Hypercalcemia can potentiate the nephrotoxicity of Bence Jones proteins

Hypercalcemia is frequently observed in patients with multiple myeloma and renal failure. Whether Bence Jones protein (BJP) is directly nephrotoxic and how and whether hypercalcemia might contribute to this putative nephrotoxicity is currently unclear. To examine this issue, we studied the effect of modest hypercalcemia on the glomerular filtration rate (GFR) of rats exposed to a BJP that by itself had been found to be nonnephrotoxic. Three groups of rats were studied. All were anesthetized and underwent a baseline measurement of inulin clearance (C_in). After this, group 1 (n = 13) rats were given 2 ml of vehicle (phosphate-buffered saline solution [PBS]) and were then made hypercalcémie with an infusion containing 0.048 mol/L CaCl₂. At the end of 2 hours a second C_in was measured. Group 2 rats (n = 8) were given 100 mg BJP in 2 ml PBS and a non-calcium-containing infusate. Group 3 (n = 11) rats were given 100 mg of the BJP in 2 ml PBS and then the calcium-containing infusate used in group 1 rats. Rats in groups 2 and 3 also had a second C_in measured at the end of 2 hours. Renal blood flow was measured with an electromagnetic flow probe. At the completion of the second clearance, kidneys were processed for renal histologic assessment. The serum calcium level measured during the second C_in period was 13.5 mg/dl for group 1, 7.9 mg/dl for group 2, and 13.7 mg/dl for group 3. No significant decrement in GFR was observed in group 1 or 2 rats. In contrast, group 3 rats had a 46% fall in GFR. This decrement in GFR could not be ascribed to intratubular cast formation nor was it associated with a fall In RBF. These results indicate the presence of a unique interaction that may occur between hypercalcemia and the BJP, which results in nephrotoxicity much greater than that which would be predicted from the effect of either agent given alone.