Insights into proliferative glomerulonephritis with monoclonal immunoglobulin deposits – is it really monoclonal or not?

PURPOSE OF REVIEW: Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), is a disease defined by the presence of glomerulonephritis with nonorganized mono-isotypic immunoglobulin (Ig) deposits. This review will discuss the pathogenesis of PGNMID and address novel techniques for detection of monoclonal Ig and pathologic B-cell clones and for distinguishing monoclonal from oligoclonal Ig deposits. RECENT FINDINGS: Because of low detection rate of circulating monoclonal Ig and nephritogenic B-cell clones and emerging reports of PGNMID-IgG in children, it has been recently argued that many PGNMID-IgG3 cases may not be monoclonal lesions. A mass spectrometry-based method, serum matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry, has been shown to have superior sensitivity than immunofixation for detection of monoclonal Ig in PGNMID and other monoclonal gammopathy of renal significance (MGRS) lesions. Two novel sequencing techniques, RNA-based immunoglobulin repertoire sequencing and single-molecule real-time sequencing of monoclonal immunoglobulin, enable identification of the full-length variable sequence of monoclonal Ig, even in MGRS patients with low tumor burden and undetectable monoclonal Ig by conventional methods. Finally, staining of kidney biopsy for Ig light chain variable domain subgroups may allow for separation of true monoclonal from oligoclonal PGNMID. SUMMARY: Novel sequencing, mass spectrometry, and immunofluorescence techniques have the potential to increase the detection rate of nephritogenic monoclonal Ig/B-cell clone and distinguish monoclonal from oligoclonal deposits in PGNMID.