Myeloma kidney cast nephropathy in a rat model of multiple myeloma

Renal insufficiency occurs in some, but not all, patients with multiple myeloma, and Bence Jones proteinuria. Many of these patients are found to have a distinctive renal lesion characterized by distal nephron cast formation. It has been proposed that the specific Bence Jones protein (BJP) which is produced by a myeloma tumor may play an important role in the genesis of this cast nephropathy and that patients excreting BJPs with the highest isoelectric points (pI) are those most likely to develop this cast nephropathy. We have utilized a rat model of multiple myeloma to further evaluate the relationship between Bence Jones proteinuria and the development of myeloma cast nephropathy. This model employed immunoglobulin-secreting tumors obtained from a unique strain of rats in which they spontaneously develop. These tumors were transplanted to a homologous strain of rats and the effect on renal function and morphology in these rats was evaluated. Four different kappa light chain synthesizing tumors were studied. Following transplantation of the tumors, all rats were maintained on a diet designed to produce an acid urine (pH 5.5 to 6.0) and maximal urinary concentration (2000 to 3000 mOsm/kg). Among the rats excreting BJP of pI 6.7, 17 of 18 had virtually normal renal histology. Of the 15 rats with BJP of pI 7.6, 11 also had normal renal histology. However, 12 of 12 rats excreting BJP of pI 5.2 developed a distal nephron, light chain containing cast nephropathy. In the pI 4.3 group, 6 of 12 rats developed acute tubular necrosis, and the remaining six animals sustained a less severe lesion which was characterized by the presence of bland hyaline casts. The mean serum creatinine level obtained at the time of sacrifice was elevated (compared to that found in sham-operated controls) in the pI 5.2 group (P < 0.001) and the pI 4.3 group (P < 0.01) but not in the pI 6.7 or 7.6 groups. These results do not support the concept that cationic BJP's are more nephrotoxic than those that carry a more negative charge and indicate that other factors must determine the nephrotoxicity of a given BJP.