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Abstract: SA-PO136

Bortezomib Increases ER Stress in Myeloma-Associated Glomerulopathy

Session Information

Category: Onconephrology

  • 1600 Onconephrology

Author

  • Dai, Dao-Fu, The University of Iowa Hospitals and Clinics Department of Pathology, Iowa City, Iowa, United States
Background

Kidney involvement by multiple myeloma (MM) is associated with worse prognosis. The success of Bortezomib, a proteosome inhibitor has been a major breakthrough in the treatment of MM patients and it is believed to have a nephroprotective effect. Bortezomibis induces ER stress to kill myeloma cells, but its role in myeloma-associated glomerulopathy is unclear.

Methods

Using MM mice carrying IL-6 Tg with concomitant Tg of i-Myc with deregulated expression of the Myc and enhancers in the IgH locus (designated IL6/Myc mice), we compared the glomerulopathy before and after treatment with 50 mg/kg single dose of Cyclophosphamide (C), Cyclophosphamide + Bortezomib at 1 mg/kg at Day 1 and 4 (BC), Cyclophosphamide + TUDCA molecular chaperone 3 doses/ week for 4 weeks (CT), or TUDCA (T) only.

Results

IL6/Myc mice developed MM at 3-6 months, characterized by significant paraproteinemia, splenomegaly and bone involvement. The presence of splenomegaly is well correlated with glomerulopathy, characterized by glomerular capillary IgM. Kappa monoclonal deposits and segmental membranoproliferative glomerulonephritis (MPGN) pattern of injury. High magnification EM showed that some of the deposits have repetitive structures, suggestive of cryoglobulinemic glomerulonephritis. Compared with pre-treatment biopsy, post-treatment kidney pathological examinations show substantial improvement in glomerulopathy in IL6/Myc mice treated with C or CT. In contrast, mice treated with BC or T show significant progression of glomerulopathy, assessed by endocapillary hypercellularity, the extent of deposits and intracapillary “hyaline /cryo-plugs”. The worsening of glomerulopathy in BC-treated kidneys is associated with increased markers of ER stress and Integrated Stress Response ATF4.

Conclusion

IL6/Myc multiple myeloma mice showed excellent chemotherapy response to Cyclophosphamide treatment. Surprisingly, the addition of Bortezomib to Cyclophosphamide significantly worsened myeloma-associated glomerulopathy, likely due to increased ER stress induced by Bortezomib. Reduction of ER stress by TUDCA by itself was not effective. However, reduction of ER stress by TUDCA in combination with Cyclophosphamide showed the best kidney protective effect. Our findings suggest that Bortezomib does not have a direct nephroprotective effect. An alternative nephroprotective strategy may need to be developed to ameliorate myeloma-associated kidney diseases.

Funding

  • NIDDK Support