Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.
Contributors
• Ahad Lodhi, M.D , Abhishek Kumar, M.D ,
Muhammad U Saqlain, M.D, Manish Suneja
M.D .
• Dept. of Nephrology,...
• Transparency Declaration:
• None to declare
Theme
• Proteasome inhibitors
• Proteasome inhibitors and AKI
• Case report with brief discussion
• Pathogenesis of TMA wi...
Proteasome Inhibitors
• The Ubiquitin proteasome pathway has a key
role in in the targeted destruction of cellular
proteins, including cell cycl...
Bortezomib
• first inhibitor of proteasome pathway to be
approved in 2003 for clinical use in US
• It is boron molecule th...
Bortezomib
• Initially approved for the treatment of
myeloma in the post transplant relapse or as a
second line treatment in patients...
Carfilzomib (CFZ)
• Second generation proteasome inhibitor that
was developed to overcome side effects with
Bortezomib, ma...
Proteasome Inhibitors and AKI
• Few cases, have been reported citing Bortezomib
and Carfilzomib as a cause of AKI
• Underlying mechanism of kidney injur...
Bortezomib and AKI
• FDA approval of bortezomib in June 2008
Phase-2 trials CREST and SUMMIT involving
54 and 202 patients...
Carfilzomib and AKI
• FDA approval of Carfilzomib in July 2012 was
phase-2 trial by Siegel et al
Siegel, D.S., et al., A p...
Siegel, D.S., et al., A phase 2 study of single-agent carfilzomib (PX-171-003-A1)
in patients with relapsed and refractory...
526 pts 24.1% inc in Cr
17.7%
treatment
related
It was interesting to note that fever, anemia and
thrombocytopenia was als...
• There have been four cases of BTZ associated
AKI with evidence of underlying TMA (table 1).
A kidney biopsy was not perf...
• Kidney biopsy showed features of TMA and
associated podocytopathy, with foot process
effacement
• This presentation was ...
Case Report
Presentation
• A 63 yo Caucasian male with multiple
myeloma (MM) IgG kappa, ISS stage II, status
post 2 autologous bone ma...
Brief HPI
• Two weeks prior to this presentation he was
started on chemotherapy with CFZ
• His sCr was 0.7 mg/dl at this t...
HPI Cont..
• He was initially diagnosed with MM about 18
months ago when he had presented with a right
pleural-based mass,...
• Worsening lower extremity swelling weight gain
• Decreasing urine output
• No diarrhea, shortness of breath, chest
disco...
EXAM
• Temp 98.6 °F (37C), BP 141/80 mm of Hg (no
evidence of orthostasis), pulse 94 /min and O2
sat 97% on RA
• Physical...
-Urinalysis was significant for
2+blood and 2+ proteins
without casts or crystals
-Urine microscopy was bland
-Urine sodiu...
-14 0 2 4 6 8 10 12 18
Creatinine 0.7 6.3 6.2 5.5 4.9 3.9 3.3 2.9 2.5
Hemoglobin 11.3 5.7 6.8 7.4 8.1 7.3 7.1 8.2 7.4
0
2
...
182
176
35 30
34
53
76
96
123
106
196
170
777
727
304
235
180
167 145
121
0
100
200
300
400
500
600
700
800
900
0
20
40
60...
Course
• A presumptive diagnosis of TTP/HUS was made
and empiric plasmapheresis was started
• Patient was not re-challenge...
Biopsy
• Patient underwent an ultrasound guided
kidney biopsy one week after presentation,
when platelets were greater tha...
• His hemoglobin, platelets, LDH and haptoglobin
normalized over the next three weeks
• Patient was treated supportively f...
Discussion
• We postulate CFZ as a potential etiology of TMA
• Discontinuation of CFZ along with supportive
management was...
• Causality is difficult to establish,
• No other obvious cause of AKI including
volume depletion, tumor lysis syndrome,
a...
• He was not exposed to any other therapeutic
agents except CFZ, pomalidomide and
dexamethasone two months before
presenta...
Proposed Pathogenesis of
Proteasome Inhibitor Associated
Thrombotic Microangiopathy
Role of VEGF in TMA
• VEGF inhibition has been proposed as one of the
potential pathological factors responsible for
TMA a...
Role of VEGF in TMA
• Podocytes and
glomerular endothelial
cells use VEGF-VEGF-R2
signaling for
transmembrane
communicatio...
Role of VEGF in TMA
• Any disruption of this
mechanism,
– production (Proteasome
inhibitors),
– bevacizumab (anti-VEGF
ant...
Proteasome inhibitors effect VEGF
pathways via NF-κB pathways
NF-κB
• NF-κB (nuclear factor kappa-light-chain-enhancer
of activated B cells) is a protein involved in the
regulation of ...
• IκB kinase (IKK) when activated by extracellular
signals described above, cause phosphorylation
of IκB leading to ubiqui...
• Thus, proteasome inhibitors decrease NF-κB
levels in nucleus leading to decreased VEGF
production potentially predisposi...
• Acknowledgements:
• Danielle G Holanda, MD
• Department of Pathology, University of Iowa
Hospitals and clinics.
Thank you
Thrombotic Microangiopathy associated with proteasome inhibitors
Thrombotic Microangiopathy associated with proteasome inhibitors
Thrombotic Microangiopathy associated with proteasome inhibitors
Thrombotic Microangiopathy associated with proteasome inhibitors
Thrombotic Microangiopathy associated with proteasome inhibitors
Thrombotic Microangiopathy associated with proteasome inhibitors
Thrombotic Microangiopathy associated with proteasome inhibitors
Thrombotic Microangiopathy associated with proteasome inhibitors
Thrombotic Microangiopathy associated with proteasome inhibitors
Upcoming SlideShare
Loading in …5
×

Thrombotic Microangiopathy associated with proteasome inhibitors

1,407 views

Published on

Medicine

Published in: Education
  • Be the first to comment

  • Be the first to like this

Thrombotic Microangiopathy associated with proteasome inhibitors

  1. 1. Contributors • Ahad Lodhi, M.D , Abhishek Kumar, M.D , Muhammad U Saqlain, M.D, Manish Suneja M.D . • Dept. of Nephrology, Internal Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Dr, Iowa City IA 52246
  2. 2. • Transparency Declaration: • None to declare
  3. 3. Theme • Proteasome inhibitors • Proteasome inhibitors and AKI • Case report with brief discussion • Pathogenesis of TMA with proteasome inhibitors
  4. 4. Proteasome Inhibitors
  5. 5. • The Ubiquitin proteasome pathway has a key role in in the targeted destruction of cellular proteins, including cell cycle regulatory proteins. This process is central for cell cycle, function and survival, making proteasome inhibition a potential target in cancer.
  6. 6. Bortezomib • first inhibitor of proteasome pathway to be approved in 2003 for clinical use in US • It is boron molecule that reversibly inhibits threonine residue of 26S proteasome
  7. 7. Bortezomib
  8. 8. • Initially approved for the treatment of myeloma in the post transplant relapse or as a second line treatment in patients unsuitable for transplantation • In 2014 ,also approved in patients who responded to prior therapy with the same and relapsed at least six months following completion Richardson PG, Barlogie B, Berenson J, et al. A Phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348:2609–17 Jagannath S, Barlogie B, Berenson J, et al. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004;127:165–72
  9. 9. Carfilzomib (CFZ) • Second generation proteasome inhibitor that was developed to overcome side effects with Bortezomib, mainly peripheral neuropathy • It was approved by FDA in 2012 for patients with MM who had relapsed from and were refractory to bortezomib and at least one thalidomide derivative Herndon TM, Deisseroth A, Kaminskas E, et al: U.S. Food and Drug Administration approval: Carfilzomib for the treatment of multiple myeloma. Clin Cancer Res 19:4559-4563, 2013 Demo SD, Kirk CJ, Aujay MA, et al: Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res 67:6383-6391, 2007
  10. 10. Proteasome Inhibitors and AKI
  11. 11. • Few cases, have been reported citing Bortezomib and Carfilzomib as a cause of AKI • Underlying mechanism of kidney injury has been unclear • Vasoconstriction of renal arteries leading to AKI, has been hypothesized by Wanchoo et al • Use of N-acetyl-L-cysteine in a reported patient partially mitigated the renal injury upon re- challenge of CFZ Jhaveri, K.D., et al., Carfilzomib-related acute kidney injury. Clin Adv Hematol Oncol, 2013. 11(9): p. 604-5 Wanchoo, R., et al., Carfilzomib-related acute kidney injury may be prevented by N- acetyl-L-cysteine. J Oncol Pharm Pract, 2014
  12. 12. Bortezomib and AKI • FDA approval of bortezomib in June 2008 Phase-2 trials CREST and SUMMIT involving 54 and 202 patients, respectively. • Acute Kidney injury or TMA was not reported as a drug-related adverse event in these early trials. Jagannath S, Barlogie B, Berenson JR, Siegel DS, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Esseltine DL, Anderson KC. Br J Haematol. 2008 Nov;143(4):537-40. doi: 10.1111/j.1365- 2141.2008.07359.x. Epub 2008 Sep 6 Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, Srkalovic G, Schenkein DP, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators. Haematologica. 2006 Jul;91(7):929-34.
  13. 13. Carfilzomib and AKI • FDA approval of Carfilzomib in July 2012 was phase-2 trial by Siegel et al Siegel, D.S., et al., A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood, 2012. 120(14): p. 2817-25
  14. 14. Siegel, D.S., et al., A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood, 2012. 120(14): p. 2817-25 266 Patients • Total no of patients in the study 25% • Inc in Cr, >1.5 5% • Cr >3 times the baseline
  15. 15. 526 pts 24.1% inc in Cr 17.7% treatment related It was interesting to note that fever, anemia and thrombocytopenia was also reported in 30%, 46% and 29% of patients respectively
  16. 16. • There have been four cases of BTZ associated AKI with evidence of underlying TMA (table 1). A kidney biopsy was not performed in any of these cases • Hobeika et al, recently published a case of a patient presenting with worsening hypertension and proteinuria after CFZ exposure BMC Nephrol. 2014 Sep 30;15:156. doi: 10.1186/1471-2369-15-156.
  17. 17. • Kidney biopsy showed features of TMA and associated podocytopathy, with foot process effacement • This presentation was not associated with Microangiopathic hemolytic anemia (MAHA) • Similar pathology has also been described in TMA associated with VEGF inhibitor exposure
  18. 18. Case Report
  19. 19. Presentation • A 63 yo Caucasian male with multiple myeloma (MM) IgG kappa, ISS stage II, status post 2 autologous bone marrow transplants (last one about 6 months prior to this presentation) was found to have AKI (sCr of 6.3mg/dl) during his routine visit to receive his second dose of CFZ.
  20. 20. Brief HPI • Two weeks prior to this presentation he was started on chemotherapy with CFZ • His sCr was 0.7 mg/dl at this time with no evidence of proteinuria • His past medical history was also significant for hypertension, dyslipidemia, urate nephrolithiasis
  21. 21. HPI Cont.. • He was initially diagnosed with MM about 18 months ago when he had presented with a right pleural-based mass, which was associated with a destructive lesion of an adjacent rib • A FNA of the lesion was performed at that time which showed sheets of plasma cells consistent with multiple myeloma • His kappa to lambda ratio (κ/λ) a year ago was 75.84 and was 1.58 at the time of this presentation
  22. 22. • Worsening lower extremity swelling weight gain • Decreasing urine output • No diarrhea, shortness of breath, chest discomfort, orthostatic symptoms or any exposure to any nephrotoxins including contrast agents • Current medications : acyclovir, dexamethasone, fluconazole, fludrocortisone, gabapentin, loratadine, omeprazole, pentamidine inhaled, propranolol, simvastatin and trazodone
  23. 23. EXAM • Temp 98.6 °F (37C), BP 141/80 mm of Hg (no evidence of orthostasis), pulse 94 /min and O2 sat 97% on RA • Physical exam revealed mild diffuse bilateral wheezing and lower extremity edema up to knees
  24. 24. -Urinalysis was significant for 2+blood and 2+ proteins without casts or crystals -Urine microscopy was bland -Urine sodium was 33mEq/L (33mmol/L) and urine Cr was 97.1 mg/dl (8583 µmol/L) with UPR of 1.5 -Antiphospholipid antibodies and ANCA serologies were negative -Serum complements (C 3 and C4) were within normal range -Renal ultrasound was unremarkable without any evidence of hydronephrosis
  25. 25. -14 0 2 4 6 8 10 12 18 Creatinine 0.7 6.3 6.2 5.5 4.9 3.9 3.3 2.9 2.5 Hemoglobin 11.3 5.7 6.8 7.4 8.1 7.3 7.1 8.2 7.4 0 2 4 6 8 10 12 Chart 1
  26. 26. 182 176 35 30 34 53 76 96 123 106 196 170 777 727 304 235 180 167 145 121 0 100 200 300 400 500 600 700 800 900 0 20 40 60 80 100 120 140 160 180 200 Chart 2 Platelets LDH Day of
  27. 27. Course • A presumptive diagnosis of TTP/HUS was made and empiric plasmapheresis was started • Patient was not re-challenged with CFZ again • Plasmapheresis was continued while ADAMTS13 levels were pending • ADAMTS13 results (more than 50%) were available on day 10 and thus plasmapheresis was stopped after 5 sessions. • Patient never required dialysis and over the next week, his sCr started to improve with improving urine out
  28. 28. Biopsy • Patient underwent an ultrasound guided kidney biopsy one week after presentation, when platelets were greater than 65000/mm3 • Biopsy revealed glomerular and arteriolar TMA with mild ATN
  29. 29. • His hemoglobin, platelets, LDH and haptoglobin normalized over the next three weeks • 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 other causes of atypical HUS (e.g. CFH autoantibodies) was not done, though normal complement level and improvement in TMA argues against it.
  30. 30. Discussion • We postulate CFZ as a potential etiology of TMA • Discontinuation of CFZ along with supportive management was associated with renal recovery in our patient • This patient presented with AKI secondary to TMA associated with MAHA (elevated LDH, low haptoglobin and schistocytes on peripheral blood smear) and thrombocytopenia
  31. 31. • Causality is difficult to establish, • No other obvious cause of AKI including volume depletion, tumor lysis syndrome, active infection (sepsis) or presence of disseminated intravascular coagulation
  32. 32. • He was not exposed to any other therapeutic agents except CFZ, pomalidomide and dexamethasone two months before presentation and was in the middle of his second cycle. • Spontaneous recovery after discontinuation of CFZ and thus his presentation was unlikely to be TA-TMA.
  33. 33. Proposed Pathogenesis of Proteasome Inhibitor Associated Thrombotic Microangiopathy
  34. 34. Role of VEGF in TMA • VEGF inhibition has been proposed as one of the potential pathological factors responsible for TMA associated with AKI • VEGF is critical in maintenance and growth of normal vasculature • It is produced by podocytes in high concentration and is considered to diffuse across the GBM against the urinary flow and with its concentration gradient to bind to its receptors on glomerular endothelial cells Eremina, V., et al., VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med, 2008. 358(11): p. 1129- 36 Eremina, V. and S.E. Quaggin, Biology of anti-angiogenic therapy-induced thrombotic microangiopathy. Semin Nephrol, 2010. 30(6): p. 582-90
  35. 35. Role of VEGF in TMA • Podocytes and glomerular endothelial cells use VEGF-VEGF-R2 signaling for transmembrane communication, which is essential for structural and functional integrity of glomerular endothelium and fenestrations Clinicopathological spectrum of kidney diseases in cancer patients treated with vascular endothelial growth factor inhibitors: a report of 5 cases and review of literature Joichi Usui MD, PhDa,b, Ilya G. Glezerman MDc, Steven P. Salvatore MDa, Chandra B. Chandran MDd, Carlos D. Flombaum MDc, Surya V. Seshan MDa,⁎
  36. 36. Role of VEGF in TMA • Any disruption of this mechanism, – production (Proteasome inhibitors), – bevacizumab (anti-VEGF antibodies), – pazopanib (inhibits VEGF 1,2 and 3) and – sunitinib (VEGF tyrosine kinase inhibitor) can potentially lead to kidney damage specifically TMA and podocytopathy causing proteinuria and hypertension N Engl J Med 2008;358:1129-36.
  37. 37. Proteasome inhibitors effect VEGF pathways via NF-κB pathways
  38. 38. NF-κB • NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein involved in the regulation of genetic transcription • NF-κB activation is in response to various extracellular signals – reactive oxygen species, – TNFα – IL-1β, – bacterial polysaccharides – radiation
  39. 39. • IκB kinase (IKK) when activated by extracellular signals described above, cause phosphorylation of IκB leading to ubiquitination of IκB • After IκB degradation, NF-κB is free to enter the nucleus and influence DNA transcription • Increase in activity of NF-κB promotes VEGF expression Oscillations in NF-kappaB signaling control the dynamics of gene expression. Nelson DE1, Ihekwaba AE, Elliott M, Johnson JR, Gibney CA, Foreman BE, Nelson G, See V, Horton CA, Spiller DG, Edwards SW, McDowell HP, Unitt JF, Sullivan E, Grimley R, Benson N, Broomhead D, Kell DB, White MR. Science. 2004 Oct 22;306(5696):704-8. NF-kappaB promotes iNOS and VEGF expression in salivary gland adenoid cystic carcinoma cells and enhances endothelial cell motility in vitro. Zhang J1, Peng B Cell Prolif. 2009 Apr;42(2):150-61. doi: 10.1111/j.1365- 2184.2009.00588.x.
  40. 40. • Thus, proteasome inhibitors decrease NF-κB levels in nucleus leading to decreased VEGF production potentially predisposing to TMA Kiriakidis, S., et al., VEGF expression in human macrophages is NF-kappaB-dependent: studies using adenoviruses expressing the endogenous NF-kappaB inhibitor IkappaBalpha and a kinase-defective form of the IkappaB kinase 2. J Cell Sci, 2003. 116(Pt 4): p. 665-74. Shibata, A., et al., Inhibition of NF-kappaB activity decreases the VEGF mRNA expression in MDA-MB-231 breast cancer cells. Breast Cancer Res Treat, 2002. 73(3): p. 237-43. Greenberger, S., et al., Targeting NF-kappaB in infantile hemangioma-derived stem cells reduces VEGF-A expression. Angiogenesis, 2010. 13(4): p. 327-35.
  41. 41. • Acknowledgements: • Danielle G Holanda, MD • Department of Pathology, University of Iowa Hospitals and clinics.
  42. 42. Thank you

×