Paraprotein-Related Kidney Disease: Glomerular Diseases Associated with Paraproteinemias

Abstract

Paraproteins are monoclonal Igs that accumulate in blood as a result of abnormal excess production. These circulating proteins cause a diversity of kidney disorders that are increasingly being comanaged by nephrologists. In this review, we discuss paraprotein-related diseases that affect the glomerulus. We provide a broad overview of diseases characterized by nonorganized deposits, such as monoclonal Ig deposition disease (MIDD), proliferative GN with monoclonal Ig deposits (PGNMID), and C3 glomerulopathy, as well as those characterized by organized deposits, such as amyloidosis, immunotactoid glomerulopathy, fibrillary GN, and cryoglobulinemic GN, and rarer disorders, such as monoclonal crystalline glomerulopathies, paraprotein-related thrombotic microangiopathies, and membranous-like glomerulopathy with masked IgGκ deposits. This review will provide the nephrologist with an up to date understanding of these entities and highlight the areas of deficit in evidence and future lines of research.

Keywords: Amyloidosis; Immunoglobulin G; Kidney Glomerulus; Paraproteinemias; Paraproteins; Thrombotic Microangiopathies; amyloidosis; cancer; cryoglobulinemia; fibrillary glomerulonephritis; glomerular disease; glomerulonephritis; immunotactoid glomerulopathy; light chain deposition disease; multiple myeloma; nephrotic syndrome.

Figure 1.

Histopathology of monoclonal Ig deposition disease (MIDD). Nodular glomerulosclerosis is the most common light microscopic appearance in MIDD. (A) (Jones methenamine silver) shows two glomeruli, which are markedly enlarged by mesangial nodule formation. The silver–positive mesangial matrix is admixed with pink silver–negative deposits, and there is prominent mesangial proliferation. Magnification, ×200. (B) Periodic acid–Schiff (PAS) staining shows the deposits of MIDD to be strongly PAS positive. This staining profile helps in differentiating MIDD from amyloidosis, where deposits are PAS pale and Congo red positive. Magnification, ×400. (C) Immunofluorescence in MIDD shows diffuse linear staining of all basement membranes in the kidney, including glomerular and tubular basement membranes and often, vessel wall myocyte basement membranes. The mesangial nodules are also seen to strongly stain with the deposited paraprotein (κ-light chain). Magnification, ×200. (D) Electron microscopy shows the characteristic punctate, powdery electron–dense deposits lining the inner surface of the glomerular basement membrane. In contrast, these granular deposits typically form along the outer surface of the tubular basement membranes (not shown). Magnification, ×20,000.

Figure 2.

Histopathologic features of proliferative GN with monoclonal IgG deposits (PGNMID). PGNMID can show a wide range of patterns of proliferation, and the case pictured here shows a membranoproliferative pattern. (A) Shows a glomerulus with nearly circumferential involvement by a crescent. The glomerular mesangium is expanded by glassy eosinophilic deposits, which are also thickening glomerular basement membranes and associated with endocapillary proliferation hematoxylin and eosin (H&E). Magnification, ×400. (B) Periodic acid–Schiff staining highlights segmental duplication of the glomerular basement membranes (arrow). Immunofluorescence reveals strong granular positivity for IgG and κ but no significant staining for λ. Magnification, ×400. (C) Staining for IgG subtypes 1–4 reveals strong staining for IgG3, but it is negative for the other IgG subtypes (not shown). Magnification, ×400. (D) Electron microscopy shows prominent subendothelial deposits without evidence of substructure. Magnification, ×6000.

Figure 3.

Light microscopy and immunofluorescence findings in light chain amyloidosis and fibrillary GN. (A) Hematoxylin and eosin (H&E) shows a glomerulus with prominent mesangial infiltration by amorphous eosinophilic material consistent with amyloid. Extensive involvement of the interstitium surrounding the glomerulus is also present. Magnification, ×400. (B) Immunofluorescence staining reveals abundant chunky deposits with λ-light chain restriction involving the glomeruli and surrounding interstitium. Fibrillary GN can have a wide range of light microscopic appearances. Magnification, ×400. (C) (Jones methenamine silver stain) shows mesangial expansion and segmental glomerular capillary infiltration by nonargyrophilic deposits characteristic of fibrillary GN. Mesangial areas also show mild segmental proliferation of mesangial cells. Before making the diagnosis of fibrillary GN, amyloidosis should be excluded by showing negative Congo red or thioflavin staining. Magnification, ×600. (D) Immunofluorescence staining in fibrillary GN typically shows smudgy deposits that stain for IgG. Most fibrillary GN will stain for both κ- and λ-light chains (not pictured); however, a minority of patients may show light chain restriction. Unlike amyloidosis, extraglomerular deposits are unusual in fibrillary GN. Magnification, ×400.

Figure 4.

Comparison of electron microscopy findings in paraproteins with organized fibrillar deposits. (A) Shows the thin, randomly oriented nonbranching fibrils characteristic of amyloidosis that typically have a mean diameter ranging between 8 and 12 nm. (B) In fibrillary GN, the randomly oriented fibrils are often admixed with granular electron–dense deposits and typically thicker than amyloid fibrils, with a mean diameter usually between 16 and 24 nm. (C) Shows microtubular deposits characteristic of immunotactoid glomerulopathy. In contrast to the random orientation of fibrils in amyloidosis and fibrillary GN, the microtubules of immunotactoid glomerulopathy are often bundled and stream together in parallel arrays. In this case, the tubules measure approximately 50 nm in diameter; however, the mean diameter of microtubules of immunotactoid glomerulopathy may vary substantially, ranging from 10 to 90 nm. The deposits of cryoglobulinemic GN can range in appearance from microtubular (as pictured in [D]) to being amorphous granular electron–dense deposits showing no well developed substructure. Scale bars, 200 nm.