MO256: IGM in Fibrillary Glomerulopathy Linked to Monoclonal Gammopathy

Abstract BACKGROUND AND AIMS Fibrillary glomerulopathy (FGN) is a rare glomerular deposit disease accounting for less than 1% of annual native kidney biopsies. Its pathogenesis is still not fully understood. Immunofluorescence (IF) techniques in the vast majority of cases reveal the presence of smudgy polytypic IgG deposits associated with C3 and, anecdotally, of scarce IgM or IgA. The majority of cases are idiopathic, but up to one-third of patients may present with a secondary cause including monoclonal gammopathy, which in previously reported series ranged from 4% to 16% of the cases. The association of FGN and monoclonal gammopathy remains controversial, nonetheless monotypic cases in the absence of multiple myeloma, wäldestrom macroglobulinemia or high-grade lymphoma are currently included in the spectrum of monoclonal gammopathy of renal significance (MGRS). The aim of the study was to describe the role of IgM in FGN as a possible marker of an underlying MGRS. METHOD A single-center, retrospective and observational study of FGN cases diagnosed during the period of 2012–2019 was performed. Kidney biopsies were retrospectively reviewed. All cases had a confirmatory diagnosis made with electron microscopy (EM). Due to a lack of material and the novelty of the marker, DNAJB9 was not performed in all samples. IF on frozen tissue was done in all cases; digestion with proteinase K was done in cases of light chain restriction to unmask possible deposits. Demographics, clinical presentations, associated conditions and outcomes were reviewed. Data were expressed as mean standard deviation (SD). RESULTS Our cohort consisted of 17 patients, all but 2 caucasians, 9 males and 8 women, with a mean age of 63.1 ± 13.2. The mean follow-up was of 34.6 months. At the time of the diagnosis, most patients presented with hypertension 70% (12). All patients had proteinuria (mean 24-h protein excretion of 4.84 g ± 5.2) and renal impairment with a medium creatinine of 203.8 ± 202. Full nephrotic syndrome was present in 29% (5) of the cases and microhematuria in 52.9% (9); complement was normal in all cases. As for related medical conditions: 23% (4) had history of autoimmune diseases, 17% (3) had diagnosis of a solid tumor, 76.5% (13) were smokers (2 with diagnosed chronic obstructive pulmonary disease) and 29% (5) had diabetes mellitus. Monoclonal gammopathy was present in 35.3% (6/17) of the cases, all of which had an identified monoclonal component detected by electrophoresis with immunofixation (SPEPE/SIF). Three of them (50%) progressed (2 to multiple myeloma, 1 to amyloidosis AL) (Fig. 1). Light microscopic study showed three distinct patterns of glomerular injury, being mesangial pattern the most common 82% (14/17). Staining with congo red was negative in all cases, 17 cases. By immunofluorescence only 82% (13) showed glomerular positivity for IgG. Unexpectedly 23% (4) showed exclusively IgM deposits; three of them had monoclonal gammopathy. Looking in depth, 5/6 of the patients with monoclonal gammopathy showed IgM deposits in contrast to the non-associated FGN cases (3/10) (Fig. 2). No cases of GNF with IgM deposits had underlying cryoglobulinemia; there was one case of diabetes mellitus. A total of 41% (7) end up needing renal replacement therapy (RRT). No differences in the rate of RRT were observed between patients with monoclonal gammopathy and without. CONCLUSION IgM deposits were observed in patients with FGN cases associated with monoclonal gammopathy. IgM deposition is a finding rarely described in the literature up to the date. In this regard, we hypothesize that IgM monoclonal gammopathy due to a conformational alteration in the protein could generate deposits in the form of fibrils triggering a possible GNF. Thus, IgM deposition in the context of GNF could be a marker of a possible underlying MGRS. Future studies proving IgM conformational alterations in these patients could corroborate our hypothesis.