Nephrotoxicity of Bence Jones proteins in the rat: importance of protein isoelectric point.

Bence Jones proteins (BJP) were isolated from the urine of 12 patients with multiple myeloma and various degrees of renal dysfunction. Proteins were characterized as to type (six type lambda and five type kappa), isoelectric point (pI), and secondary structure by circular dichroism (CD). Clinical renal function was more impaired with type-lambda proteins and with proteins of pI greater than 5.7. CD studies distinguished kappa from lambda proteins in most cases but did not correlate with nephrotoxicity. Protein dimer preparations were tested for nephrotoxicity in aciduric, hydropenic, female, Sprague Dawley rats by following renal function and morphology over 6 hours after injection i.p. of 300 mg of protein. Twelve rats of urine pH less than 5.5 injected with four BJP of pI less than 5.7 showed a mean rise in SUN of 5.3 mg/dl and in creatinine of 0.06 mg/dl, compared with a mean rise of 28.0 mg/dl (SUN) and 0.75 mg/dl (creatinine) in 21 rats injected with seven BJP of pI greater than 5.7 (P less than 0.01). Seven sodium-bicarbonate-fed rats of urine pH greater than 8 injected with a BJP of pI 6.2 showed mean rise in SUN of 1.8 mg/dl and in creatinine of 0.01 mg/dl, compared with 19.3 mg/dl (SUN) and 0.55 mg/dl (creatinine) in 7 aciduric rats injected with the same BJP (P = 0.009). Morphologic and immunohistologic studies showed distal cast formation in 9 rats with acute deterioration in renal function. It is concluded that BJP of pI greater than urine pH are acutely nephrotoxic in the rat by a mechanism that may involve a charge interaction in the distal nephron.