Javaugue, Vincent

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.

Abstract Proliferative glomerulonephritis (GN) with monoclonal immunoglobulin deposits (PGNMIDs) is a recently described entity among the spectrum of monoclonal gammopathy of renal significance (MGRS). The disease is renal limited and manifests with chronic glomerular disease, altered renal function and albuminuria, sometimes in the nephrotic range. Acute nephritic syndrome is rare. PGNMID occurs mostly in the sixth decade, but it may affect young adults. Histologically, PGNMID is characterized predominantly by membranoproliferative GN and less frequently by diffuse endocapillary GN, mesangioproliferative GN or atypical membranous GN. Immunofluorescence and electron microscopic studies are the cornerstone of diagnosis, showing granular deposits involving glomeruli only, and composed of monotypic immunoglobulin G (IgG), with a single heavy chain subclass (most commonly IgG3) and light chain (LC) restriction (usually κ), admixed with complement deposits. PGNMID variants with monotypic LC-only, IgA or IgM deposits are uncommon. Ultrastructurally, deposits are amorphous with predominant subendothelial and mesangial distribution. PGNMID should be distinguished from type 1 cryoglobulinemic GN and immunotactoid GN, which share some common pathological features. Contrary to other MGRS lesions, the rate of detection of the nephrotoxic monoclonal Ig in the serum or urine, and of an abnormal bone marrow B-cell clone, is only ∼30%. Renal prognosis is poor, with progression to end-stage renal disease in 25% of patients within 30 months and frequent early recurrence on the renal allograft. The pathophysiology of PGNMID is unclear and its treatment remains challenging. However, recent studies indicate that clone-targeted chemotherapy may significantly improve renal outcomes, opening future perspectives for the management of this rare disease.