There are several separate conditions designated as MGRS which are associated with kidney damage (either directly or indirectly) due to monoclonal immunoglobulins (M proteins). Most kidney diseases associated with MGRS are glomerular disorders. AL amyloidosis is an immunoglobulin light chain associated amyloidosis that involves the deposition of misfolded amyloid light chain (AL) immunoglobulins. These AL light chains are misfolded leading to the disordered deposition of amyloid multimers and fibrils in the glomeruli and blood vessels of the kidney. Other types of amyloidosis related MGRS disorders include heavy chain amyloidosis (deposition of only heavy amyloid chains in the kidney)(AH) and heavy and light chain amyloidosis (AHL)(deposition of heavy and light chains). Amyloidosis is the most common form of MGRS, with the AL subtype being the most common type. Extra-renal manifestations, such as heart failure, gastrointestinal symptoms, secondary neuropathy (carpal tunnel syndrome), liver involvement and peripheral neuropathy are very common with amyloidosis related MGRS. Light microscopy findings in AL, AH or AHL amyloidosis include acellular deposits in the glomeruli and blood vessels that stain pale eosinophilic, Congo red positive and the presence of apple green birefringence on polarized light. Findings on electron microscopy include non-branching fibrils randomly arranged with thickness of 7-14 nm. Light chain proximal tubulopathy (LCPT) involves light chains with mutations of the hydrophobic residues of the variable domain causing them to have resistance to proteolysis; this causes the light chains to form intracytoplasmic aggregates in the proximal tubule of the nephron. Light microscopy findings in LCPT include proximal tubular swelling with electron microscopy findings showing proximal tubule light chain crystals or lysosomal inclusions. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) involves monoclonal immunoglobulins (usually IgG) depositing in the glomeruli and activating compliment leading to glomerular inflammation. Light microscopy shows a membranoproliferative, endocapillary proliferative or membranous glomerulonephropathy with electron dense deposits in the glomeruli being present on electron microscopy. The lesions stain positive for the Ig (usually IgG) as well as compliment; leading to granular immunofluorescent deposits in the mesangium and glomerular basement membrane. Monoclonal immunoglobulin deposition disease (MIDD) involves light chains with unusual characteristics of the variable domain (such as a positive charge, abnormal glycosylation, hydrophobic residues) depositing in the tubular, vascular or glomerular basement membranes of the nephron. These immune deposits activate TGF-β which leads to matrix accumulation and remodeling of the mesangium. The heavy chain variant of MIDD occurs when a deletion of the first constant domain of immunoglobulin heavy chains renders them unable to bind to light chains to form a complete immunoglobulin; the heavy chains are then deposited in the glomeruli. On light microscopy MIDD is seen as a nodular glomerulosclerosis with thickening of the tubular basement membrane with linear deposits along the glomerular, tubular vascular basement membranes seen on immunofluorescence. C3 glomerulopathy is characterized by glomerular deposits of C3 compliment protein (with scant or absent Ig immunoglobulin deposits) due to mutations or inhibition of compliment regulatory proteins causing dysregulation of the alternative complement pathway. C3 glomerulopathy presents in light microscopy as mesangial proliferative, membranoproliferative or endocapillary proliferative glomerulonephritis. Unlike other causes of MGRS, the monoclonal immunoglobulins in C3 glomerulopathy are not deposited in the kidney nor do they directly cause kidney damage. In C3 glomerulopathy monoclonal immunoglobulins inhibit factor H (a compliment regulatory protein) causing uninhibited activation of the alternative compliment pathway and C3 deposition in the kidneys. Cryoglobulinemic glomerulonephritis is characterized by glomerular involvement in those with cryoglobulinemia. In light microscopy it presents as a membranoproliferative or endocapillary proliferative glomerulonephritis with intracapillary monocytes and immune deposits that stain positive for PAS. On immunofluorescence the deposits consist of monoclonal light and heavy chains (most commonly IgG) and compliment. Immunofluorescence can help distinguish the various subtypes of cryoglobulinemic glomerulonephritis. In a subtype of cryoglobulinemic glomerulonephritis known as crystalglobulinemia; monoclonal immunoglobulins may precipitate in the small arterioles and capillaries of the glomeruli when exposed to colder temperatures causing endothelial injury and microthrombi.
Monoclonal gammopathy of renal significance
Monoclonal gammopathy of undetermined significance
Familial renal amyloidosis
AL amyloidosis
Secondary systemic amyloidosis
Myeloma cast nephropathy
Haemodialysis-associated amyloidosis
AA amyloidosis