Amyloidogenic lambda Light Chain Renal Toxicity: Oxidative Stress Implicated.

The kidney is the most common organ involved in systemic light-chain amyloidosis (AL), seen in up to 40% of patients. Renal involvement can result in proteinuria and/or renal insufficiency. The mechanism of renal injury in amyloidosis remains unclear. We present data supporting a central role for oxidative stress in amyloid-induced renal damage. Soluble free light chains(LCs) were isolated from plasma of AL and myeloma patients obtained at the time of stem cell collection. LCs were purified by liquid-phase iso-electric fractionation of pooled plasma samples from each patient. Purified LC were incubated with cultured rat renal epithelial cells, both wild-type and heme oxygenase-1 (HO-1) over-expressing, for 16 hours. Macrophage chemoattractant protein-1 (MCP-1) induction was measured in the media by ELISA. LC from myeloma patients were used as negative controls. Significant induction of MCP-1, a sensitive indicator of oxidative stress, was seen in 4/5 patients with lambda light-chain amyloidosis and 0/4 kappa light-chain amyloidosis patients. Induction of MCP-1 was seen in only 1/8 myeloma patients tested (4 lambda and 4 kappa). Induction of MCP-1 was reduced in the presence of HO-1 overexpression, implicating oxidative stress as a critical pathway of toxicity of amyloidogenic lambda light chains in this system. These results suggest that lambda and kappa light chains may cause renal injury through distinct pathways in the kidney.