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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

Features of ongoing TMA under treatment. TMA-type changes. These changes were very focal in the biopsy, and most arteries and glomeruli were essentially unremarkable or showed nonspecific ‘ischemia/recovery’ changes. (A) Focal small interlobular artery/pre-arterioles: luminal narrowing with pale mucoid edema (arrow), and endothelial cell reaction, with erythrocyte fragmentation and ‘entrapment’ (arrowheads) within the intimal layer, which shows myointimal widening and clearing of cytoplasm in the myocyte cell layer (H&E stain 40× magnifications). Adjacent renal tubules show features of acute tubular injury. The inset figure shows a trichrome stain (60× magnification), which enhances the fragmented erythrocytes (the hallmark finding of microvascular hemolysis) in red and a pale intima with no significant collagen deposition (which would have stained blue). (B) Glomerulus: capillary loop ‘double-contours’ [arrow, sharp silver positive (black) linear staining on each of the capillary loop sides, which does not stain in between them], which indicate glomerular basement membranes reduplication response to endothelial damage (note the ‘plump’ endothelial cell occlusion, asterisk). Also noted is ischemic wrinkling (‘collapse’—arrowhead) of other glomerular capillary loops (Jones methenamine silver stain, 60× magnification). BC (Bowman's capsule).
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SFV059F1: Features of ongoing TMA under treatment. TMA-type changes. These changes were very focal in the biopsy, and most arteries and glomeruli were essentially unremarkable or showed nonspecific ‘ischemia/recovery’ changes. (A) Focal small interlobular artery/pre-arterioles: luminal narrowing with pale mucoid edema (arrow), and endothelial cell reaction, with erythrocyte fragmentation and ‘entrapment’ (arrowheads) within the intimal layer, which shows myointimal widening and clearing of cytoplasm in the myocyte cell layer (H&E stain 40× magnifications). Adjacent renal tubules show features of acute tubular injury. The inset figure shows a trichrome stain (60× magnification), which enhances the fragmented erythrocytes (the hallmark finding of microvascular hemolysis) in red and a pale intima with no significant collagen deposition (which would have stained blue). (B) Glomerulus: capillary loop ‘double-contours’ [arrow, sharp silver positive (black) linear staining on each of the capillary loop sides, which does not stain in between them], which indicate glomerular basement membranes reduplication response to endothelial damage (note the ‘plump’ endothelial cell occlusion, asterisk). Also noted is ischemic wrinkling (‘collapse’—arrowhead) of other glomerular capillary loops (Jones methenamine silver stain, 60× magnification). BC (Bowman's capsule).

Mentions: Plasmapheresis was continued while ADAMTS13 levels were pending. ADAMTS13 results (>50%) were available on Day 10, and thus plasmapheresis was stopped after five sessions. The patient never required dialysis, and over the next week, his sCr started to improve with improving urine out. The patient underwent an ultrasound guided kidney biopsy 1 week after presentation, when platelets were >65 000 mm3. The biopsy revealed glomerular and rare arteriolar TMA with mild acute tubular necrosis (Figure 1A and B). There was no diagnostic evidence of renal involvement by myeloma or paraproteins. His hemoglobin, platelets, lactate dehydrogenase (LDH) and haptoglobin were normalized over the next 3 weeks. The patient was treated supportively for the rest of his stay. His sCr continued to improve, and last known value 45 days after the initial presentation was 1.8 mg/dL (159 µmol/L). Workup for atypical HUS (e.g. complement factor H autoantibodies) was not done, though normal complement level and improvement in TMA argue against it.Fig. 1.


Thrombotic microangiopathy associated with proteasome inhibitors.

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

Features of ongoing TMA under treatment. TMA-type changes. These changes were very focal in the biopsy, and most arteries and glomeruli were essentially unremarkable or showed nonspecific ‘ischemia/recovery’ changes. (A) Focal small interlobular artery/pre-arterioles: luminal narrowing with pale mucoid edema (arrow), and endothelial cell reaction, with erythrocyte fragmentation and ‘entrapment’ (arrowheads) within the intimal layer, which shows myointimal widening and clearing of cytoplasm in the myocyte cell layer (H&E stain 40× magnifications). Adjacent renal tubules show features of acute tubular injury. The inset figure shows a trichrome stain (60× magnification), which enhances the fragmented erythrocytes (the hallmark finding of microvascular hemolysis) in red and a pale intima with no significant collagen deposition (which would have stained blue). (B) Glomerulus: capillary loop ‘double-contours’ [arrow, sharp silver positive (black) linear staining on each of the capillary loop sides, which does not stain in between them], which indicate glomerular basement membranes reduplication response to endothelial damage (note the ‘plump’ endothelial cell occlusion, asterisk). Also noted is ischemic wrinkling (‘collapse’—arrowhead) of other glomerular capillary loops (Jones methenamine silver stain, 60× magnification). BC (Bowman's capsule).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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SFV059F1: Features of ongoing TMA under treatment. TMA-type changes. These changes were very focal in the biopsy, and most arteries and glomeruli were essentially unremarkable or showed nonspecific ‘ischemia/recovery’ changes. (A) Focal small interlobular artery/pre-arterioles: luminal narrowing with pale mucoid edema (arrow), and endothelial cell reaction, with erythrocyte fragmentation and ‘entrapment’ (arrowheads) within the intimal layer, which shows myointimal widening and clearing of cytoplasm in the myocyte cell layer (H&E stain 40× magnifications). Adjacent renal tubules show features of acute tubular injury. The inset figure shows a trichrome stain (60× magnification), which enhances the fragmented erythrocytes (the hallmark finding of microvascular hemolysis) in red and a pale intima with no significant collagen deposition (which would have stained blue). (B) Glomerulus: capillary loop ‘double-contours’ [arrow, sharp silver positive (black) linear staining on each of the capillary loop sides, which does not stain in between them], which indicate glomerular basement membranes reduplication response to endothelial damage (note the ‘plump’ endothelial cell occlusion, asterisk). Also noted is ischemic wrinkling (‘collapse’—arrowhead) of other glomerular capillary loops (Jones methenamine silver stain, 60× magnification). BC (Bowman's capsule).
Mentions: Plasmapheresis was continued while ADAMTS13 levels were pending. ADAMTS13 results (>50%) were available on Day 10, and thus plasmapheresis was stopped after five sessions. The patient never required dialysis, and over the next week, his sCr started to improve with improving urine out. The patient underwent an ultrasound guided kidney biopsy 1 week after presentation, when platelets were >65 000 mm3. The biopsy revealed glomerular and rare arteriolar TMA with mild acute tubular necrosis (Figure 1A and B). There was no diagnostic evidence of renal involvement by myeloma or paraproteins. His hemoglobin, platelets, lactate dehydrogenase (LDH) and haptoglobin were normalized over the next 3 weeks. The patient was treated supportively for the rest of his stay. His sCr continued to improve, and last known value 45 days after the initial presentation was 1.8 mg/dL (159 µmol/L). Workup for atypical HUS (e.g. complement factor H autoantibodies) was not done, though normal complement level and improvement in TMA argue against it.Fig. 1.

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