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AL amyloidosis is caused by the conversion of monoclonal immunoglobulin light chains into amyloid fibrillar aggregates that deposit in tissue and lead to organ dysfunction. Diagnosis is histological and relies primarily on non-invasive biopsies, showing Congo red-positive amorphous deposits containing immunoglobulin light chains, most commonly of lambda isotype. The clinical presentation is extremely polymorphous, due to the large number of organs that can be affected by the disease. The kidneys and the heart are most frequently involved organs, in about two thirds of patients each, responsible for nephrotic syndrome and restrictive cardiomyopathy. Treatment is based on chemotherapy aimed at eliminating the medullary clone producing the pathogenic monoclonal light chains. It is guided by risk assessment, based on the serum levels of cardiac biomarkers. Its effectiveness must be regularly assessed by the serum free light chain assay. Current reference regimens combine an alkylating agent, with high doses of dexamethasone and most often a proteasome inhibitor. They are effective in the majority of patients. The overall prognosis depends on the importance of the initial severity of organ involvement, particularly the heart, and is strongly influenced by the haematological response. The treatment must be rapidly modified in non-responders, especially in those with severe cardiac disease, with the introduction of immunomodulatory drugs and antibodies targeting plasma cells. However, effective therapies for patients with the more severe amyloid cardiopathy are an unmet need. Strategies directly accelerating the removal of amyloid deposits, despite disappointing preliminary results, could further improve the prognosis of this disease.

Cryoglobulins are circulating immunoglobulins that precipitate with cold temperature and dissolve with rewarming. Type 1 cryoglobulinemia is composed of a single monoclonal immunoglobulin and is associated with renal involvement in up to 40% of cases. Type 1 cryoglobulinemia is related to an underlying B-cell haematological malignancy in 60% of patients. In the remaining cases, in the absence of criteria for malignancy, the diagnosis of monoclonal gammopathy of renal significance should be established. The clinical and biological setting and histological features of type 1 cryoglobulinemia are globally similar to those of mixed cryoglobulinemia. In case of haematological malignancy, the treatment is guided by the nature of the underlying disease, and aims at inducing haematological remission, which is necessary for the renal response. The management of monoclonal gammopathy of renal significance has been clarified by an international consensus group and is based on the nature of the underlying clone. In case of monoclonal cryoglobulinemia associated with a plasma-cell clone (IgG or IgA), the treatment is based on the combination of bortezomib, cyclophosphamide and dexamethasone. In case of IgM monoclonal cryoglobulinemia, the treatment is similar to that of Waldenström macroglobulinemia, and is based on rituximab. The clinical course of renal monoclonal cryoglobulinemia is intimately associated with the haematological response, and is usually favourable.

The spectrum of glomerular disorders with organized immunoglobulin (Ig) deposits is heterogeneous. It encompasses 2 mains categories: glomerulopathies with fibrillary deposits are mostly represented by immunoglobulinic amyloidosis (most commonly AL amyloidosis, characterized by monoclonal light chain deposits often of the lambda isotype), and pseudo-amyloid fibrillary glomerulonephritis in which deposits predominantly contain polyclonal IgG4. Glomerulopathies with microtubular deposits include cryoglobulinemic glomerulonephritis (type I and type II, with or without detectable serum cryoglobulin) and glomerulonephritis with organized microtubular monoclonal Ig deposits (GOMMID) also referred to as immunotactoid glomerulopathy. Pathological diagnosis requires meticulous studies by light microscopy (with systematic Congo red staining), immunofluorescence with specific conjugates, and electron microscopy. Ultrastructural studies are required to differentiate amyloid fibrils (8 to 10 nm in external diameter), pseudo-amyloid fibrils (15-20 nm) and microtubules (10 to 50 nm in external diameter, with a central hollow core). Glomerular deposits in type I cryoglobulinemic glomerulonephritis are arranged into parallel straight microtubules similar to those observed in GOMMID, but with different topography that allows distinction between the two entities. Glomerular substructures composed of circulating Igs should be distinguished from collagen fibrils that are commonly observed in glomerular disorders with or without deposition of monoclonal or polyclonal Igs.

Monoclonal immunoglobulin (Ig) deposition disease (MIDD) is a rare complication of plasma cell disorders, defined by linear Congo red-negative deposits of monoclonal light chain (LCDD), heavy chain (HCDD) or both (LHCDD) along basement membranes. MIDD should be suspected in patients presenting with glomerular proteinuria and monoclonal gammopathy, but none of these criteria is necessary for the diagnosis although renal involvement is prominent. Since an abnormal serum κ/λ ratio is found in virtually all MIDD patients, including those with HCDD, serum free light chain assay should be included in the initial workup in patients older than 50 presenting with kidney disease. Bortezomib-based regimens are efficient and well tolerated, resulting in improvement in both renal and global survival, comparatively to historical series. High dose melphalan with autologous stem cell transplantation may be proposed as second line therapy in selected patients. The achievement of hematological response, based on the difference between involved and uninvolved serum free light chains (dFLC), is mandatory. In a recent series, post-treatment dFLC40mg/L was the major predictive factor of renal response and was associated with improvement of both renal and global survival. In MIDD, bortezomib-based therapy is safe and efficient when introduced early after diagnosis. dFLC response is a favorable prognostic factor for renal survival.

Glomerulonephritis with organized immunoglobulin deposits are heterogeneous and may be encountered in a variety of renal disorders. It is particularly important to determine the exact types of immunoglobulin deposited and their monotypy/monoclonality, using specific anti-light chain conjugates and in some instances, anti-heavy chain subclass conjugates. The histologic pattern and identification of monotypic Ig deposits in renal tissue are in some cases sufficient for the diagnosis of AL amyloidosis, type I cryoglobulinic glomerulonephritis or "Randall-type" monoclonal immunoglobulin deposition disease (MIDD). Electron microscopy is particularly valuable for the precise localization of Ig deposits and for determing the pattern of deposition: organized, homogeneous (non-organized or granular) or mixed. New entities in the broad spectrum of Ig deposition diseases are emerging from electron microscopy studies of renal diseases. We propose here a comprehensive classification for diseases featuring the organized deposition in tissues of Ig.