Pathogenesis and Translational Perspectives in Myeloma-Associated Nephropathy

Kidney injury associated with the tubulointerstitial disease that occurs in multiple myeloma is a multi-factorial and potentially reversible process that centers on the monoclonal free light chain (FLC). FLCs promote kidney damage through mechanisms that include precipitation with uromodulin to initiate the formation of obstructing casts in the distal nephron and activation and injury to proximal tubule epithelium. These processes generate tubulointerstitial inflammatory and fibrotic pathways that lead to progressive kidney failure if not interrupted. Important predisposing factors include the physicochemical characteristics and the amount of the FLC present in the tubular nephron. Precipitating factors for the two lesions – cast formation and proximal tubulopathy - are also discussed. Current evidence shows both pathomechanisms can occur independently or synergize to promote kidney failure. This narrative review integrates obstructive cast formation and proximal tubulopathy to consider a unified translational therapeutic approach for myeloma kidney to improve outcomes in this devastating complication of multiple myeloma.