Revisiting proliferative glomerulonephritis with monoclonal immunoglobulin deposits through immunoglobulin repertoire sequencing

Abstract

Introduction: Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is classified within the spectrum of monoclonal gammopathy of renal significance (MGRS). However, PGNMID features an unexpected low rate of detectable monoclonal gammopathy, questioning the reality of an underlying clonal disorder in most cases.

Methods: We reviewed a cohort of 56 patients with PGNMID focusing on hematological characteristics. To detect discrete underlying clones, we used a highly sensitive high-throughput immunoglobulin (Ig) repertoire sequencing assay from RNA bone marrow (RACE-RepSeq). We also challenged the monoclonality of kidney deposits using immunofluorescence with antibodies specific for light chain (LC) variable region subgroups.

Results: RACE-RepSeq detected a bone marrow clone corresponding to the deposited Ig in only 23% of the whole cohort. As previously reported, PGNMID-IgG3 was the predominant subtype (41/56, 73%), with an over-representation of IgG3 kappa deposits (33/56, 59%). The low prevalence of clonal disorders was driven by PGNMID-IgG3 cases, with only 4/41 (9.8%) patients showing an IgG3-secreting bone marrow clone by RACE-RepSeq. In all seven clone-negative PGNMID-IgG3 kappa cases studied by immunofluorescence with anti-LC variable domain antibodies, glomerular deposits stained for all tested Vκ subgroups, ruling out their monoclonal nature. Compared to control individuals, immunoglobulin repertoire analyses in 24 patients without a detectable clone failed to detect any bias toward the deposited isotype, but showed increased IgG1 representation, suggesting an infectious trigger.

Conclusions: Our results suggest that PGNMID is a heterogeneous condition. The predominant subtype most often involves oligoclonal or polyclonal production of nephrotoxic IgG3 and may not derive from a clonal B-cell disorder. Such cases should no longer be classified as MGRS.

Keywords: B-cell repertoire; RNA; immunoglobulin sequencing; kidney biopsy; mass spectrometry monoclonal gammopathy of renal significance; next-generation sequencing; proliferative glomerulonephritis with monoclonal immunoglobulin deposits.