II. Bortezomib Provides Effective Therapy for Antibody- and Cell-Mediated Acute Rejection
The authors concluded that Bortezomib therapy provides effective treatment of AMR and ACR with minimal toxicity. It also provides sustained reduction in iDSA and non-iDSA levels. Bortezomib represents the first effective antihumoral therapy with activity in humans that targets plasma cells.
-
- How did the author make this conclusion?
- 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?
Conclusion made on weak case evidence scenario
Case serious studies
Bortezomib, sold under the brand name Velcade among others, is an anti-cancer medication used to treat multiple myeloma and mantle cell lymphoma.[1] This includes multiple myeloma in those who have and have not previously received treatment.[2] It is generally used together with other medications.[2] It is given by injection.
Common side effects include nausea, diarrhea, tiredness, low platelets, fever, numbness, low white blood cells, shortness of breath, rash and abdominal pain.[1] Other severe side effects include low blood pressure, tumour lysis syndrome, heart failure, and reversible posterior leukoencephalopathy syndrome.[1][2] It is in the class of medications known as proteasome inhibitor.[1] It works by inhibiting proteasomes, cellular complexes that break down proteins.[2]
References
“Bortezomib Monograph for Professionals”. Drugs.com. Retrieved 13 October 2019.
^ a b c d e “Velcade”. European Medicines Agency (EMA). 17 September 2018. Retrieved 13 October 2019.
^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^ a b Curran MP, McKeage K (2009). “Bortezomib: a review of its use in people with multiple myeloma”. Drugs. 69 (7): 859–88. doi:10.2165/00003495-200969070-00006. PMID 19441872. Archived from the original on 2011-10-08. Retrieved 2010-03-26.
Bortezomib Provides Effective Therapy for Antibody- and Cell-Mediated Acute Rejection
The authors concluded that Bortezomib therapy provides effective treatment of AMR and ACR with minimal toxicity. It also provides sustained reduction in iDSA and non-iDSA levels. Bortezomib represents the first effective antihumoral therapy with activity in humans that targets plasma cells.
How did the author make this conclusion?
the conculsion based on weak evidnce of case series from single centre with heterogenous IS protocal and short follow up , two of six cases they back to dialysis.rebound expression of DSA noted in some cases , however the author conculed that Bortezomib effective treatment for mixed rejection with minimal tolerated side effect .
Summarise the methodology and the conclusion of this study in your own words.
the author review the data of six cases of kidney transplant recipients from single centre most LD first transplant only one DD , with PRA 0 , negative crossmatch by CDC, AHG CDC , Fxm for both T- , B cells ,induction with basiliximab in 3 cases and rATG in another 3 cases with heterogenenous maintenance IS protocal including inevstigational drug in some cases
Definition of acute rejection is an increase in sCr level at least 20% above baseline sCr with histologic evidence of acute rejection defined by Banff’97 criteria,for bothACR, AMB while mixed acute rejection is defined as ACR with DSA present or positive C4d staining in PTC or both.all biopies reviewed by single pathologist .
all six cases with histological finiding of Mixed type of rejctions they used bortizemab as second line after failure of the conventional therapies like plasmaphersis , ATG, IVIG, PMP , Rituxmab , bortizemab protocal of 1.3mg /kg ( total 4 doses ) , FU with repeat biopies , Scr level , and DSA assay
Two cases failed all therapies including bortizemab as second line and back to dialysis and another two cases have chronic TG , over all FU was short , to address the longterm out come .however Bortezomib therapy provided resolution of refractory ACR in treated patients. this can be explained the effects of bortezomib on T-cell function including apoptosis and inactivation ,in this case series bortezemab lead to reduction of iDSA and non i DSA with in 2-4 weeks of treatment and sustained inhibtion for months after treatment , however rebound in DSA levels was noted in some cases.no serious side effects or apportunestic infection reported with the use of bortezimab.
one way to enhance the bortizemab efficacy is by using repeated cycles with longer interval 10-11 days ,or use bortizemab in combination with rituximab as its showed in two cases in this series, by targeting combined deletion of mature, antibody-secreting plasma cells and their precursors, we need more studies with prosepctive design and longer FU to address the bortizemab efficacy and safey profile .
What is the mechanism of action of this drug?
Bortezomib is a selective inhibitor of 26S proteasome.
FDA approved for MM bortezomib have dirct effect on mature plasma cells and other immune modulating effect like apopotosis with multiple effects on T and plasma cells
– NF-kB inhibition
-Reduced major HLA class I expression, and decreased Th1 responses.
– Inhibit B cells maturation through the inhibition of IL6 production by bone marrow stromal cells and lead to apoptosis in various stages of B-cell maturation.
What are the side effects of therapy?
gastritis, nusea, vomtting, diarhea
Heamtological side effects like thrombocytopenia , lecupenia , anemia
peripheral neuropathy
Q1: Refractory mixed rejections were treated with bortezomib that resulted in survival of graft without sever adverse effects. They had this idea that bortezomib a proteasome inhibitor has different inhibitory effects on both T cell and ß cell and also dendritic cells. It is an effective treatment against plasma cells. Which are not blocked by other rejection treatments.
Q2: Six patients with B episodes of mixed acute rejection were treated with an anti- plasma cell agent (bortezomib) and their biopsy results and level of DSA were studied.
This intervention results in good results. They concluded that bortezomib is an effective treatment in mixed rejection without substantial toxic side effects that causes a reduction in DSA because of its effects on plasma cell.
Q3: Bortezomib is a proteasome inhibitor with FDA approval against plasma. This anti-plasma cell drug can suppress T cell function, dendritic cells, too.
Q4:
Bortezomib side effects:
GI: Diarrhea, nausea, vomiting
Hematological: TMA, anemia thrombocytopenia leukopenia
Liver disease or problems weakness, neuropathy, cough, wheezing and respiratory involvements, Jaundice and elevated liver enzymes.
Fever, PRES, rash.
Bortezomib Provides Effective Therapy for Antibody- and Cell-Mediated Acute Rejection
How did the author make this conclusion?
The authors made a conclusion according the results of bortezomib use on 6 case reports of transplant recipients with AMR and ACR. It showed satisfactory findings yet the study population were heterogenous.
Mechanism of actions:
a) Effect on T cells – apoptosis of activated T cells, T cell depletion, inhibition of NF kB, reduction in MHC class I expression as well as reduced Th1 response
b) Effect on dendritic cells -reducing co-stimulatory molecule responses, reducing cytokine production and apoptosis of dendritic cells.
c) Effect on B cells – inhibiting IL-6 production by bone marrow stromal cells leading to apoptosis in various stages of B cell maturation. It act on plasma cells, and the DSA can be directly destroyed.
2. Summarise the methodology and the conclusion of this study in your own words.
Methodology:
Case-series of 6 kidney transplant recipients with bortezomib treated AMR and ACR
Inclusion criteria:
1) Baseline serum creatinine: Mean of 5 consecutive serum creatinine prior to the episode of acute rejection
2) Acute rejection: > 20% increase in serum creatinine from baseline and biopsy showing features of acute rejection as per Banff criteria.
3) AMR: On the basis of 2 out of 3 criteria namely, Biopsy showing AMR, C4d stain in peritubular capillaries and DSA presence.
4) ACR: Defined by Banff criteria 2017
5) Mixed acute rejection: ACR with DSA and/or C4d staining in peritubular capillaries.
All the patients were having AMR/ ACR refractory to plasmapheresis, IVIG/ rATG/ Rituximab.
Bortezomib able to
a) Improvement in the graft function
b) Reversal of rejection
c) The reversal of rejection was sustained for at least 5 months
d) Significant reduction in DSA level
e) Sustained reduction in DSA level
The side-effects associated with bortezomib:
· Gastrointestinal toxicity (nausea, diarrhea).
· Haematological –Thrombocytopenia, leucopenia
· Neurology – paresthesias
In the summary:
Bortezomib can be used in refractory AMR and ACR and associated with sustained and significant reduction in DSA levels, both immunodominant and non-immunodominant DSAs
3. What is the mechanism of action of this drug?
Mechanism of actions:
a) Effect on T cells – apoptosis of activated T cells, T cell depletion, inhibition of NF kB, reduction in MHC class I expression as well as reduced Th1 response
b) Effect on dendritic cells -reducing co-stimulatory molecule responses, reducing cytokine production and apoptosis of dendritic cells.
c) Effect on B cells – inhibiting IL-6 production by bone marrow stromal cells leading to apoptosis in various stages of B cell maturation. It act on plasma cells, and the DSA can be directly destroyed
4. What are the side effects of therapy?
• Gastrointestinal toxicity (nausea, diarrhea).
• Haematological –Thrombocytopenia, leucopenia
• Neurology – paresthesias
The conclusion is made depending on case series of 6 patients with mixed AMR and CMR that was refractory to usual treatment and recovered after bortezomib therapy. The case series provides low level of evidence .
This article is about case series of 6 patients with mixed AMR and ACR that was refractory to the standard treatment and received bortezomib and found that bortezomib was effective at reversing ACR and also was effective at reducing DSA level in these patients with minimum side effects during the period of the study.
Bortezomib )proteasome inhibitor ( induces apoptosis of peripheral plasma cells and this leads to reduction of antibody production .
Also bortezomib inhibit T cells and inhibit IL-6 dependent B cell maturation and differentiation.
GIT symptoms , thrombocytopenia and leucoopenia which predispose to infection, peripheral neuropathy.
How did the author make this conclusion?
A case series study design was conducted on six transplanted patients who were exposed to rejection episodes of mixed both AMR and CMR .
Those patients recieved Bortezomib as anti rejection therapy, it was found that:
(1) Rejection episodes was reversed ( despite resistance to other Is modalities)
(2) Improved renal allograft functions
(3) No recurrent episodes of rejection for the following 5 months
(4) Reduction in DSA to nondetetable levels ( both dominant and nondominent) within 2 weeks and persistant low levels for at least 5 months
SBortezomib also provided a marked and sustained reductioninbothiDSAandnon-iDSAinallpatientswithin2to 4 weeks following regardless of the magnitude of DSA levelsummarise the methodology and the conclusion of this study in your own words.
Methodology:
Patient selection: kidney transplant recipients who were exposed to graft rejection episodes of mixed antibody mediated and cellular mediated rejection
Rejection was defined as rising serum creatinine 20% above baseline denoting graft dysfunction
Patients underwent graft biopsy , Histological phenotyping of rejection ( AMR, CMR) was identified based on Banff criteria (2005) (1),
AMR was confirmed when two of the three following present:
(1) Serum anti DSA levels detected using Luminex assay
(2) Histologic evidence of AMR in biopsy
(3) Positive peritubular C4D staining
(10)
Conclusion:
Interpretation of results and analysis concluded that Bortezomid has a potent effect on reversal of acute rejection episodes of mixed type without recurrence at least for 5 months, it helps lowering DSA levels and improves graft survival, with associated minimal side effects and toxicities.
Bortizomib represents a first anti humoral agent used as anti rejection therapy
What is the mechanism of action of this drug?
· Effect on plasma cell ( anti plasma cell. Antihumoral agent)
Anti proteosomal effect : produce proapoptotic effects on plasma cell
· Effect on T cell:
Anti proteosomal effect : suppress T-cell function apoptosis in activated T cell, depletion of NF-KB , decrease T helper1 response (2)
· Effect on Dendritic cells:
reduced costimulatory molecule expression, reduced cytokine production, and apoptosis) (3).
· Effect on B cell lineage: inhibition of IL^ production thus inhibits various stages of B cell differentiation and proliferation (4)
· reduced major histocompatibility complex class I expression,
What are the side effects of therapy?
Gastro intestinal toxicity mainly diarrhea and vomiting , thrombocytopenia and leucopenia, peripheral neuropathies, parathesia and infection
References:
(1) Racusen LC, Colvin RB, Solez K, et al. Antibody-mediated rejection criteria—An addition to the Banff 97 classification of renal allograft rejection. Am J Transplant 2003; 3: 708.
(2) Adams J. The proteasome: A suitable antineoplastic target. Nat Rev Cancer 2004; 4: 349.
(3) Nencioni A, Garuti A, Schwarzenberg K, et al. Proteasome inhibitorinduced apoptosis in human monocyte-derived dendritic cells. Eur J Immunol 2006; 36: 681.
(4) HideshimaT, Richardson P, Chauhan D, et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in humanmultiplemyelomacells.CancerRes2001;61:3071.
Bortezomib Provides Effective Therapy for Antibody- and Cell-Mediated Acute Rejection
Summarize the methodology and conclusion
Methodology:
Sex transplant recipients diagnosed with mixed AMR and ACR were treated with bortezomib at labelled dosing. The effect of the treatment was monitored with serial donor-specific anti-human leukocyte antigen-antibody (DSA) levels and repeated allograft biopsies.
Definition of acute rejection based on:
definitions used to diagnose rejection in the study includes serum creatinine values plus histological evidence:
Acute Rejection is defined as an increase in sCr level at least 20% above the baseline. (Baseline sCr: which is the mean of five consecutive sCr measurements immediately before acute rejection) with histological evidence of acute rejection defined by Banff 97 criteria.
AMR is defined by Banff criteria, biopsies consistent with AMR required two of three following characteristics:
1- Donor-specific anti-human leukocyte antigen (HLA) antibody (DSA)
2- Histological changes consistent with AMR
3- Positive C4d staining in peritubular capillaries
Acute cellular rejection (ACR) is defined by Banff,97 criteria (update 2005)
Mixed acute rejection is defined as ACR with DSA present or positive C4d staining in PTC or both
C4d staining was performed on each biopsy, and all evaluations were performed by a single pathologist.
Donor-Specific Antibody Testing
DSAs detected by Luminex assay using antigen bead panels.
Conclusion:
Bortezomib gives effective treatment for mixed rejection (AMR and ACR) with minimal toxicity and it provides a sustained reduction in DSA and non-DSA levels.
Mechanism of action of the Bortezomib
It is a proteosomal inhibitor, target the mature antibody-producing plasma cell.
· These effects include:
effect on T-cell function including apoptosis induction in activated T cells, T-cell depletion, NF-kB inhibition, reduced major histocompatibility complex class I expression and decreased Th1 responses.
· proteosomal inhibition effects on dendritic cell function (reduced costimulatory molecule expression, reduced cytokine production, and apoptosis) may have contributed
· Effects on B lymphocyte linage cells include inhibition
ofIL-6productionbybonemarrowstromalcellsleadingtoapoptosis in various stages in B-cell maturation
Side effects of therapy:
Opportunistic infection (which did not occur in these patients)
Seizer, skin rash, allergic reaction, bruising, chest pain, headache, anaemia.
The authors concluded that Bortezomib therapy provides effective treatment of AMR and ACR with minimal toxicity. It also provides sustained reduction in iDSA and non-iDSA levels. Bortezomib represents the first effective antihumoral therapy with activity in humans that targets plasma cells.
How did the author make this conclusion?
By studying 6 recipients with mixed rejection in different post-transplant times. Bortezomib therapy provided resolution of refractory ACR in treated patients. Bortezomib also provided a marked and sustained reduction in both iDSA and non-iDSA in all patients within 2 to 4 weeks following regardless of the magnitude of DSA levels. Pre-bortezomib therapies may have provided a “milieu” that allowed effective bortezomib therapy.
Summarise the methodology and the conclusion of this study in your own words.
Case series of six patients had mixed rejection.
bortezomib therapy provides effective treatment of mixed (AMR and ACR) rejection with minimal toxicity and provides sustained iDSA and non-iDSA reduction. Bortezomib represents the first approach for targeting plasma cells in humoral responses, whose clinical potential
should be promptly investigated in transplantation and autoimmune diseases.
What is the mechanism of action of this drug?
bortezomib action on T-cell function including
1. apoptosis induction in activated T cells 2. T-cell depletion 3. NF-kB inhibition 4. reduced major histocompatibility complex class I expression5.and decreased Th1 responses .6.effects on dendritic cell function (reduced costimulatory molecule expression, reduced cytokine production, and apoptosis) 7. Effects on B lymphocyte linage cells include inhibition of IL-6 production by bone marrow stromal cells leading to apoptosis in various stages in B-cell maturation.
8. Marked and sustained reduction in both iDSA and non-iDSA in all patients within 2 to 4 weeks following regardless of the magnitude of DSA levels.
9. Targeting plasma cells, bortezomib may directly eliminate the source of deleterious DSA.
What are the side effects of therapy?
-Fatigue, generalized weakness
-Peripheral neuropathy
-Nausea, vomiting ,diarrhea ,poor appetite ,constipation
-Fever
– Anemia and thrombocytopenia
1. How did the author make this conclusion?
Bortezomib therapy:
Provided resolution of refractory ACR in treated patients.
Each allograft was salvaged and opportunistic infection did not occur.
Bortezomib also provided a marked and sustained reduction in both iDSA and non-iDSA
in all patients within 2 to 4 weeks following regardless of the magnitude of DSA levels.
Pre-Bortezomib therapies may have provided a “milieu” that allowed effective
Bortezomib therapy. However, as evidenced by the treatment of patient, who received
Bortezomib without prior antihumoral therapy, DSA reduction can be achieved with
Bortezomib alone.
2-What is the mechanism of action of this drug?
Bortezomib Proteosome inhibition ,its effect on T-cell function including apoptosis
induction in activated T cells, T-cell depletion, NF-kB inhibition, reduced major
histocompatibility complex class I expression, and decreased Th1 responses.
Also, Proteosome inhibition effects on dendritic cell function (reduced costimulatory y
molecule expression, reduced cytokine production, and apoptosis) may have
contributed.
Effects on B lymphocyte Effects on B lymphocyte linage cells include inhibition of IL-6
production by bone marrow stromal cells leading to apoptosis in various stages in B-cell
maturation.
3-Summarise the methodology and the conclusion of this study in your own words.
Case Series.
Conclusion:
Bortezomib therapy provides effective treatment of mixed (AMR and ACR) rejection with
minimal toxicity and provides sustained iDSA and non-iDSA reduction. Bortezomib
represents the first approach for targeting plasma-cells in humoral responses, whose
clinical potential should be promptly investigated in transplantation and autoimmune
diseases.
4-What are the side effects of therapy?
Headache and fatigue.
Gastrointestinal toxicity, in particular nausea and diarrhea.
Peripheral neuropathy.
Anemia, thrombocytopenia, and leukocytopenia.
The author concluded this on the basis of the results of bortezomib use for 6 Tx recipients with ACR and AMR that Bortezomib therapy provides effective treatment of AMR and ACR with minimal toxicity as well as reduction in DSA.
Summary:
This was a case-series of 6 kidney transplant recipients with AMR and ACR who were treated with bortezomib
All the patients were having AMR/ ACR refractory to plasmapheresis, IVIG/ rATG/ Rituximab.
By using bortezomib in all the cases, there was improvement in the graft function, reversal of rejection, the reversal of rejection was sustained for at least 5 months, significant reduction in DSA level and sustained reduction in DSA level.
Bortezomib use in refractory AMR and ACR is helpful in successful treatment with insignificant side effects. Its use is also associated with sustained and significant reduction in DSA levels.
Mechanism of action of this drug:
Bortezomib is a selective proteasome inhibitor . It induces apoptosis of rapidly diving and metabolically active cells including T cells , B cells and dendritic cells .
Side effects:
Nausea, diarrhea, Thrombocytopenia and neuropathy .
The author observed bortezomib effect in 6 patients with resistance to conventional therapies , the cases include mixed types of rejection , all of which improved with documented reduction in DSA levels and biopsy showing resolution of ACR , and so the author concluded the beneficial effects of bortezomib on cellular and antibody mediated rejection.
6 patients with mixed acute rejections at different points post transplant, most of which were treated with methyprednisolon , plasma exchanges, IVIG , ATG and retuximab without response,
The 6 of which received bortezomib at a dose of 1.3 mg / m2 for 4 doses , follow up renal biopsies and follow up DSA levels were recorded showing resolution of rejections in renal biopsies and marked reduction in DSA levels .
This was associated with reduction in serum creatinine and no significant infectious side effects
Bortezomib is a proteosome inhibitors targeting plasma cells
It’s FDA approved in treatment of plasma cell tumors
It affects T cells functions as it induce T cell apoptosis ,decreases Thelper responses .
Side effects of bortezomib include
Weakness, headache
Nausea and vomiting
Diarrhea, constipation
Peripheral neuropathy
Arthralgia
Anemia ,thrombocytopenia
1- How did the author make this conclusion? The author had 6 patients who had AMR& ACR episodes at different time interval post kidney transplantation. These patient received Bortezomib ,they showed improvement in serum creatinine and marked reduction of DSA .
Summarise the methodology and the conclusion of this study in your own words. This is a case series study . In which 6 transplanted recipient who had both ACR and AMR , which received plasmapheresis , IV Ig ,rATG and Rituximab but no improvement . All patient received bortezomib with serial monitoring of DSA and repeated allograft biopsy .After treatment improvement in serum creatinine , significantly reduced DSA and reversed histological finding .
.
What is the mechanism of action of this drug? Bortezomib is a reversible inhibitor of the 26S proteasome, a multicatalytic enzyme complex localized in the cell nucleus and cytosol. Due to their high rate of antibody synthesis, plasma cells are particularly sensitive to proteasome inhibition, and bortezomib has been shown to deplete plasma cell levels. Its action :
-T-cell : activated T cells apoptosis induction, T-cell depletion
– NF-kB inhibition
– dendritic cell :reduce costimulatory molecule expression, reduce cytokine production, and apoptosis
– B lymphocyte : inhibition of bone marrow production leading to apoptosis in various stages in B-cell maturation
What are the side effects of therapy?
GIT: Nausea ,Diarrhea ,Anorexia ,Constipation and Vomiting,
CNS: Peripheral neuropathy, Headache, Insomnia, Dizziness, Paresthesia
Hematology : Anemia,thrombocytopenia and Neutropenia .
1. The conclusion was made by authors of this article based only on the observation of the anti-rejection effect of Bortezomib in a few numbers of cases and so the level of evidence for such a conclusion is weak (level 5) and this observation should be confirmed with precise and robust randomized clinical trials.
2. This article is a case series that evaluates the anti-rejection effect of Bortezomib in 8 episodes of mixed AMR and ACR (refractory to plasmapheresis, IVIG, rATG, and Rituximab) with monitoring of DSA level and allograft repeated biopsy findings.
In each case, Bortezomib therapy for rejection correlates with prompt rejection reversal, marked and sustained reduction in DSA (both iDSA and non-iDSA), improving kidney allograft function, and suppression of recurrent rejection with minimal toxicity.
Rebound in DSA levels was shown in some patients.
3. Bortezomib is a first in a class proteosomal inhibitor that targets mature antibody producing plasma cells. Bortezomib expresses its effect in a pleiotropic manner. It has a potent proapoptotic effect on non-transformed and antibody producing plasma cells. In addition, Bortezomib suppresses T cell activity and can be used for prevention and treatment of ACR.
The effects of bortezomib on T-cell function including apoptosis induction in activated T cells, T-cell depletion, NF-kB inhibition, reduced major histocompatibility complex class I expression, and decreased Th1 responses. In addition, it affects dendritic cells and various stages of B cell maturation.
4. Bortezomib related toxicity consists of gastrointestinal (diarrhea), neurological (paresthesia), and hematological (thrombocytopenia) toxicities.
Points to be noticed by all readers of this article:
All cases were PRA 0, cross match and DSA negative and with an aggresive combined rejection sometimes non relenting,
with no mention of non cmplience was it inefficient IS!
Some cases had (investigational drug)in place of CNI was it cyclosporine?
Prompt occurance of TG.in 1to2weeks.
Diff modes in using the drug:
case3 used straight away without the conventional anti AMR protocols.
Attempts to enhance the effect by combining synchronously with rATG ,Retuximab. or change doses and cycle frequecy.
Most of you mentioned the mechanisms of action and not mentioning that it targets PLASMA cell!
How did the author make this conclusion?
Through following the course of 6 patients who had AMR& ACR episodes at different time interval post kidney transplantation. He followed the type and level of DSA which was reduced after treatment with Bortezomib .he did biopsies and the histopathological changes were reversed with Bortezomib. The serum creatinine also improved.
Summarise the methodology and the conclusion of this study in your own words.
This is a cases reports of 6 patients who are kidney transplant recipients. all had negative ptretransplant crossmatch, all had received either rATG or basiliximab induction , biopsies revealed ACR and AMR rejection episodes which did not respond to plasmapheresis, IVIg + rATG+ Rituximab. DSA testing revealed de novo DSA.
Bortezomib was given to the 6 patients and resulted in resolution of biopsy finding , reduction of DSA and improvement of serum Cr .
What is the mechanism of action of this drug?
1- Bortezomib is a first in class proteosomal inhibitor and it a reversible inhibitor of the 26S proteasome complex in mammalian cells(large protein complex involved in degradation of ubiquitinated proteins to regulate the intracellular concentration of various proteins to keep normal cell homeostasis).1
2- T-cell : activated T cells apoptosis induction, T-cell depletion
3- NF-kB inhibition
4- MHC class I: Reduction of expression and decrease Th1 responses
5- dendritic cell :reduce costimulatory molecule expression, reduce cytokine production, and apoptosis
6- B lymphocyte : inhibition of bone marrow production leading to apoptosis in various stages in B-cell maturation
7- iDSA and non-iDSA : reduction within 2 to 4 weeks through targeting plasma cells
1-Hideshima et al (2005). Vladimir Beljanski, in xPharm: The Comprehensive Pharmacology Reference, 2007
1. What are the side effects of therapy?
Diarrhea and Thrombocytopenia as in the first patient
GIT: Nausea ,Anorexia ,Constipation, Vomiting, Dehydration, Abdominal pain
CNS: Peripheral neuropathy, Headache, Insomnia, Dizziness, Paresthesia
Hematology : Anemia, Neutropenia
MSK: Arthralgia, Limb pain, Back pain, Bone pain, Myalgia, Muscle spasms
Cardiopulmonary : Dyspnea, Edema, Cough, Hypotension, Pneumonia
Constitutional: Pyrexia, Rigors, Anxiety
Skin : Rash, Pruritus, Herpes zoster
Post marketing ReportsCardiovascular: AV block complete, cardiac tamponade
GI: Ischemic colitis, hepatitis, acute pancreatitis
CNS: Encephalopathy, dysautonomia, PML,acute diffuse infiltrative pulmonary disease, PRES, herpes meningoencephalitis, GBS, demyelinating polyneuropathy
Hematologic: DIC
Pulmonary: Acute diffuse infiltrative pulmonary disease
Skin: Toxic epidermal necrolysis, SJS, acute febrile neutrophilic dermatosis (Sweet’s syndrome);
Sensory: Optic neuropathy, deafness bilateral, blindness, chalazion/blepharitis, and ophthalmic herpes
The authors concluded that Bortezomib therapy provides effective treatment of AMR and ACR with minimal toxicity. It also provides sustained reduction in iDSA and non-iDSA levels. Bortezomib represents the first effective antihumoral therapy with activity in humans that targets plasma cells.
1. How did the author make this conclusion?
The authors concluded this on the basis of the results of bortezomib use on 6 transplant recipients with AMR and ACR. The reason for satisfactory treatment of AMR/ ACR in these patients was probably due to multi-pronged action of bortezomib:
a) On T cells by apoptosis of activated T cells, T cell depletion, inhibition of NF kB, reduction in MHC class I expression as well as reduced Th1 response
b) On dendritic cells by reducing co-stimulatory molecule responses, reducing cytokine production and apoptosis of dendritic cells.
c) On B cells by inhibiting IL-6 production by bone marrow stromal cells leading to apoptosis in various stages of B cell maturation.By acting on plasma cells, the source of DSA can be directly destroyed.
2. Summarise the methodology and the conclusion of this study in your own words.
Methodology:
This was a case-series of 6 kidney transplant recipients with 8 episodes of AMR and ACR who were treated with bortezomib
The cases were taken up on the basis of defined criteria:
1) Baseline serum creatinine: Mean of 5 consecutive serum creatinine prior to the episode of acute rejection
2) Acute rejection: > 20% increase in serum creatinine from baseline and biopsy showing features of acute rejection as per Banff criteria.
3) AMR: On the basis of 2 out of 3 criteria namely, Biopsy showing AMR, C4d stain in peritubular capillaries and DSA presence.
4) ACR: Defined by Banff criteria
5) Mixed acute rejection: ACR with DSA and/or C4d staining in peritubular capillaries.
All the patients were having AMR/ ACR refractory to plasmapheresis, IVIG/ rATG/ Rituximab.
By using bortezomib in all the cases, there was:
a) improvement in the graft function
b) reversal of rejection
c) the reversal of rejection was sustained for at least 5 months
d) significant reduction in DSA level
e) sustained reduction in DSA level
The side-effects associated with bortezomib use were transient and there were no opportunistic infections.
Conclusion:
Bortezomib use in refractory AMR and ACR is helpful in successful treatment with insignificant side effects. Its use is also associated with sustained and significant reduction in DSA levels, both immunodominant and non-immunodominant DSAs
3. What is the mechanism of action of this drug?
Bortezomib is a selective inhibitor of 26S proteasome. It induces apoptosis of rapidly diving and metabolically active cells. Its action is at multiple levels:
a) On T cells: apoptosis of activated T cells, T cell depletion, inhibition of NF kB, reduction in MHC class I expression as well as reduced Th1 response
b) On dendritic cells: reducing co-stimulatory molecule responses, reducing cytokine production and apoptosis of dendritic cells.
c) On B cells: inhibiting IL-6 production by bone marrow stromal cells leading to apoptosis in various stages of B cell maturation.
4. What are the side effects of therapy?
The major side-effects seen with bortezomib use include:
a) Gastrointestinal toxicity (nausea, diarrhea).
b) Thrombocytopenia
c) Paresthesias due to neuropathy
Excellent
How did the author make this conclusion?
They studied eight episodes of mixed AMR and ACR in six transplant recipients received bortezomib which resulted in improvement on different ways with prompt rejection reversal, marked and prolonged reductions in DSA levels, improved renal allograft function, and suppression of recurrent rejection for at least 5 months.
with reduction of both iDSA and non IDSA by more than 50% within 14 days and remained substantially suppressed for up to 5 months.
So they concluded that Bortezomib represents the first effective antihumoral therapy with activity in humans that targets plasma cells.
Summary of methodology and the conclusion
They studied 6 patients with both ACR and AMR (mixed rejection); rejection episodes refractory to plasmapheresis, IVIg,rATG and rituximab.
They noticed according to their experience that limitation of these treatments were
(1) AMR reversal tends to be gradual than prompt.
(2) expense.
(3) rejection reversal rates below 80%.
(4) common appearance of chronic rejection after AMR treatment.
(5) long-term persistence of DSA after therapy. these limitations may be due to the lack of effects on mature plasma cells .
They used for all of the 6 patients Measuring the baseline serum creatinine ( defined by mean of the five consecutive serum creatinine (sCr) measurements immediately preceding acute rejection)
with histologic evidence of acute rejection defined by Banff 97 criteria (update 2005) with biopsies consistent with AMR requiring two of three of the following DSA, histologic changes consistent with AMR, and positive C4d staining in peritubular capillaries and/ or other structures.
DSA were identified using antigen bead panels by Luminex assay. Fluorescence intensity values were converted to molecules of equivalent soluble fluorescence (MESF) using a standard curve.
Patients received bortezomib one cycle
conclusion, bortezomib therapy provides effective treatment of mixed (AMR and ACR) rejection with minimal toxicity and provides sustained iDSA and non-iDSA reduction.
Bortezomib represents the first approach for targeting plasma-cells and its role should be investigated in larger studies.
mechanism of action of this drug?
It is proteosomal inhibitor, effects of bortezomib on T-cell function including apoptosis of activated T cells, T-cell depletion, NF-kB inhibition, reduced HLA class I expression, and decreased Th1 responses
Also, reduce dendritic cell function by reduced costimulatory molecule expression, reduced cytokine production, and apoptosis.
Effects on B lymphocyte linage cells include inhibition of IL 6 production leading to apoptosis in various stages in B-cell maturation
side effects of therapy
It includes transient gastrointestinal toxicity mainly diarrhea and vomiting ,hematological toxicity,
bone marrow depression (anemia ,thrombocytopenia and leukopenia)
The results were not that coclusive please read the above notes for suggested enhancement protocols.
Case series were used to investigate bortezomib’s impact on ACR and ABMR in 8 episodes resistant to standard treatment. Bortizomib’s benefit was confirmed by serum creatinine, DSA, and renal biopsy.
6 patients had 8 ACR and ABMR events.
With the histologic confirmation of acute tissue damage, capillaritis and/or glomerulitis, as well as antibody interaction with vascular endothelium and/or circulating DSA, ACR was identified. ACR plus DSA or positive C4d staining in peritubular capillaries or both.
Six individuals with refractory ACR and ABMR experienced 8 bouts of ABMR and ACR unresponsive to standard therapy. Bortezomib 1.3 mg/m2 was given . Bortezomib improved renal biopsy rejection characteristics and significantly reduced DSA in refractory ABMR and ACR with few side effects.
Proteome inhibitors cause Cell apoptosis and arrest of the cell cycle. The main effect is on plasma cells. That will prevent antibody production.
Anaemia, thrombocytopenia, and leukopenia; GIT complication such as diarrhoea and vomiting; neurological toxicity; increased risk of infection.
fine but to cmplete your informatoin read the above notes.
How did the author make this conclusion?
The authors made this conclusion based on:
Summarise the methodology and the conclusion of this study in your own words?
Study Type:
case series ,cohort-prospective study.
Criteria for cases included in the study:
Study Population and technique :
What is the mechanism of action of this drug?
Bortezomib is a proteasome inhibitor:
What are the side effects of therapy?
Exellent v. good you noticed the SINGLE pathologist which saves a lot of disaggreament.
To complete your work go through the above for enhancement methods.
How did the author make this conclusion?
The in vitro and in vivo evidence of bortezomib’s activity against mature, antibody secreting plasma cells may underlie bortezomib’s antihumoral efficacy in humans. Thus, by targeting plasma cells, bortezomib may directly eliminate the source of deleterious DSA . The effectiveness of bortezomib in reducing DSA levels may be of significance in AMR as recent studies have shown correlation between AMR and DSA levels during and after therapy .
Summarise the methodology and the conclusion of this study in your own words.
This is a case series study . In which 6 transplanted recipient who had both ACR and AMR (mixed rejection ) , which is refractory to plasmapheresis , IV Ig ,rATG and rituximab . All patient received bortezomib with serial monitoring of DSA and repeated allograft biopsy .
bortezomib therapy provides effective treatment of mixed (AMR and ACR) rejection with minimal toxicity and provides sustained iDSA and non-iDSA reduction .
What is the mechanism of action of this drug?
Bortezomib targets plasma-cells
The effects of bortezomib on T-cell function including ;
apoptosis induction in activated T cells
T-cell depletion
NF-kB inhibition
reduced major histocompatibility complex class I expression,
decreased Th1 responses
Proteosomal inhibition effects on dendritic cell function (reduced co stimulatory molecule expression, reduced cytokine production, and apoptosis) .
Effects of bortezomib on B lymphocyte linage cells include inhibition of IL 6 production by bone marrow stromal cells leading to apoptosis in various stages in B-cell maturation
.
What are the side effects of therapy?
Bortezomib-related toxicities (gastrointestinal toxicity,thrombocytopenia, and paresthesias) were all transient.
1. How did the author make this conclusion?
He discussed 6 cases that already received standard therapy for treatment both ACR and AMR then followed by giving bortizomib at the end
the results can’t be conclusive because of small number, multiple interventions, no control group ,no randomization.
2. Summarize the methodology and the conclusion of this study in your own words.
6 cases report received bortozomib without control, without randomization open labeled study.5 patients underwent biopsy proven (both ACR and AMR event) then received the standard therapy including shifting to tacrolimus, steroid pulses, ATG, plasmapharesis and rituximab then bortozomib except patient 5 whom biopsy showed only borderline ACR and chronic changes upon which he was shifted to tacrolimus from sirolimus , pulse steroids, plasmapheresis then bortezomib (ACR responded to tac shift and steroids pulse and DSA titre decreased after plasmapheresis). the study methodology didn’t achieved any standard requirements for provid results of good quality
2. no control group
3. no randomization
4. open labelled
5. small number
6. multiple interventions by giving standard therapy then bortozomib
1. What is the mechanism of action of this drug?
proteosomal inhibitor targeting plasma cells causing its apoptosis
2. What are the side effects of therapy?
· hematological and bone marrow depression cauing anemia ,thrombocytopenia and leukopenia
· GIT complication such as diarrhea and vomiting
· neuronal toxicity
· increase risk of infection.
This a small drug trial the patient is his own control except patient 3 were it was used before cnventional anti rejection protocol.Otherwise read the above points.
1-How did the author make this conclusion?
The authors concluded that Bortezomib is an efficient treatment for AMR and ACR with minimal toxicity by studying 6 kidney transplant recipients where they demonstrated rejection reversal, marked and prolonged reductions in DSA levels, improved renal allograft function, and suppression of recurrent rejection for at least 5 months.
2-Summarise the methodology and the conclusion of this study in your own words.
Methodology
Measuring the baseline serum creatinine with histologic evidence of acute rejection defined by Banff’97 criteria (update 2005) with biopsies consistent with AMR requiring two of three of the following DSA, histologic changes consistent with AMR, and positive C4d staining in peritubular capillaries.
DSA were identified using antigen bead panels by Luminex assay. Fluorescence intensity values were converted to molecules of equivalent soluble fluorescence (MESF) using a standard curve.
This was applied to 6 kidney transplant recipients
Follow-up ranged from 31 to 310 days, with a mean of 140 days.
Conclusion
Bortezomib is effective in treatment of mixed (AMR and ACR) rejection with minimal toxicity
3-What is the mechanism of action of this drug?
It acts as a proteosomal inhibitor, it possess activity against plasma cells , suppresses T-cell function , NF-kB inhibition, reduces HLA class I expression, and decreases Th1 responses, also has inhibition effects on dendritic cell function and inhibits IL 6productionby bone marrow stromal cells leading to apoptosis in various stages in B-cell maturation
4-What are the side effects of therapy?
It includes gastrointestinal events, asthenia, hematological toxicity, and peripheral neuropathy
Not all the cases improved two went back to HD your cnclusions were too optimistic
TG occured in 1to 2 weeks in some
CONCLUSION would be that:
current treatment of AMR and mixed rejection is still not enough
Bortizomib is a very promising anti plasma cell agent but will need further trials to give better results.
Bortezomib is an anti-plasma cell agent and proteozomal inhibitor that can suppress T cell function, It was used in 6 patients with mixed AMR and ACR and resulted in:
rapid reversal of rejection with improvement of renal allograft function
decrease in immunodominant DSA (iDSA) levels by >50% within 14 days and remained reduced for 5 months.
decrease of non-iDSA to undetectable levels
prevention of recurrence of rejection for up to 5 months
Methodology:
6 patients with 8 episodes of mixed AMR and ACR were treated with bortezomib.
Baseline serum creatinine was determined by mean serum creatinine before AR
AMR was defined by presence of two of the following: DSA, histologic changes consistent with AMR and positive C4d
ACR was defined by Banff criteria
mixed AR was defined by ACR with DSA or positive C4d or both
DSAs were monitored using Luminex assay, iDSA were DSA with highest level and noni-DSA were DSA present at lower concentrations
Fluorescein intensity were converted to molecule of equivalent soluble fluorescein
Conclusion:
Bortezomib could allow effective and sustained treatment of mixed rejection and provide maintained reduction in iDSA and non-iDSA
It inhibit T cell immune response and inhibit proteosome pathway
has ability to trigger apoptosis of bone marrow derived plasma cells
mediate apoptosis of activated T cells
suppress maturation of dendritic cells that present HLA antigens to T cells
inhibit angiogenesis involved in chronic allograft injury
gastrointestinal effects: nausea, diarrhea and vomiting
hematological toxicity: anemia, thrombocytopenia and neutropenia
neurological toxicity: peripheral neuropathy
Eskandary F, Regele H, Baumann L, Bond G, Kozakowski N, Wahrmann M, Hidalgo LG, Haslacher H, Kaltenecker CC, Aretin MB, Oberbauer R. A randomized trial of bortezomib in late antibody-mediated kidney transplant rejection. Journal of the American Society of Nephrology. 2018 Feb 1;29(2):591-605.
Schmidt N, Alloway RR, Walsh RC, Sadaka B, Shields AR, Girnita AL, Hanseman DJ, Woodle ES. Prospective evaluation of the toxicity profile of proteasome inhibitor–based therapy in renal transplant candidates and recipients. Transplantation. 2012 Aug 27;94(4):352-61.
Shah N, Meouchy J, Qazi Y. Bortezomib in kidney transplantation. Current opinion in organ transplantation. 2015 Dec 1;20(6):652-6.
can you ellaborate more on angiogenesis inhibition in chronic allograft injury.
found it in the diagram provided by BEN mehrez.
1.Through case series ,authors tried to explore the effect of bortizomib on ACR and ABMR in 8 episodes not responding to conventional therapy. Bortizomib beneficial effect was proved through monitoring of serum creatinine, DSA and renal biopsy.
2.6 patients were included who developed 8 episodes of ACR and ABMR .ACR was diagnosed using banff 97 criteria; updated 2005and ABMR was considered with histologic proof of acute tissue injury ;capillaritis and or glomerulitis in addition to presence of antibody interaction with vascular endothelium and or circulating DSA .Mixed acute rejection when there is ACR in addition to DSA or positive C4d staining in peritubular capillaries or both.
Conclusion: Refractory ACR and ABMR were responding to bortizomib as shown through improvement in rejection items in renal biopsy with signiificant DSA reduction associated with little toxic side effects.
3.Mechanism of action :
it is a proteosome inhibitor inducing selective inhibition of 26Sproteosome leading to apoptosis of highly active dividing cells affecting plasma cells T cells, NK cells and dendritic cells .Other actions include decrease of HLA class i expression and costimulatory molecules.
4.Side effects are mainly gastrointestinal and hematological. ;nausea, diarrhoea thrombocytopenia in addition to malignancy and risk of infection with encapsulated organisms and peripheral neuropathy.
What about action on Bcells, Plasma cells, DC.
* T-cell depletion and reduces Th1 responses.
Case series study, aimed to assess the effect of bortezomib on treatment of acute rejection ( ABMR & ACMR).
Author conclusion:
This study was the first one use bortezomib in treatment of rejection, & the results show persistent reduction in DSA( immune & non immune) level & reversal of rejection process during follow-up.
Summery:
The study include 6 renal transplant recipients who followed for 31-310 days.
Baseline s.creatinine mean the average of 5 consecutive creatinine measurement immediately before rejection. AR diagnosis depend on Banff 97 criteria( renal biopsy finding & DSA level detected by Lumenix technology).
All 6 recipient who were at different age group, onset of rejection at different times post transplantation ( 2 early & the others after >4 years), different induction ( rATG, IL-2R Ab), & different HLA mismatch. CDC, FCXM results were negative for all recipients ( except one patient had only CDC negative)
All of them develop both ABMR & ACMR( mixed rejection) not responding to treatment ( IV MP, rATG, plasmapheresis+IVIG & rituximab). Therefore they receive one cycle of bortezomib 1.3mg. During follow-up by graft biopsy & DSA level found that 5 patients show resolution of ACMR & sustained reduction or undetected DSA level ( both iDSA & non iDSA).
In conclusion it was found that bortezomib is effective in treatment of both types of acute rejection with insignificant increase in opportunistic infection.
Mechanism of action of bortezomib:
It inhibit chymotrypsin-like site of 20S proteolytic that leading to increase cell-cycle arrest & apoptosis via inhibiting NF-kB signaling.
Side effects of bortezomib:
asthenia, nausea & vomiting, diarrhea, constipation, thrombocytopenia, peripheral neuropathy, pyrexia, anemia, headache, neutropenia & others.
There are post marketing CV complication ( AV block, cardiac tamponade), GI ( ischemic colitis, hepatitis), CNS( encephalitis, PML, PRES, GBS), & DIC.
The term is iDSA immunodominant meaning with higher numbers vs. non i DSA
Summarise the methodology and the conclusion of this study in your own words. How did the author make this conclusion?
What is the mechanism of action of this drug?
Proteome inhibitor that cause the following:
What are the side effects of therapy?
Welldone
The conclusion of this study was based on the results of several kidney transplant recipients receiving bortezomib as a treatment for mixed ACR and antibody mediated rejection defined based on Banff criteria 2005.
Authors explanation of the impact of bortezomib is mediated by its effect on T-cell function including:
– Apoptosis induction in activated T cells,
– T-cell depletion,
– NF-kB inhibition,
– Reduced HLA class I expression, and decreased Th1 responses. Th1 cells are known to be implicated in the cellular cytotoxic response, secrete IFN-gamma and IL-2. Th1 are involved activation of macrophages. T helper type 1 response is also responsible of antibodies production in particular IgG1.
– Proteosomal inhibition effects on dendritic cell function (reduced costimulatory molecule expression, reduced cytokine production, and apoptosis) may have contributed.
– Inhibition of IL-6 production by bone marrow stromal cells leading to apoptosis in various stages in B-cell maturation.
Summarize the methodology and the conclusion of this study in your own words
This is a case series of 6 cases receiving Bortezomib as second line treatment following the failure of conventional immunosuppression in the treatment of biopsy proven mixed ACR with features of antibody mediated rejection.
Renal biopsy results based on Banff criteria 2005, and DSA were identifies by Luminex technique
Bortezomib therapy represents the first approach for targeting plasma-cells in humoral response. Bortezomib provides effective treatment of mixed rejection as it has inhibitory effects on immune active cells, inhibits B cells stimulation and proliferation by the blockade of T cells. By inhibition of antigen presenting cells, the development of immune response also affected. The study reported minimal toxicity of Bortezomib. Bortezomib could be the drug of choice in mixed acute rejection if initial measures and treatment fail.
What is the mechanism of action of this drug?
Bortezomib is a selective inhibitor of the 26S proteasome, preventing the activation of NF-κB. It induces apoptosis of rapidly dividing, metabolically active cells with extensive protein synthesis. Bortezomib target plasma cells preventing antibody production.
Side effects
Common side effects include nausea, diarrhea, tiredness, low platelets, fever, numbness, low white blood cells, shortness of breath, rash and abdominal pain. Other severe side effects include low blood pressure, tumour lysis syndrome, heart failure, and reversible posterior leukoencephalopathy syndrome.
Welldone
How did the author make this conclusion?
Bortezomib therapy provided resolution of refractory ACR, this is likely due to the effect of bortezomib on T cell function including apoptosis induction in activated T cells, T cell depletion, NF-KB inhibition, reduced HLA class I expression, and decrease Th1 responses. also the effect on dendritic cells may contribute. Inhibition of IL-6 production leading to apoptosis in various stages in B cell maturation. By targeting plasma cells, bortezomib may directly eliminate the source of DSA.
Summarise the methodology and the conclusion of this study in your own words
Methodology:
Six renal transplant recipients, eight episodes of mixed ACMR+ ABMR, treated with bortezomib.
Definitions:
baseline serum creatinine: mean of five consecutive serum creatinine measurement immediately preceding acute rejection
acute rejection: increase in serum creatinine level at least 20% above baseline with histological evidence of acute rejection by banff 97( updated at 2005).
ABMR: two of three criteria: DSA, histologic changes consistent with ABMR, and positive C4d staining in the peritubular capillaries and/or other structures.
ACMR: defined by banff 97 criteria ( updated at 2005)
mixed acute rejection: ACMR with positive DSA or positive C4d staining in PTC or both.
Results:
In each case, bortezomib provides:
1. prompt rejection reversal.
2. marked and prolonged reduction in DSA level
3. improvement in graft function
4. suppression of recurrent rejection for at least 5 months
SE are all transient.
Conclusion:
bortezomib provides:
1. effective treatment of ABMR & TCMR with minimal toxicity
2. sustained reduction of iDSA and non-iDSA levels
What is the mechanism of action of this drug?
It is a selective inhibitor of the 26S proteasome , it induces apoptosis of rapidly dividing, metabolically active cells. it has the ability to target plasma cells.
What are the side effects of therapy?
1. GI toxicity( paralytic ileus).
2. thrombocytopenia
3. neuropathy
Exellent Hoda this is well read ,understood and derived conclusions.
thank you
Mechanism of action of bortezomib it is first generation proteasome inhibitor, it is antiplasma cells , it decrease alloantibody production and allows plasma cells apoptosis and prevent T cell activation so has role in decreasing DSA level and prevent rejection.
Side effects;
1- Gastrointestinal side effects and toxicity like nausea, diarrhea
2- Infections with encapsulated organisms
3- Malignancy
4- Peripheral neuropathy
The author make this conclusion: based on the study of cases according to serum creatinine, DSA level, and tissue diagnosis of cellular and antibody rejection together with the incidence of occurrence of side effects of bortezomib.
The methodology and the conclusion of this study:
1- Serum creatinine
2- Tissue biopsy incidence of rejection…cellular and antibody mediated.
3- DSA level
All before and after treatment
conclusion : bortezomib therapy provides effective treatment of mixed (AMR and ACR) rejection with minimal toxicity and provides sustained DSA reduction.
How did the author make this conclusion?
Patients in this series had substantial rejection episodes refractory to plasmapheresis, IVIg, rATG, rituximab. Bortezomib therapy provided resolution of refractory ACR in treated patients. Bortezomib also provided a marked and sustained reduction in both iDSA and non-iDSA in all patients within 2 to 4 weeks following regardless of the magnitude of DSA levels. As evidenced by the treatment of patient 5, who received bortezomib without prior anti humoral therapy, DSA reduction Could be achieved with bortezomib alone.
Summarise the methodology and the conclusion of this study in your own words.
Methodology-
Definations
Baseline serum creatinine– is the mean of the five consecutive serum creatinine measurements immediately preceding acute rejection
Acute rejection – increase in sCr level at least 20% above baseline sCr with histologic evidence of acute rejection defined by Banff’97 criteria (update 2005)
AMR– requires two of three following characteristics
donor-specific antihuman leukocyte antigen (HLA) antibody (DSA)
histologic changes consistent with AMR
positive C4d staining in peritubular capillaries (PTC) acute cellular rejection (ACR) is defined by Banff ’97 criteria (update 2005)
Mixed acute rejection – defined as ACR with DSA present or positive C4d staining in PTC or both.
Renal biopsies were graded using Banff ’97 criteria (update 2005) (10). C4d immunohistochemical staining was performed on each biopsy, and all evaluations performed by a single pathologist .
DSAs were identified using antigen bead panels by Luminex assay (Labscreen TM, One Lambda, Canoga Park).
Fluorescence intensity values were converted to molecules of equivalent soluble fluorescence (MESF) using a standard curve generated with Quantum TM 27 microbeads.
6 case reports of patients having AMR or mixed AMR and ACR refractory to plasmapheresis, IvIg, ATG, Rituximab described followed by use of Bortezomib which lead to resolution of rejection and decrease in DSA levels.
Conclusion –
Bortezomib therapy provides effective treatment of mixed (AMR and ACR) rejection with minimal Toxicity.
Provides sustained iDSA and non-iDSA reduction.
Bortezomib represents the first approach for targeting plasma-cells in humoral responses.
Multiple cycles may be a reasonable approach for enhancing bortezomib therapy.
What is the mechanism of action of this drug?
Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. By this mechanism bortezomib has effects on T-cell function including apoptosis induction in activated T cells, T-cell depletion, NF-kB inhibition, reduced major histocompatibility complex class I expression, and decreased Th1 responses. Also, proteasomal inhibition has effect on dendritic cell function (reduced costimulatory molecule expression, reduced cytokine production, and apoptosis) which may contribute. Effects on B lymphocyte linage cells include inhibition of IL6 production by bone marrow stromal cells leading to apoptosis in various stages in B-cell maturation.
What are the side effects of therapy?
Peripheral Neuropathy
Hypotension
Cardiac Toxicity
Pulmonary Toxicity
Posterior Reversible Encephalopathy Syndrome (PRES)
Gastrointestinal Toxicity
Thrombocytopenia/Neutropenia
Tumor Lysis Syndrome
Hepatic Toxicity
Embryo-fetal Risk
Exellent but better summary would present the mechanism of action as you did in the side effects. however v . good.
Hematological side effects are high on the list.