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Abstract: FR-PO970

The Spectrum of Renal Involvement in Four Murine Models of Multiple Myeloma

Session Information

Category: Pathology and Lab Medicine

  • 1601 Pathology and Lab Medicine: Basic

Author

  • Dai, Dao-Fu, University of Iowa, Coralville, Iowa, United States
Background

Approximately 20-50% of multiple myeloma involves kidneys, and additional ~38% of monoclonal gammopathy involves kidney (MGRS). The renal manifestations range from tubulopathies to a spectrum of glomerular diseases that can present with varying degrees of proteinuria and renal dysfunction, to amyloidosis and myeloma cast nephropathy. Although several mouse models of multiple myeloma have been reported, the studies of murine models of myeloma-associated kidney diseases are rather limited.

Methods

We examined renal pathology of four murine models of multiple myeloma (MM): First, mice carrying a human IL-6 Tg driven by the major histocompatibility complex H2-Ld promoter (IL-6), Second, IL6-Tg with concomitant Tg of i-Myc with deregulated expression of the Myc oncogene and enhancers in the IgH locus (designated i-Myc/IL6), Third, IL6-Tg with concomitant Tg of pro-survival oncoprotein Bcl2 (designated Bcl2/IL6), Fourth, xenograft model with mouse myeloma cells injected into KaLwRij strain mice.

Results

All four models of MM demonstrated M-spike paraproteinemia. The presence of second transgene in the IL6-Tg background significantly accelerated and aggravated the tumor burden and progression of MM, which developed at 3-6 months, characterized by paraproteinemia, marked splenomegaly and bone involvement. Light-chain restricted casts with variable acute tubular injury resembling cast nephropathy was present in 50-75% of IL6, i-Myc/IL6 and in Bcl2/IL6 mice. Features suggestive of light chain tubulopathy were present in ~25-50% of these three models. Various glomerular deposits were identified in ~50% of Bcl2/IL6 and ~80% of i-Myc/IL6, but not in the IL6 mice. The spectrum of glomerular involvement ranged from light chain deposition disease to intracapillary paraprotein plugs resembling cryoglobulin or crystalglobulin glomerulopathy. Surprisingly, the xenograft model did not show any significant paraprotein nephropathy, however, myeloma cells infiltration of renal tissue was observed in ~30% of xenograft model. Amyloidosis is not identified in any of the mouse models.

Conclusion

Transgenic IL6 mice develop various paraprotein-associated nephropathies and may serve as good preclinical models of myeloma-associated kidney diseases, to study the molecular pathogenesis and to develop nephroprotective strategies for myeloma-associated kidney diseases.

Funding

  • Other NIH Support