Protease resistance and binding of Ig light chains in myeloma-associated tubulopathies. Kidney tubule dysfunction and lesions are frequent complications of myeloma, 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 tubulopathy. 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 K chain in the four Fanconi's syndrome patients; in two out of four the V domain was also completely resistant to trypsin. Western and dot blots revealed similar patterns of reactivity of light chains from patients with the Fanconi's syndrome towards other light chains. Properties of cast-nephropathy light chains were more heterogeneous but clearly differed from those of Fanconi's syndrome: (i) 9 out of 12 were of the A-type; (ii) only four yielded a transient 12 kDa fragment after cathepsin B digestion, but all showed some resistance to proteolysis of the entire molecule or a fragment thereof to at least one protease, at variance with control light chains; (iii) they displayed 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 presented with cast nephropathy and the Fanconi's syndrome, the light chain exhibited both partial resistance of the VK domain to cathepsin B and the highest reactivity with THP. These results suggest that light chain toxicity in Fanconi's syndrome is related to the resistance of the V domain to degradation in lysosomes of proximal tubule epithelial cells. In contrast, cast nephropathy is an heterogeneous entity whose pathogenesis may involve multiple factors such as protease resistance, in addition to light chain reactivity with THP. Kidney tubule alterations related to monoclonal immunoglobulin (Ig) light chains are frequent complications of myeloma (1 case out of 3) [1]. They often lead to end-stage renal failure and may thus be considered as severe prognosis factors. The most common form is myeloma cast nephropathy, in which characteristic lesions consist of tubular atrophy associated with the presence of dense fractured casts surrounded by macrophagic cells predominantly located in the lumina of distal tubules and collecting ducts [2]. Formation of these casts, which mainly contain the
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