Half of patients with multiple myeloma develop kidney failure, which represents the second leading cause of death in this condition. A majority has cast nephropathy. Work from this laboratory has demonstrated the cause of cast nephropathy, which relates to the immunoglobulin light chain interacting with Tamm-Horsfall protein, which is made in the kidney. Although typically progressive, cast nephropathy is potentially reversible. Even with chemotherapy, circulating monoclonal light chains often remain elevated for months after initiation of treatment. This proposal will define the molecular interactions between these proteins and lead to new treatments that prevent this important complication of myeloma.