cost-effectiveness
1. Summarise the methodology and the conclusion of this study in your own words. This is a review of the 267 cases, who received live donor kidney transplantation, who had detectable DSA before desensitization.2 4 patients had early oliguria and rising creatinine within the first month of transplant with histology consistent with AMR and rising DSA.The patient received PP , IVIg and steroids and were divided into 3 groups according to salvage therapy which was splenectomy, eculizumab or both.
Splenectomy plus eculizumab patients had no graft loss and almost no transplant glomerulopathy at 1 year. This study depend on the fact that splenectomy removes antibody-producing cells and eculizumab protects the endothelium from injury while PP clears the circulating antibody.
2. What is the mechanism of action of this drug? Eculizumab is a humanized monoclonal antibody that targets complement protein C5, inhibiting cleavage into C5a and C5b, and therefore preventing formation of the membrane attack complex (MAC).
What are the side effects of therapy? The high rate of both noninfectious and infectious complications .
Bleeding and clotting were the most common noninfectious complications Infectious complications, especially surgical site and blood stream infections, occurred at a high rate.
1. management of AMR based on this study?No , The study has small sample so low power non randomized methodology, and couldn’t adjust confounders
Eculizumab is very expensive
there is high risk of infection due to the heavy immunosuppression and
post splenectomy thrombotic complications .
1-Retrospective study aiming at exploring use of Eculizumab and splenectomy either alone or in combination as a salvage tool in severe ABMR following HLA incompatible Tx. Total 267 patients with live donor Tx with detectable DSA were included. The 24 patients who developed ABMR 3 weeks post Tx were treated by plasmapheresis and IV Ig with different modalities of eculizumab and splenectomy ;alone or in combination .Follow up data: clinical ,biochemical and pathological were collected at time of rejection and at 6 &12 months with protocol biopsy. In splenectomy group, graft loss was found in 4/14 patients .In eculizumab group ,graft loss was found in 4/5 of patients .In group of combined splenectomy and eculizumab no graft loss occurred.
Conclusion:
Combined splenectomy and eculizumab proved efficacy in keeping graft function in patients with severe ABMR.
2- Mechanism of action :Eculizumab is humanized monoclonal AB exerts its effect through binding to C5 preventing its cleavage to C5aand C5b.So,C5b in availability will stop membrane attack complex formation and subsequent cell lysis.
3- Side effect s:increased risk of infection mainly meningococcal infection and others like UTI ,GIT and respiratory infections. Vaccination against Neisseria meningitides is recommended .
4-Non availability and cost of eculizumab are considerable obstacles to its use despite encouraging results.
This study suggested that for patients manifesting early severe AMR, splenectomy plus eculizumab may provide an effective intervention for rescuing and preserving allograft function.
1. Summarise the methodology and the conclusion of this study in your own words.
Methodology: The study included retrospective analysis of a prospective database involving 24 highly sensitized renal transplant recipients (post desensitization) with severe oliguric AMR presenting within first 3 weeks post transplant. The patients received Plasmapheresis and IVIG with or without rituximab. 14 patients underwent splenectomy, 5 patients received eculizumab and 5 patients received splenectomy combined with eculizumab. Post-transplant protocol biopsies were done at 6 months and at one year. Graft loss was seen in 4 out of 14 in splenectomy group and 4 out of 5 in eculizumab group. There was no graft loss in the combined group. Transplant glomerulopathy (TG) at 6 months and 12 months was seen in 2 patients and 5 patients in splenectomy group and 2 patients and one patient in eculizumab group. None of the combined group patients developed TG at 6 months while one patient developed TG at 1 year.
Conclusion: Combination of splenectomy and eculizumab with Plasmaphereis and IVIG is useful in treating AMR and preventing graft loss. Splenectomy removes antibody-generating cells (plasmablasts) and Eculizumab prevents endothelial damage by preventing MAC formation. Plasmapheresis removes remaining antibodies present in the peripheral blood circulation.
2. What is the mechanism of action of this drug?
Eculizumab is a humanized monoclonal antibody.
It attaches to the complement protein C5, inhibiting its cleavage, hence preventing formation of C5b which is important for generation of membrane attack complex, without which cell lysis cannot take place.
This provides protection from endothelial injury and microvascular damage
3. What are the side effects of therapy?
The side-effects of Eculizumab include hypertension, peripheral edema, headache, insomnia, fatigue, dizziness, hypokalemia, diarrhea, abdominal pain, anemia, leukopenia, infections (UTI, bacterial infections, surgical site infection, C. difficle infection), cough, nasopharyngitis, fever and venous thromboembolism,
4. Will you change your management of AMR based on this study?
On the basis of this study, use of eculizumab in refractory AMR looks promising but there are many limitations:
1) Cost of Eculizumab
2) This was a non-randomized study
3) This study had a small sample size, hence it is difficult to extrapolate it on a large scale.
So, I will not be able to change my management only on the basis of this study.
Methodology of the study
This is an originally cohort prospective study(retrospective analysis of a prospective database).
267 patient were enrolled in this study, allocated in 3 groups: Eculizumab Alone , Splenectomy Alone and Splenectomy plus Eculizumab .Plasmapheresis was an additional treatment for all groups.
Data were analyzed using Stata 12.0 (StataCorp, College Station, TX).
Conclusion of the study
Combination of splenectomy and eculizumab may offer an effective intervention for rescuing and preserving allograft function.
In the splenectomy group, only 29% of the patients had functioning allografts and a 1-year biopsy free of transplant glomerulopathy. In the eculizumab cohort, all grafts were lost or had transplant glomerulopathy. In the combined group, 80% of the patients had functioning grafts free of transplant glomerulopathy. Combining splenectomy and eculizumab produced the best results, with 100% rescue and 1-year graft survival.
Eculizumab without splenectomy was not effective in this small cohort, and all five patients treated lost their allograft or developed transplant glomerulopathy.
What is the mechanism of action of this drug?
What are the side effects of therapy?
Transplant Glomerulopathy at drug withdrawal.
Bleeding and clotting
Infectious complications, especially surgical site and blood stream infections, occurred at a high rate.
Headache, tiredness, nausea, vomiting, diarrhea and muscle pain.
Will you change your management of AMR based on this study?
Of course I wil choose the combination therapy as it offers 100% rescue and 80% graft survival at one year.
Retrospective study where 267 patients had live donor kidney transplant with HLA incompatibility, detectable DSA and had desensitization.
24 patients had early oliguria and rising creatinine within the first month of transplant with histology consistent with AMR and rising DSA
The patients received corticosteroids, plasmapheresis, IVIG and were divided into 3 groups according to salvage therapy which was splenectomy, eculizumab or both.
The study showed that combining splenectomy and eculizumab had 100% rescue and one year graft survival as splenectomy stop new antibody production, eculizumab protect endothelium from injury and plasmapheresis clear residual circulating antibodies
conclusion:
Splenectomy and eculizumab can preserve allograft function in early severe AMR and splenectomy alone is effective in graft salvage but leads to transplant glomerulopathy which reduce long term graft survival.
Eculizumab binds complement protein C5 and prevent its cleavage to C5a and C5b so inhibit formation of membrane attack complex and cell lysis, preventing antibody mediated injury to vascular endothelium preventing the irreversible microvascular damage
Both eculizumab and splenectomy cause heavy immunosuppression leading to high rate of infectious complications especially surgical site and blood stream infections
they both increase susceptibility to infection with encapsulated bacteria
splenectomy leads to thromboembolic complications and may lead to DVT or pulmonary embolism
Eculizumab:
increase susceptibility to infection with encapsulated bacteria especially Neisseria meningitides
risk of developing human anti-human antibodies which could neutralize eculizumab
may lead to long term hepatotoxicity
No, as the study has several limitations, non randomized methodology, small sample size and couldn’t adjust confounders
Eculizumab is very expensive
the risk of infection due to the heavy immunosuppression is a concern
post splenectomy thrombotic complications due to hypercoagulable state
Wijnsma KL, Duineveld C, Wetzels JF, van de Kar NC. Eculizumab in atypical hemolytic uremic syndrome: strategies toward restrictive use. Pediatric Nephrology. 2019 Nov;34(11):2261-77.
Buzelé R, Barbier L, Sauvanet A, Fantin B. Medical complications following splenectomy. Journal of visceral surgery. 2016 Aug 1;153(4):277-86.
Summarise the methodology and the conclusion of this study in your own words.
This is a review of the 267 cases, attending Johns Hopkins who received live donor kidney transplantation, who had detectable DSA before desensitization. It included 24 patients who had Severe, oliguric AMR developed within the first month after transplantation. PP , IVIg and steroids were applied to decrease the DSA aiming at low MFI or resolution of biopsy finding. Management measures included splenectomy alone (n=14), eculizumab alone (n=5), or splenectomy plus eculizumab (n=5).
Splenectomy was done emergently once AMR was confirmed. Eculizumab was given IV (1,200 mg) on the day of the AMR diagnosis , on the next day(900 mg), After each PP treatment(600 mg), weekly (900 mg )during PP and up to 1 month after the initial dose ,after week 5( 1200 mg) were administered every 2 weeks for patients who remained on the drug. Eculizumab was stopped once the DSA dropped or the biopsy revealed resolution of AMR signs.
Splenectomy plus eculizumab patients had no graft loss and almost no transplant glomerulopathy at 1 year. This study depend on the fact that splenectomy removes antibody-producing cells and eculizumab protects the endothelium from injury while PP clears residual circulating antibody.
What is the mechanism of action of this drug?
Eculizumab is a humanized monoclonal antibody that binds complement protein C5 preventing cleavage into C5a and C5b.
What are the side effects of therapy?
Splenctomy adverse events are : either non-infectious complications( postoperative bleeding ,venous thromboembolic events , fascial dehiscence, erosive gastritis or esophagitis , gastrointestinal bleeding and perinephric fluid collection )
or infectious complications( urinary tract infection , pneumonia , CMV viremia ,bacteremia or sepsis ,skin or soft tissue infection and surgical site infection and C. difficile infection, cryptosporidia infection.)
Eculizumab adverse events are: meningococcal infection, Upper respiratory infection, UTI, Upper respiratory tract infection and Herpes simplex virus infections
Headache, Nasopharyngitis, Vertigo, Flu-like illness, Back pain, Pyrexia, Fatigue, Arthralgia, Anemia, Leukopenia, Nausea, Cough, Peripheral edema, Hypertension , Diarrhea, Constipation, Vomiting,
Will you change your management of AMR based on this study?
The study has low power as it has small sample size.
We usually avoid transplantation in the presence of DSA in HLA-incompatible candidates.
If we face a similar case and we get stuck with AMR not responding to the traditional measures, we might consider this approach but with precautions.
Summarise the methodology and the conclusion of this study in your own words.
Methodology ;
Study design ;
This is a retrospective analysis of a prospective database which undergoes annual review by the Johns Hopkins Institutional Review Board.
Study aim ;
Is to review the experience in rescuing kidney allograft with severe AMR phenotype by using splenectomy alone , eculizumab alone or splenectomy plus eculizumab in addition to plasmapheresis.
Population and Study area ;
267 patients underwent live donor kidney transplantation at Johns Hopkins and had detectable DSA before desensitization.
Approval ;
An Investigational New Drug application for off-label compassionate use of eculizumab was initially approved by the Food and Drug Administration for the indication of severe AMR .
Patients ;
Severe, oliguric AMR developed within the first month after transplantation in 24 patients.
Antibody-mediated rejection was treated with PP and IVIg until DSA strength fell below a level sufficient to yield a positive flow cytometric cross-match (roughly 5,000 mean fluorescence intensity [MFI]) or until AMR resolved on follow-up biopsy.
Corticosteroids were also used to treat AMR (dexamethasone 100 mg or methylprednisolone 500 mg for 3 days followed by a taper). Additionally, the patients received splenectomy, eculizumab, or both splenectomy and eculizumab. Splenectomy was performed emergently as soon as the diagnosis of this AMR phenotype was confirmed.
Clinical and biochemical data abstracted from the database and pathologic data from renal allograft tissue obtained at the time of the AMR-defining episode and from protocol biopsies at 6 and 12 months were analyzed.
Eculizumab Administration;
Eculizumab was given intravenously at a dose of 1,200 mg on the day of the AMR diagnosis and 900 mg the next day. After each PP treatment, an additional 600 mg of eculizumab was administered. During PP and up to 1 month after the initial dose, patients also received a weekly dose of 900 mg. Beginning on week 5, doses of 1200 mg were administered every 2 weeks for patients who remained on the drug. Eculizumab was discontinued when the DSA dropped below a strength that would yield a positive FCXM or AMR had resolved on biopsy.
Desensitization and Immunosuppression;
All patients received PP and DSA monitoring before and after transplantation by protocol as previously described . Every other day and in some cases daily PP treatments were followed by IVIg (100 mg/kg) administration.
Twenty-one of 24 patients received at least one dose of antiCD20 antibody (rituximab, 375 mg/m2).
Mycophenolate mofetil (2 g/day) and tacrolimus (target serum level 8Y12 ng/mL) were administered beginning with the first pre transplant PP
treatment.
Induction therapy was achieved with daclizumab (2 mg/kg for the initial dose and then 1 mg/kg every 2 weeks for 5 total doses), anti thymocyte globulin (1.5 mg/kg for 5 days), or basiliximab (20 mg on post transplant days 1 and 4). Methylprednisolone 500 mg was administered daily for 3 days beginning intraoperatively, corticosteroids were tapered over 5 days, and converted to prednisone 30 mg daily. Prednisone was then tapered over a 3-month period to 5 mg daily.
Antibody Testing Cross-match tests, including antihuman globulin-enhanced lymphocytotoxicity (AHG-CDC) with T cells, one wash CDC with B cells, and flow cytometry with T and B cells were performed.
Conclusion ;
These data suggest that for patients manifesting early severe AMR, splenectomy plus eculizumab may provide an effective intervention for rescuing and preserving allograft function.
What is the mechanism of action of this drug?
Eculizumab is a humanized monoclonal antibody that binds complement protein C5, preventing cleavage into C5a and C5b. The latter is required for membrane attack complex formation and cell lysis .
What are the side effects of therapy?
The high rate of both noninfectious and infectious complications .
Bleeding and clotting were the most common noninfectious complications and are always a challenge among patients undergoing major reoperations, heparin therapy, and daily plasmapheresis.
Infectious complications, especially surgical site and blood stream infections, occurred at a high rate.
Will you change your management of AMR based on this study?
I will not depend on this study in management of AMR because of ;
– The small sample size and the inability to adjust for important con-founders limits our ability to draw definitive conclusions about the best treatment for severe AMR after HA-incompatible live donor kidney transplantation
-Limitations of this study primarily stem from the non randomized methodology and the fact that significant changes in technology and best practices occurred over the study period.
– The desensitization protocol remained consistent throughout, and changes in DSA testing were mitigated in part by retesting the serum from earlier time periods using current techniques.
-Larger multi center trials will be necessary to answer this question definitively.
Methodology
A retrospective analysis of 267 HLA incompatable patients undergoing live donor kidney transplantation at Johns Hopkins, 24 cases had AMR treated with PP , IVIg and corticosteroids along with either splenectomy, or eculizumab, or both splenectomy and eculizumab.
Induction was done by daclizumab , antithymocyte globulin or basiliximab then maintenance by tac, MMF and steroids
Cross matching with B and T cells , Flow cytometry with both cells, Single antigen assay and Luminex with MFI was done
Renal biopsies were analysed for cell-mediated rejection and AMR based on updated Banff 97 criteria at the time of the AMR-defining episode and from protocol biopsies at 6 and 12 months
Conclusion
Splenectomy plus eculizumab can be used to manage early severe AMR, to preserve allograft function and 1 year graft survival
2.What is the mechanism of action of this drug?
Eculizumab is a humanized monoclonal antibody that binds complement protein C5, preventing its cleavage, C5b is needed for the membrane attack complex formation therefore preventing the stimulation of complement pathway that leads to irreversible microvascular damage.
3.What are the side effects of therapy?
Infectious complications, specially at surgical site and blood stream infections,muscle cramps, headache dizziness and gastrointestinal manifestations
4.Will you change your management of AMR based on this study?
Ecluzimab with splenectomy along with PP was used in this study in sensitised recipents because splenectomy can control new antibody production, but high levels of soluble antibody must still be cleared by PP while the renal endothelium is exposed to complement mediated cytolysis so complement inhibition by eculizumab was used in patients experiencing severe AMR salvaging the graft
Infact the drug is expensive and multiple doses are needed
Out of 267 HLA-incompatible kidney transplant recipients, this facility treated 24 high-risk ABMR patients with splenectomy alone (14), eculizumab alone (5), or splenectomy with eculizumab (5 patients)
All patients get plasmapheresis.
Splenectomy is beneficial in treating AMR but not for a year after which chronic glomerulopathy develops. The combination of splenectomy with eculizumab may be successful, although the benefit fades if eculizumab is stopped.
What is the drug’s mechanism of action?
An anti-complement monoclonal antibody, Eculizumab, binds to complement protein C and prevents cleavage to complement-dependent cell lysis (C5a and C5b).
What are the side effects?
Increased risk of meningococcal, gastrointestinal, and respiratory infections. Pretreatment is recommended. Hypertension, Diarrhoea, Headache and leukopenia.
Will you change your management of AMR based on this study?
The evidence is weak. I can not depend on this small study to take a critical decision in transplantation. eculizumab is a costly medication before prescription needs justification.
Good responses.
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Summarise the methodology and the conclusion of this study in your own words.
This is a retrospective study that evaluated the effect of splenectomy and /or eculizumab in the management of antibody mediated rejection in presensitized recipients.
The study assessed the renal outcomes at one year.
Sample size of the studied patients was 24 from one center receiving plasmapheresis in addition ot one of the following treatments:
Splenectomy alone – 14 patients
Eculizumab alone – 5 patients
Splenectomy plus eculizumab -5 patients
Results
In patients treated with splenectomy 4 had graft loss
In patients treated with eculizumab 80% developed graft loss
No graft loss was reported in patients treated with eculizumab and splenectomy
In conclusion, splenectomy is associated with better prognosis in regards to graft loss comparing to treatment with eculizumab. The combination of splenectomy and eculizumab was shown to be more effective in preserving allograft function irrespective of desensitization protocols.
What is the mechanism of action of this drug?
Eculizumab is a humanized monoclonal antibody that binds complement protein C, preventing cleavage to C5a and C5b, preventing of activation of complement dependent cell lysis.
What are the side effects of therapy?
Headache (44%)
Nasopharyngitis (23%)
Back pain (19%)
Nausea (16%)
Cough (12%)
Fatigue (12%)
Hypertension (47%)
Headache (41%)
Diarrhea (35%)
Anemia (35%)
Vomiting (29%)
Upper respiratory infection (29%)
UTI (24%)
Leukopenia (24%)
Fatigue (18%)
Peripheral edema (18%)
Pyrexia (18%)
Cough (12%)
Will you change your management of AMR based on this study?
This is a single center experience with small sample size. Patients were selected based on the diagnosis of acute antibody mediated rejection but not on the risk of AMR ( type o DSA, number of HLA mismatches, type of induction and maintenance therapies)
I would not change my management based on this study, but in patients with severe antibody mediated rejection not responding to conventional treatment with thigh risk of graft loss , splenectomy could be selected if the risk of surgical procedure is low.
Retrospective study, aimed to evaluate the effect of splenectomy & /or eculizumab in treating severe AMR in presensitized recipients.
24 recipients develop AMR ( diagnosed by Banff 97 criteria) in first month post transplantation. All patients treated with PP+ IVIG in addition to:
14 patients had emergency splenectomy after diagnosis of rejection phenotype
5 patients treated with eculizumab
5 patients treated with combination of splenectomy + eculizumab.
All recipients were desensitized by PP+ IVIG + rituximab( in 23 patients), induction was with rATG or IL2-R inhibitors & maintenance IS with MMF, CNI, tapering dose of steroids.
Dose of eculizumab:
Conclusion:
splenectomy is effective in treatment of AMR but this effect is not prolonged to the first year when chronic glomerulopathy developed. Combination of splenectomy & eculizumab effect can be effective in treatment but this effect reversed after discontinuation of eculizumab.
Side effects: head ache, nasopharyngitis, back pain , nausea & vomiting, cough, fatigue, leukopenia, anemia, & fatal infection Nesseria gonorrhoeae, N. meningitides.
I will not use eculizumab in treating highly sensitized recipients with AMR because it need long term use of eculizumab with very high cost.
Summarise the methodology and the conclusion of this study in your own words.
Patients characteristics, most of the patients included are :
The endpoint is graft function at 1 year
Conclusion
What is the mechanism of action of this drug?
What are the side effects of the therapy?
Will you change your management of AMR based on this study?
No … this is because of the following:
1- Efficacy and safety
2- Very costly drug
Summarise the methodology and the conclusion of this study in your own words
Methodology:
Settings: John Hopkins from October 2012- June 2012
Design: retrospective analysis of prospective data
Patients: 267 patients, undergoing live donor kidney transplantation and had detectable DSA before desensitization, some patients had ABO incompatibility with their donors and one had a strongly positive endothelial XM in addition to ABO incompatibility. Twenty four patients developed ABMR 3 weeks post transplantation and followed for 533 days and treated by either eculizumab, splenectomy, and combination of eculizumab and splenectomy in addition to PP& IVIG. Clinical and biochemical data are abstracted from the database and the pathological data are obtained from allograft biopsy done at the time of rejection and from protocol biopsies at 6 and 12 months were analysed.
Exclusion criteria: not mentioned.
Ethical Approval: Johns Hopkins Institutional Review Board.
Results:
Graft loss noticed in:
4/14 of patients treated with splenectomy
4/5 of patients treated with eculizumab
no graft loss in patients treated with eculizumab + splenectomy
Conclusion:
For patients with acute severe ABMR, A combination of splenectomy and eculizumab may be effective for preserving graft function.
What is the mechanism of action of this drug?
Eculizumab is a humanized monoclonal antibody that binds complement protein C5, preventing cleavage to C5a and C5b, the later required for membrane attack complex formation and cell lysis.
What are the side effects of therapy?
Increase the susceptibility to meningococcal infection and other infections such as UTI, gastrointestinal, and respiratory. So the patients should be vaccinated against Neisseria Meningitides before treatment.
Will you change your management of AMR based on this study?
Despite the good results showed by this study, the cost and non availability of the drug are limiting factors.
Summarise the methodology and the conclusion of this study in your own words.
Methodology-
This is a retrospective analysis of a prospective database which undergoes annual review by the Johns Hopkins Institutional Review Board. Between October 2003 and June 2012, 267 patients underwent live donor kidney transplantation at Johns Hopkins and had detectable DSA before desensitization.
Desensitization protocol
Plasmapheresis done every other day and in some cases daily PP treatments were followed by IVIg (100 mg/kg) administration.
Twenty-one of 24 patients received at least one dose of antiCD20 antibody (rituximab, 375 mg/m2 ).
Mycophenolate mofetil (2 g/day) and tacrolimus (target serum level 8-12 ng/mL) were administered beginning with the first pretransplant PP treatment.
Induction therapy was achieved with –
daclizumab (2 mg/kg for the initial dose and then 1 mg/kg every 2 weeks for 5 total doses) or
antithymocyte globulin (1.5 mg/kg for 5 days),
or basiliximab (20 mg on posttransplant days 1 and 4).
Methylprednisolone 500 mg was administered daily for 3 days beginning intraoperatively, corticosteroids were tapered over 5 days, and converted to prednisone 30 mg daily. Prednisone was then tapered over a 3-month period to 5 mg daily.
Severe oliguric AMR was defined as –
sudden, early renal dysfunction with oliguria (urine output falling by 950% in 24 hr) and a 50% rise in serum creatinine
with a concomitant increase in DSA and
histology consistent with AMR (including features associated with severe AMR, such as extensive endothelial injury, fibrin thrombi, micro-infarctions, interstitial hemorrhage as well as C4d and margination of neutrophils in the peritubular capillaries.
Treatment of AMR-
PP and IVIg until DSA strength fell below 5,000 [MFI]) or until AMR resolved on follow-up biopsy.
dexamethasone 100 mg or methylprednisolone 500 mg for 3 days followed by a taper.
splenectomy, eculizumab, or both splenectomy and eculizumab.
Splenectomy was performed emergently as soon as the diagnosis of this AMR phenotype was confirmed.
Eculizumab was given intravenously at a dose of 1,200 mg on the day of the AMR diagnosis and 900 mg the next day. After each PP treatment, an additional 600 mg of eculizumab was administered. During PP and up to 1 month after the initial dose, patients also received a weekly dose of 900 mg. Beginning on week 5, doses of 1200 mg were administered every 2 weeks for patients who remained on the drug. Eculizumab was discontinued when the DSA dropped below 5000 MFI or AMR had resolved on biopsy.
Conclusion –
It has not been possible to predict which patients will develop early AMR, prophylactic use of eculizumab means treating all desensitized patients, when only 9% will develop graft-threatening AMR. It is unclear whether the additional cost of eculizumab will allow its use in the 91% of patients who will not develop severe AMR.
Preliminary data suggest that splenectomy is effective at graft salvage, but long-term graft survival is poor, primarily because of transplant glomerulopathy.
What is the mechanism of action of this drug?
Eculizumab is a monoclonal antibody that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9 and thus provide protection against antibody mediated injury to the vascular endothelium, preventing activation of the cascade that leads to irreversible microvascular damage. Blocking acute complement-mediated injury might allow time for DSA removal with aggressive PP.
What are the side effects of therapy?
Headache
Nasopharyngitis
Back pain
Nausea
Fatigue
Cough
Herpes simplex infections
Sinusitis
Respiratory tract infection
Constipation
Myalgia
Pain in extremity
Influenza-like illness
Will you change your management of AMR based on this study?
Eculizumab being costly (6500 USD) in India for 1200mg dose and with low medical insurance penetration in India it can be used rarely . splenectomy is to be done immediately after early acute AMR which usually occurs in the first week post tx.
Also eculizumab has 2b and splenectomy 3c evidence .
Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019
Expert Consensus From the Transplantion Society Working Group