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Thrombotic microangiopathy associated with proteasome inhibitors.

Lodhi A, Kumar A, Saqlain MU, Suneja M - Clin Kidney J (2015)

Bottom Line: The ubiquitin proteasome pathway plays a key role in cell cycle, function and survival.Bortezomib (BTZ) and Carfilzomib (CFZ) are the first two inhibitors of the proteasome pathway, indicated in treatment of patients with multiple myeloma.In the past few years, there have been few case reports that have highlighted the association between proteasome inhibitors (BTZ and CFZ) with acute kidney injury (AKI).

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology, Internal Medicine , University of Iowa Hospitals and Clinics , Iowa City, IA 52246 , USA.

ABSTRACT
The ubiquitin proteasome pathway plays a key role in cell cycle, function and survival. Bortezomib (BTZ) and Carfilzomib (CFZ) are the first two inhibitors of the proteasome pathway, indicated in treatment of patients with multiple myeloma. In the past few years, there have been few case reports that have highlighted the association between proteasome inhibitors (BTZ and CFZ) with acute kidney injury (AKI). In most of these case reports and initial trials, the underlying mechanism of AKI has been unclear. In this article, we discuss the association and pathogenesis of proteasome inhibitors-associated AKI. We also report the first case of CFZ-associated AKI with kidney biopsy evidence of thrombotic microangiopathy and the presence of microangiopathic hemolytic anemia.

No MeSH data available.


Related in: MedlinePlus

Proposed pathogenesis of proteasome inhibitor-associated thrombotic microangiopathy.
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SFV059F2: Proposed pathogenesis of proteasome inhibitor-associated thrombotic microangiopathy.

Mentions: Proteasome inhibitors affect VEGF pathways via NF-κB pathways [33, 34, 36] (Figure 2). NF-κB is a protein involved in the regulation of genetic transcription. NF-κB activation in response to various extracellular signals (including reactive oxygen species, TNFα, IL-1β, bacterial polysaccharides and radiation) is initiated by degradation of IκB (inhibitor of NF-κB). IκB kinase (IKK), when activated by extracellular signals described above, causes phosphorylation of IκB leading to ubiquitination of IκB. After IκB degradation, NF-κB is free to enter the nucleus and influence DNA transcription [37]. An increase in the activity of NF-κB promotes VEGF expression [38]. Proteasome inhibitors prevent ubiquitination of IκB even after phosphorylation by IKK; this in turn prevents NF-κB from entering the nucleus and effecting transcription. Thus, proteasome inhibitors decrease NF-κB levels in the nucleus leading to decreased VEGF production [39–41], potentially predisposing to TMA.Fig. 2.


Thrombotic microangiopathy associated with proteasome inhibitors.

Lodhi A, Kumar A, Saqlain MU, Suneja M - Clin Kidney J (2015)

Proposed pathogenesis of proteasome inhibitor-associated thrombotic microangiopathy.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581378&req=5

SFV059F2: Proposed pathogenesis of proteasome inhibitor-associated thrombotic microangiopathy.
Mentions: Proteasome inhibitors affect VEGF pathways via NF-κB pathways [33, 34, 36] (Figure 2). NF-κB is a protein involved in the regulation of genetic transcription. NF-κB activation in response to various extracellular signals (including reactive oxygen species, TNFα, IL-1β, bacterial polysaccharides and radiation) is initiated by degradation of IκB (inhibitor of NF-κB). IκB kinase (IKK), when activated by extracellular signals described above, causes phosphorylation of IκB leading to ubiquitination of IκB. After IκB degradation, NF-κB is free to enter the nucleus and influence DNA transcription [37]. An increase in the activity of NF-κB promotes VEGF expression [38]. Proteasome inhibitors prevent ubiquitination of IκB even after phosphorylation by IKK; this in turn prevents NF-κB from entering the nucleus and effecting transcription. Thus, proteasome inhibitors decrease NF-κB levels in the nucleus leading to decreased VEGF production [39–41], potentially predisposing to TMA.Fig. 2.

Bottom Line: The ubiquitin proteasome pathway plays a key role in cell cycle, function and survival.Bortezomib (BTZ) and Carfilzomib (CFZ) are the first two inhibitors of the proteasome pathway, indicated in treatment of patients with multiple myeloma.In the past few years, there have been few case reports that have highlighted the association between proteasome inhibitors (BTZ and CFZ) with acute kidney injury (AKI).

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology, Internal Medicine , University of Iowa Hospitals and Clinics , Iowa City, IA 52246 , USA.

ABSTRACT
The ubiquitin proteasome pathway plays a key role in cell cycle, function and survival. Bortezomib (BTZ) and Carfilzomib (CFZ) are the first two inhibitors of the proteasome pathway, indicated in treatment of patients with multiple myeloma. In the past few years, there have been few case reports that have highlighted the association between proteasome inhibitors (BTZ and CFZ) with acute kidney injury (AKI). In most of these case reports and initial trials, the underlying mechanism of AKI has been unclear. In this article, we discuss the association and pathogenesis of proteasome inhibitors-associated AKI. We also report the first case of CFZ-associated AKI with kidney biopsy evidence of thrombotic microangiopathy and the presence of microangiopathic hemolytic anemia.

No MeSH data available.


Related in: MedlinePlus