Dysproteinemias and Glomerular Disease

Abstract

Dysproteinemia is characterized by the overproduction of an Ig by clonal expansion of cells from the B cell lineage. The resultant monoclonal protein can be composed of the entire Ig or its components. Monoclonal proteins are increasingly recognized as a contributor to kidney disease. They can cause injury in all areas of the kidney, including the glomerular, tubular, and vascular compartments. In the glomerulus, the major mechanism of injury is deposition. Examples of this include Ig amyloidosis, monoclonal Ig deposition disease, immunotactoid glomerulopathy, and cryoglobulinemic GN specifically from types 1 and 2 cryoglobulins. Mechanisms that do not involve Ig deposition include the activation of the complement system, which causes complement deposition in C3 glomerulopathy, and cytokines/growth factors as seen in thrombotic microangiopathy and precipitation, which is involved with cryoglobulinemia. It is important to recognize that nephrotoxic monoclonal proteins can be produced by clones from any of the B cell lineages and that a malignant state is not required for the development of kidney disease. The nephrotoxic clones that do not meet requirement for a malignant condition are now called monoclonal gammopathy of renal significance. Whether it is a malignancy or monoclonal gammopathy of renal significance, preservation of renal function requires substantial reduction of the monoclonal protein. With better understanding of the pathogenesis, clone-directed strategies, such as rituximab against CD20 expressing B cell and bortezomib against plasma cell clones, have been used in the treatment of these diseases. These clone-directed therapies been found to be more effective than immunosuppressive regimens used in nonmonoclonal protein-related kidney diseases.

Light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits is associated with a high detection rate of the pathogenic plasma cell clone

“…nephropathy); activation of the alternative pathway of complement (APC) (e.g., C3 glomerulopathy or thrombotic microangiopathy associated with monoclonal gammopathy); autoantibody activity (e.g., C3 glomerulopathy and monoclonal membranous glomerulopathy); and cytokine activation (e.g., POEMS syndrome-polyneuropathy, organomegaly, endocrinopathy, monoclonal plasmaproliferative disorder, skin changes). [1][2][3][4][5][6][7][8][9][10][11][12] Aside from myeloma cast nephropathy and Waldenström's macroglobulinemic glomerulopathy, which result from high tumor mass, 13,14 most MIgassociated renal lesions, which were recently classified as monoclonal gammopathy of renal significance (MGRS) lesions, are governed by the physicochemical properties of the pathogenic MIg rather than the proliferation rate or tumor burden of the clones that produce them. 4,15,16 Due to their small molecular weight, Ig LCs are freely filtered through the glomerular filtration barrier and may produce specific tubular injury (e.g., myeloma cast nephropathy, LC proximal tubulopathy).…”

Emerging role of clinical mass spectrometry in pathology

“…The pathogenesis of ITG is largely unknown, and treatment depends on the underlying haematological process 80. In pathology, ITG is characterised by proliferative glomerulonephritis pattern by LM, monotypic IgG (>90% cases) with κ or λ light chain restriction and C3 staining by IF, and protein deposits defined by microtubular structure with distinct hollow centres measuring 10–90 nm in diameter deposited in organised, parallel arrays in the mesangium, subendothelial and subepithelial space of the glomeruli by EM 63 81. LMD-MS confirmed the presence of monotypic immunoglobulins, and the activation of classical and terminal pathways of complement as C3 and C4 was identified in ITG cases 80.…”

Fibrillary Glomerulopathy with a High Level of Myeloperoxidase-ANCA: A Case Report

“…FGN can present morphologically with varying patterns of glomerular injury, including crescent formation. In FGN, the mesangial proliferative glomerulonephritis pattern is seen in as many as 70% of the cases [10], and the endocapillary proliferative glomerulonephritis, segmental membranous nephropathy, and diffuse sclerosing glomerulonephritis patterns are also recognized. Crescent formation is common and has been observed in 17-31% of patients [4,7,11].…”