Light chains, casts, sheets and fibrils: monoclonal immunoglobulin diseases and immunotactoid/fibrillary glomerulopathy.

I mmunoglobulin (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.” Treatments for multiple myeloma and AL amyloidosis have progressed remarkably rapidly during the past decade, making these diseases particularly wellsuited for a series entitled “Moving Points.” In the article on multiple myeloma, Seema Singhal and Jayesh Mehta point out that the recent identification of three new therapeutic agents for this disease (thalidomide, lenalidomide, and bortezomib) has been associated with a substantial increase in median survival and has provided treatment options for the high proportion of patients who have disease relapse after an initial response to high-dose melphalan-based chemotherapy. AL amyloidosis, previously a nearly uniformly fatal disease, is now curable in a sizable proportion of patients with the use of myeloablative chemotherapy and autologous hematopoietic stem cell transplantation. Applying this treatment approach to AL amyloidosis may seem like an obvious extension of the experience using aggressive anti-plasma cell chemotherapy for multiple myeloma, a much more common disease. However, as described in the article by Vaishali Sanchorawala, the use of high-dose chemotherapy in systemic AL amyloidosis has unique challenges imparted by the substantial organ dysfunction present in individuals with this disease. Indeed, it is the treatment for those patients too ill to undergo high-dose chemotherapy with stem cell transplantation that is one of the current “moving Published online ahead of print. Publication date available at www.cjasn.org.