An Update on the Classification & Pathologic Diagnosis of MGRS Lesions

Updated: Jun 7

SEMINARS IN NEPHROPATHOLOGY

By Dr. Pravir Baxi

Key points:

Monoclonal Gammopathy of Renal Significance (MGRS)

Defined as: plasma cell and B-cell clonal proliferative disorders that produce nephrotoxic monoclonal immunoglobulin (Ig) but do not meet classic hematological criteria for treatment
Term includes MGUS, Smoldering MM, Waldenstrom macroglobulinemia, CLL, and other B-cell lymphoproliferative disorders
MGRS lesions are governed by the physicochemical properties of the monoclonal Ig
Not every patient with monoclonal gammopathy + kidney disease has MGRS
The following clinical scenarios should raise suspicion for MGRS and warrant further investigation with kidney biopsy if feasible:
Monoclonal gammopathy and unexplained kidney disease
CKD attributed to common risk factors but presenting with an atypical clinical course
Monoclonal gammopathy and kidney disease in patients <50 years

Pathomechanisms of MGRS

MGRS-associated Renal Lesions: International Kidney and Monoclonal Gammopathy Research Group (IKMG) Categorization 2019

Monoclonal Ig deposits
Organized structure
Fibrillar: Ig related amyloidosis, Monoclonal fibrillary GN
Microtubular: Immunotactoid GN, Cryoglobulinemic GN type 1 & 2
Inclusions or crystalline deposits: Light chain proximal tubulopathy, Crystal storing histiocytosis, (Cryo) crystalglobulin GN
Non-organized structure: Monoclonal Ig deposition disease (MIDD), Proliferative GN and monoclonal Ig deposits (PGNMID), Miscellaneous (monoclonal membranous, anti-GBM, HSP)
No monoclonal Ig deposits
C3 GN with monoclonal gammopathy
TMA with monoclonal gammopathy

Pathologic Evaluation for Suspected MGRS

Definitive diagnosis of MGRS requires a kidney biopsy
Immunofluorescence (IF) on frozen tissue which will establish the diagnosis of MGRS
Light and electron microscopy (LM, EM) help determine the specific MGRS lesion
Limitations: 1) Lack of tissue/technology (LM, IF, EM), 2) IgG subtype staining needed, 3) Monoclonal Ig can be masked, truncated or very sparse
Ancillary techniques to establish pathologic diagnosis of MGRS
IF on paraffin tissue (instead of frozen tissue) after antigen retrieval by a protease
Valuable salvage method that is more sensitive for certain MGRS lesions and may be needed for lesions with masked deposits (e.g. membranous-like GN with masked IgG kappa deposits)
Helpful in non-renal complications of paraprotein diseases (e.g. paraprotein-induced crystalline keratopathy)
IF staining for IgG subtypes
Helps support monoclonality of IgG+ LC restriction and aids in differentiating amongst the MGRS lesions
Only works with frozen tissue and it alone does not provide definitive evidence for monoclonality
Laser microdissection/mass spectrometry
Useful in a subset of patients with renal amyloidosis
Not clinically validated for non-amyloid MGRS lesions
Immunoelectron microscopy