The ultrastructural basis of renal pathology in monoclonal gammopathies.

The kidney is frequently involved in the course of monoclonal gammopathies (MG). Renal involvement presents different clinical-morphological patterns, which can occur either at the onset or in a late phase of the hematological disease, as well as after chemotherapy. The reasons for the organ tropism of monoclonal immunoglobulins (Igs) are still unknown. Currently, it is well known that some primary structure alterations in monoclonal Igs and/or in their segments correlate to nephrotoxicity. On the other hand, it is impossible to predict the pathogenicity and the clinical manifestations induced by a specific monoclonal Ig based on its specific conformational modifications. Pathogenicity and organ tropism are probably complex phenomena, which involve specific protein factors, patient factors, target organ characteristics and monoclonal plasmacellular mass entities. However, aminoacidic sequence analysis of nephrotoxic Igs and some recent in vitro studies have allowed two different monoclonal light chain (LC) types to be distinguished. Glomerulopathic LCs (G-LCs) in the mesangium recognize their target structure and induce two distinct mesangiopathies, monoclonal Ig deposition disease (MIDD) and AL-amyloidosis (AL). Tubulopathic LCs (T-LCs) act on the proximal or on the distal tubule and cause, respectively, Fanconi syndrome (FS) and cast nephropathy. Pathogenic monoclonal Igs have the propensity to deposit in different renal parenchymal structures in extracellular sites, because of the transformation of soluble precursors in insoluble products. Evidence suggests that somatic mutations can destabilize the normal LCs globular soluble structure and this could be the major driving force for precipitation. Based on these features, MG can be classified as conformational and depositional diseases. Electronmicroscopy (EM) analysis of renal biopsies in MG patients with glomerular diseases distinguishes two morphological aspects. MIDD and a recently identified entity named proliferative glomerulonephritis (GN) with monoclonal IgG deposits are both characterized by non-organized granular electrondense deposits. AL, immunotactoid (IT) glomerulopathy and monoclonal cryoglobulinemia are, instead, characterized by organized deposits such as fibrils or microtubules. Tubular diseases in MG patients produce two different histological patterns. In FS, monoclonal Igs form crystals in the renal interstitium able to induce a local intense flogosis, while in cast nephropathy monoclonal Igs precipitate with Tamm-Horsfall protein (THP) in the proximal tubular lumen and induce tubular obstruction. The different morphological aspects are unrelated to specific clinical manifestations, while renal biopsy can diagnose different entities that can respond to different therapeutical schedules. This reveals the importance of the renal biopsy in the clinical management of the renal pathology in plasma cells dyscrasias, mainly when supported by the most advanced techniques of immunoelectronmicroscopy and polymerase chain reaction (PCR)-mediated analysis. Further elucidation of the molecular events involved in the pathogenesis of the different forms of renal damage is needed to design new and more effective therapeutical strategies. In particular, urinary proteomics seem to be promising in this setting.