Why are LCs toxic to the kidney?
Kidney injury is principally related to the LC component of myeloma because, unlike Igs, LC are freely filtered at the glomerulus and reabsorbed in the proximal tubule. Under normal conditions only small amounts of LC are filtered and reabsorbed, but in myeloma the amount of LC may rise to extreme levels that overwhelm the capacity and function of the proximal tubular cell (and induce proximal tubular injury) and pass to the distal tubule where they interact with uromodulin (Tamm-Horsfall protein) to form insoluble casts that obstruct the tubule, rupture the basement membrane, and induce an inflammatory response.
Recent data suggest that the cysteine residues present at the N and C termini of the FLC-binding domain are linked through an intramolecular disulfide bridge, which places the two histidine residues in close proximity to permit potential ionic interaction with the CDR3 domain of FLC. Capitalizing on this observation, a study analyzed this interaction and showed that the secondary structure and key amino acid residues on the CDR3 of the FLCs were critically important determinants of the molecular interaction with Tamm–Horsfall glycoprotein. These findings permitted the development of a strongly inhibiting cyclized competitor peptide. When used in a rodent model of cast nephropathy, this cyclized peptide construct inhibited cast formation and the associated functional manifestations of AKI in vivo. However, not all LC are toxic, and some patients can excrete large quantities without AKI. Specific molecular variants of the LC molecule form specific forms of kidney injury, such as myeloma cast nephropathy or amyloidosis.
