Diagnostic and Therapeutic Aspects of Monoclonal Gammopathies of Renal Significance (MGRS): An Update

Abstract

Monoclonal gammopathy of renal significance (MGRS) refers to a group of renal disorders caused by a monoclonal immunoglobulin (MIg), secreted by a non-malignant B-cell clone. Unlike overt multiple myeloma or B-cell proliferation, MGRS does not meet those diagnostic criteria. However, it is associated with significant morbidity, due to severe renal, and sometimes systemic, lesions induced by the MIg. Early recognition is crucial, as chemotherapy to suppress MIg secretion often improves outcomes. The spectrum of renal diseases in MGRS is broad, including both well-known conditions like AL amyloidosis and newly described lesions. Kidney biopsy is essential to determine the specific lesion associated with MGRS and assess its severity. Diagnosis involves integrating morphologic alterations using techniques such as light microscopy, immunofluorescence (IF), electron microscopy, and, in some cases, IF staining for Ig isotypes, immunoelectron microscopy, and proteomic analysis. Additionally, a complete hematologic evaluation, including serum and urine protein electrophoresis, immunofixation, and a serum-free light-chain assay, is necessary.

Keywords: chronic kidney disease; light-chains; lymphoproliferative disorders; monoclonal gammopathies; paraprotein-related renal disease; renal biopsy.

Figure 1

Localization of renal lesions in monoclonal gammopathy of renal significance (MGRS). Renal lesions associated with MGRS can include one or more renal compartments. In immunotactoid glomerulonephritis, C3 Glomerulopathy, and Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits (PGNMID), MGRS-associated lesions affect only the glomeruli, whereas in light-chain proximal tubulopathy (LCPT), the lesions involve only the proximal tubules. MGRS-associated lesions in cryoglobulinemic glomerulonephritis mainly involve the glomeruli, but can occasionally affect blood vessels (intravascular cryoglobulins or endovascular Ig-related vasculitis). Amyloidosis and monoclonal immunoglobulin deposition disease (MIDD) usually affect all renal compartments (glomeruli, vessels, and tubule-interstitium).

Figure 2

Pathogenesis of renal damage induced by light-chains in monoclonal gammopathy of renal significance (MGRS).

Figure 3

Histological lesions on renal biopsy in monoclonal gammopathy of renal significance (MGRS). Renal lesions associated with MGRS are firstly categorized according to the presence or absence of monoclonal immunoglobulin deposits on renal biopsy. These lesions are further divided based on the ultrastructural characteristics of the deposits, which can be either organized or unorganized. Organized deposits are further classified as fibrillar, microtubular, or inclusions or crystals. HCDD, heavy-chain deposition disease; LCDD, light-chain deposition disease; LHCDD, light- and heavy-chain deposition disease.

Figure 4

AL amyloidosis. (A) Glomerulus characterized by mesangial expansion due to accumulation of hypocellular material, weakly silver-positive (yellow arrows) [Silver-Methenamine, ×200]. (B) Accumulation of Congo-red-positive acellular material (black arrows) [hematoxylin eosin, ×200]. (C) Positive immunofluorescence for lambda-type light-chains with a homogeneous, predominantly mesangial pattern (white thin arrows) (×200). (D) On high magnification at the ultrastructural level, presence of fibrillar material, mainly in the mesangial area [electron microscopy, ×46,000].

Figure 5

Light-chain proximal tubulopathy (LCPT). (A) Numerous proximal tubules showing cytoplasm filled with weakly PAS-positive protein material (black arrows) [hematoxylin eosin, ×200]. (B) Diffuse intracytoplasmic protein inclusions (black arrows) in proximal tubules [PAS, ×200]. (C) Positive diffuse immunofluorescence for tubular intracytoplasmatic kappa-type light-chains (white thin arrows) [×100]. (D) On high magnification at the ultrastructural level, amorphous granular accumulation, sometimes in crystalline form, of light-chains within the proximal tubular cells (red arrows); increased volume of lysosomes with a speckled appearance (yellow thin arrows) [electron microscopy, ×46,000].

Figure 6

Monoclonal immunoglobulin deposition disease (MIDD). (A) Glomerulus with lobulated appearance, endocapillary hypercellularity, and presence of PAS-positive mesangial nodules (black arrow) [PAS, ×200]. (B) Glomerulus with lobulated appearance, endocapillary hypercellularity, double contours of the basement membranes, fibrous crescent (white thin arrow), and silver-positive mesangial nodules (white thick arrow) [Silver-Methenamin, ×200]. (C) At immunofluorescence, deposits of kappa light-chains at the glomerular level (homogeneous and linear mesangial along the capillary basement membranes) (white thick arrows) and along the tubular basement membranes (linear) (white thin arrows) [×200]. (D) On high magnification at the ultrastructural level, electron-dense deposits with “salt and pepper” appearance on the external side of the tubular basement membranes (black arrows). IS, interstitial space; TL, tubular lumen [electron microscopy, ×46,000].

Figure 7

Proliferative Glomerulonephritis with Monoclonal IgG Deposits (PGNMID). (A) A Glomerulus with lobulated appearance and presence of a mesangial nodule (black arrow), which is strongly PAS-positive [PAS, ×200]. (B) Glomerulus with lobulated appearance and numerous double contours of the basement membranes (black thick arrows) associated with cellular interposition (membrane-proliferative pattern). There is also an increase in the matrix and mesangial cellularity [Trichrome, ×400]. Presence of double contours, cellular interposition, and jaline deposits (black thin arrow) in the thickness of the membranes [Trichrome, ×1000]. (C) At immunofluorescence, ribbon-like IgG deposits along the glomerular basement membranes [×400]. (D) On high magnification at the ultrastructural level, subendothelial electron-dense deposits (white arrows). CL, capillary lumen; GBM, glomerular basement membrane; US, urinary space [electron microscopy, ×46,000].

Figure 8

Diagnostic algorithm for hematologic disease if renal biopsy shows renal lesions related to monoclonal gammopathy of renal significance (MGRS).