Figure 1.

Proximal tubule toxicity of immunoglobulin free light chains (FLC). Once certain monoclonal FLCs with specific V region sequences^29,51, 52, 53, 54, 55 are endocytosed through the megalin/cubilin complex on the luminal surface of the proximal tubule, they are concentrated in the endolysosomal (L) system and promote cell injury. A large variety of FLCs produce proximal tubulopathy from the generation of oxidative stress and direct cytotoxicity (red arrows at left indicate proximal tubule segments with significant cellular injury). FLCs with κ restriction can specifically undergo homotypic polymerization to form crystals (red arrows at right), producing proximal tubule crystallopathy. Direct toxicity of these FLCs leads to lysosomal dysfunction and the clinical manifestations of Fanconi syndrome. The natural history of both conditions includes the clinical manifestations of progressive chronic kidney disease from tubule atrophy, interstitial inflammation, and interstitial fibrosis.