Light Chains, Casts, Sheets and Fibrils

Abstract

Immunoglobulin (Ig)-mediated kidney disorders can be divided into those that result from deposition into the kidney of intact Ig molecules and those caused by components of Ig molecules—usually light chains or light chain fragments, and, less frequently, heavy chains or heavy chain fragments. In the intact Ig disorders, such as IgA nephropathy, membranous nephropathy, lupus nephritis, and anti–glomerular basement membrane disease, the Ig molecules are typically polyclonal and deposit either as pre-formed immune complexes or interact directly with kidney antigens. In contrast, in the disorders caused by Ig components, the pathogenic protein is usually produced by a clonal population of plasma cells or B lymphocytes and thus is monoclonal. Monoclonal light chains can impair kidney function in a variety of ways: (1) by depositing into the glomerular basement membrane and/or tubular basement membranes as in light-chain deposition disease, (2) by forming casts within tubular lumens as in myeloma cast nephropathy, (3) by directly injuring proximal tubule epithelial cells as in Fanconi syndrome, and (4) by forming fibrils high in -pleated sheet content that deposit in the basement membranes, mesangium, interstitium and vessels, as in light-chain (AL) amyloidosis. The subject of this Moving Points in Nephrology series is disorders associated with monoclonal Ig-mediated kidney disease and immunotactoid/fibrillary glomerulopathy. One might wonder why immunotactoid/fibrillary glomerulopathy is included in the series when, in this entity (or group of entities), the Ig component of the fibrils often appears not to be monoclonal and, in many cases, the fibrils contain intact Ig molecules rather than simply light chains or heavy chains. However, the fibril-forming capacity of the pathogenic protein(s) makes the disorder similar in an important respect to AL amyloidosis, and the morphologic uniformity of the fibrils within individual patients, as well as the presence of a lymphoproliferative disorder in some patients, raises the question of whether a monoclonal component is a critical factor in the formation of the fibrils. Although clearly not established, it is plausible that the apparent polyclonality of immunotactoid/ fibrillary glomerulopathy results from incorporation of Ig molecules into a fibril that has a monoclonal “core.”