Figure 1.

Pathological features of AKI secondary to multiple myeloma. Abbreviations: THP, Tamm–Horsfall protein; FLCs, free light chains; MAPK, mitogen-activated protein kinases; NF-κB, nuclear factor-κB; IL-6, interleukin-6; MCP-1, monocyte chemoattractant protein-1; TGF-β1, transforming growth factor β1; NLRP3, NOD-like receptor family protein 3; IL-1β, interleukin-1β. Under normal conditions, FLCs are endocytosed by the cubilin–megalin complex in the proximal tubule cell. Almost all FLCs will ultimately degrade in lysosomes. However, mass-produced immunoglobulins and FLCs are present in the serum as a result of clonal proliferation of plasma cells, exceeding the renal tubular reabsorption capacity. The massive amount of FLCs will induce hydrogen peroxide and redox signaling, leading to the activation of proinflammatory pathways, such as MAPK and NF-κB. Then, the transcription of inflammatory and profibrotic cytokines, such as IL-6 and MCP-1, is initiated. In the distal tubule, FLCs can bind to Tamm–Horsfall protein to form casts that obstruct the tubules, which leads to tubular rupture and extravasation of Tamm–Horsfall protein. These effects lead to local inflammation, inflammatory cell infiltration, and migration around tubules, and even to atrophy of tubules. There are also postulations that the crystalline organization of casts participates in inflammation and giant cell reactions by activating NLRP3 and secreting IL-1β.