Managing light chain deposition disease.

In this issue of Leukemia and Lymphoma , Minarik and colleagues report three patients with renal biopsy-proven light chain deposition disease [1]. All three were treated with bortezomib and achieved hematologic responses with normalization of the free light ratio in all, a 50% reduction in proteinuria in all, and 50% reduction in creatinine in two of the three. Signifi cant neurotoxicity was seen requiring discontinuation of bortezomib in two. Th e renal manifestations associated with monoclonal immunoglobulin light chains are many. Th e most common occurs when an immunoglobulin light chain binds to a common site on Tamm-Horsfall protein, a glycoprotein secreted by the thick ascending limb of Henle loop. Aggregation of these protein complexes produces casts that obstruct tubule fl uid fl ow resulting in renal failure, so-called myeloma cast nephropathy [2]. IgM monoclonal proteins can bind to polyclonal IgG immunoglobulin resulting in immune complexes that can deposit in the kidney leading to proteinuria and an active urinary sediment. When immune complexes precipitate in the cold they are type II cryoglobulins. Occasionally, monoclonal immunoglobulin K chains can form crystalline deposits in the proximal renal tubule leading to the disruption of transport of glucose, uric acid, phosphorus and amino acids. Th e characteristic laboratory fi nding is amino aciduria and the complex is referred to as Fanconi syndrome. Th e loss of phosphorus in the urine and the resulting rise in parathyroid hormone leads to vitamin D-resistant rickets. Microscopic bone fractures are the presenting clinical manifestation [3]. Th ere are two renal disorders associated with monoclonal immunoglobulin light chains that result from protein misfolding. One is light chain amyloidosis where fragments of immunoglobulin light chain, usually λ or heavy chain, misfold into a β -pleated sheet confi guration. Th ese misfolded light chains are insoluble and deposit as fi brils in any tissue, with the kidney being the most frequently aff ected. Th e clinical manifestation is nephrotic range proteinuria. Th e other form of monoclonal immunoglobulin light chain deposition is usually associated with K light chains. Th is syndrome was fi rst described by Randall [4] and is referred to as light chain deposition disease, Randall type, in order to distinguish light chain deposition from light chain cast nephropathy. On renal biopsy, the characteristic glomerular lesion is nodular glomerulosclerosis, the lesions seen resemble diabetes mellitus. Free K light chains are found in the urine and serum. In contrast to amyloidosis which frequently presents with multi-organ involvement, most patients with K light chain deposition disease present with isolated renal involvement; although, there is some risk of cardiac or hepatic involvement. Th ere is always a monoclonal bone marrow plasma cell population which does not fulfi ll criteria for multiple myeloma. Th e deposits are granular and non-organized compared to the β -pleated sheets of amyloidosis [5]. Monoclonal immunoglobulin deposition disease occurs at a median age 15 years younger than patients with multiple myeloma and amyloidosis. Th ere is a preponderance of males. Treatment has focused on cytotoxic chemotherapy to suppress K