PROTEASE RESISTANCE AND BINDING OF IG LIGHT-CHAINS IN MYELOMA-ASSOCIATED TUBULOPATHIES

Kidney tubule dysfunction and lesions are frequent complications of my eloma, related to unknown properties of the monoclonal light chain. We have analyzed protease sensitivity and binding properties of urinary light chains from four patients with Fanconi's syndrome, 12 with cast nephropathy, and four control patients without myeloma-associated tubu lopathy. All light chains were normal-sized, monomeric and/or dimeric, and none was N-glycosylated. Kinetic studies of light chain digestion by pepsin and the lysosomal enzyme cathepsin B showed the generation of a protease-resistant 12 kDa fragment, corresponding to the V domain of the kappa chain in the four Fanconi's syndrome patients; in two ou t of four the V domain was also completely resistant to trypsin. Weste rn and dot blots revealed similar patterns of reactivity of light chai ns from patients with the Fanconi's syndrome towards other light chain s. Properties of cast-nephropathy light chains were more heterogeneous but clearly differed from those of Fanconi's syndrome: (i) 9 out of 1 2 were of the lambda-type; (ii) only four yielded a transient 12 kDa f ragment after cathepsin B digestion, but all showed some resistance to proteolysis of the entire molecule or a fragment thereof to at least one protease, al variance with control light chains; (iii) they displa yed various patterns of reactivity with other light chains; (iv) 7 out of 12 reacted specifically with Tamm-Horsfall protein (THP) by ELISA, in contrast with those of Fanconi's syndrome. In one patient who pres ented with cast nephropathy and the Fanconi's syndrome, the tight chai n exhibited bath partial resistance of the V kappa domain to cathepsin B and the highest reactivity with THP. These results suggest that lig ht chain toxicity in Fanconi's syndrome is related to the resistance o f the V domain to degradation in lysosomes of proximal tubule epitheli al cells. In contrast, cast nephropathy is an heterogeneous entity who se pathogenesis may involve multiple factors such as protease resistan ce, in addition to light chain reactivity with THP.