Proliferative Glomerulonephritis With Hidden Monotypic IgG3κ Deposits: A Case Report

Rare cases of immunoglobulin G (IgG)-dominant immune complex–mediated glomerulonephritis demonstrate immunoglobulin subclass restriction without light chain restriction. Some of these cases may represent proliferative glomerulonephritis with monotypic immunoglobulin deposits (PGNMID) in which monotypic immunoglobulin is obscured by coexisting polytypic immunoglobulin. However, rigorous demonstration of this possibility is lacking to date. Here, we describe a case of IgG3-restricted immune complex–mediated glomerulonephritis without light chain restriction that apparently “transformed” into IgG3κ-PGNMID in a subsequent biopsy. We demonstrate, using several ancillary techniques, including use of the newly described antibodies directed against the conformational epitope at the junctions of heavy and light chains (HLC-IF), that the first biopsy likely represents IgG3κ-PGNMID in which monotypic IgG3κ was hidden by polytypic IgM. This case underscores the need to consider PGNMID in a differential diagnosis of IgG-dominant immune complex–mediated glomerulonephritis without light chain restriction and highlights the potential utility of IgG subclass staining and HLC-IF in such cases to detect monotypic immunoglobulin that may be obscured by coexisting IgM and/or IgA deposits. Rare cases of immunoglobulin G (IgG)-dominant immune complex–mediated glomerulonephritis demonstrate immunoglobulin subclass restriction without light chain restriction. Some of these cases may represent proliferative glomerulonephritis with monotypic immunoglobulin deposits (PGNMID) in which monotypic immunoglobulin is obscured by coexisting polytypic immunoglobulin. However, rigorous demonstration of this possibility is lacking to date. Here, we describe a case of IgG3-restricted immune complex–mediated glomerulonephritis without light chain restriction that apparently “transformed” into IgG3κ-PGNMID in a subsequent biopsy. We demonstrate, using several ancillary techniques, including use of the newly described antibodies directed against the conformational epitope at the junctions of heavy and light chains (HLC-IF), that the first biopsy likely represents IgG3κ-PGNMID in which monotypic IgG3κ was hidden by polytypic IgM. This case underscores the need to consider PGNMID in a differential diagnosis of IgG-dominant immune complex–mediated glomerulonephritis without light chain restriction and highlights the potential utility of IgG subclass staining and HLC-IF in such cases to detect monotypic immunoglobulin that may be obscured by coexisting IgM and/or IgA deposits. Proliferative glomerulonephritis with monotypic immunoglobulin deposits (PGNMID) is characterized by the presence of immunoglobulin class, subclass, and light chain–restricted (monotypic) glomerular deposits, usually IgG3 subclass with κ light chain (IgG3κ).1Nasr S.H. Markowitz G.S. Stokes M.B. et al.Proliferative glomerulonephritis with monoclonal IgG deposits: a distinct entity mimicking immune-complex glomerulonephritis.Kidney Int. 2004; 65: 85-96Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar Rare cases of idiopathic IgG-dominant immune complex–mediated glomerulonephritis not otherwise specified (ICGN-NOS) demonstrate IgG subclass restriction without light chain restriction. It has been suggested that some of these cases may represent PGNMID in which the monotypic immunoglobulin is obscured by co-deposits of polytypic immunoglobulin; however, to date, there is no direct evidence to support this hypothesis.2Hemminger J. Nadasdy G. Satoskar A. Brodsky S.V. Nadasdy T. IgG subclass staining in routine renal biopsy material.Am J Surg Pathol. 2016; 40: 617-626Crossref PubMed Scopus (27) Google Scholar,3Miller P. Xiao A.Y. Kung V.L. et al.Progression of proliferative glomerulonephritis with monoclonal IgG deposits in pediatric patients.Pediatr Nephrol. 2021; 36: 927-937Crossref PubMed Scopus (7) Google Scholar In fact, there is evidence to the contrary, since some cases of IgG3-restricted ICGN-NOS without restricted light chain staining demonstrate both IgGκ and IgGλ deposition using antibodies directed against the conformational epitope at the junction of the heavy and light chain constant regions (HLC-IF) and, therefore, are unlikely to be PGNMID with hidden monotypic IgG3 deposits.4Nasr S.H. Fidler M.E. Said S.M. Koepplin J.W. Altamirano-Alonso J.M. Leung N. Immunofluorescence staining for immunoglobulin heavy chain/light chain on kidney biopsies is a valuable ancillary technique for the diagnosis of monoclonal gammopathy-associated kidney diseases.Kidney Int. 2021; 100: 155-170Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar We describe a unique case with serial kidney biopsies that initially showed ICGN-NOS and subsequently demonstrated PGNMID with IgG3κ deposits. Using HLC-IF, we demonstrate that the first biopsy also contained PGNMID in which monotypic IgG3κ was obscured by coexistent polytypic IgM deposits. This case illustrates the potential value of IgG subclass staining and HLC-IF in cases of IgG-dominant ICGN-NOS,2Hemminger J. Nadasdy G. Satoskar A. Brodsky S.V. Nadasdy T. IgG subclass staining in routine renal biopsy material.Am J Surg Pathol. 2016; 40: 617-626Crossref PubMed Scopus (27) Google Scholar,3Miller P. Xiao A.Y. Kung V.L. et al.Progression of proliferative glomerulonephritis with monoclonal IgG deposits in pediatric patients.Pediatr Nephrol. 2021; 36: 927-937Crossref PubMed Scopus (7) Google Scholar especially in the presence of unequal light chain staining and coexisting IgM and/or IgA deposits. A patient in their 50s with hypertension, diabetes, and hypothyroidism presented with acute on chronic kidney injury accompanied by gross hematuria. The patient had a history of former tobacco use and no family history of kidney disease. There was no history of skin lesions or peripheral neuropathy. Laboratory evaluation demonstrated a serum creatinine concentration (Scr) of 3.1 mg/dL (increased from a baseline of 2.6 mg/dL), 24-hour urine protein of 1.1 g, and serum albumin of 3.2 g/dL. Serologic evaluations showed negative or normal antinuclear antibody, serum C3, C4, anti–streptolysin O, hepatitis B surface antigen, anti-neutrophil cytoplasmic antibody, and anti–glomerular basement membrane antibody. Kidney biopsy contained 14 glomeruli for light microscopy, 3 of which were globally sclerotic. The remaining glomeruli demonstrated mild mesangial hypercellularity, accompanied by focal endocapillary hypercellularity by mononuclear leukocytes and neutrophils. Five glomeruli demonstrated cellular crescents. Tubular atrophy and interstitial fibrosis involved ∼50% of the cortex, accompanied by patchy mononuclear interstitial infiltrates. Vessels demonstrated moderate arteriosclerosis, without arteritis. Immunofluorescence (IF) demonstrated global mesangial and glomerular capillary wall staining for IgG (3+), accompanied by IgM (2+), C3 (2+), C1 (2+), and κ (3+) and λ (2+ to 3+) light chain in a similar distribution (Fig 1). No extraglomerular immune deposits were seen. Ultrastructural examination revealed abundant mesangial and subendothelial electron-dense deposits and rare small subepithelial electron-dense deposits without organized substructure. No secondary causes of ICGN were identified and the pathologic diagnosis was ICGN-NOS. The patient was treated with oral prednisone and mycophenolate mofetil, followed by stabilization of Scr at ∼2 mg/dL after 3 months. However, the patient developed varicella-zoster virus infection, necessitating treatment with intravenous acyclovir and valacyclovir and discontinuation of immunosuppression. Serologic evaluation performed at the time of infection demonstrated small IgMλ in serum with normal serum free light chain ratio and no M-protein in the urine. The patient’s Scr continued to rise (peaking at 6.20 mg/dL), requiring hemodialysis. A second kidney biopsy performed 1 month after the time of infection and 8 months after the first contained 21 glomeruli for light microscopy, including 3 with global sclerosis. The remaining glomeruli demonstrated diffuse mesangial and endocapillary hypercellularity by mononuclear leukocytes. Six glomeruli demonstrated crescents, including 3 cellular and 3 fibrocellular. Tubular atrophy and interstitial fibrosis involved 70% of the cortex. Vessels showed moderate arteriosclerosis without arteritis. IF demonstrated global mesangial and glomerular capillary wall staining for IgG (3+), accompanied by C3 (2+), C1 (1+), and κ light chain (2+); λ light chain was negative. IgG subclass staining demonstrated IgG3 in a similar distribution (3+), with negative staining for IgG1, IgG2, and IgG4. The first biopsy was re-stained for IgG subclasses and demonstrated staining for IgG3 (3+), with negative staining for IgG1, IgG2, and IgG4. Ultrastructural examination demonstrated abundant mesangial and subendothelial electron-dense deposits. No subepithelial deposits or organized substructures were seen. Repeat conventional IF and pronase IF for IgG and κ and λ light chain confirmed the results of initial IF in both biopsies, with no “unmasking” of λ light chain staining in the second biopsy. In addition, mass spectrometry of laser-capture microdissected glomeruli from both biopsies failed to demonstrate higher intensity for κ or λ light chain compared to normal glomeruli (log fold change <1; P > 0.05), despite numerical enrichment for IgG3 (log fold increase 4.6; P > 0.05; Item S1), likely owing to the sparsity of the glomerular deposits and contamination from serum. In addition, HLC-IF for IgG κ and λ light chain was performed (Fig 2). This showed IgGκ staining (2+) in both biopsies with negative staining for IgGλ, confirming the presence of monotypic IgG3κ in both biopsies. Furthermore, HLC-IF for IgMκ and IgMλ in the first biopsy demonstrated staining (1+ to 2+) for both IgMκ and IgMλ. Taken together, these findings are consistent with IgG3-PGNMID in which concurrent polytypic IgM obscured the presence of monotypic IgG3κ in the first biopsy. Following the second biopsy, the patient continued on dialysis. Bone marrow biopsy performed 1 month after the second biopsy demonstrated normocellular marrow with no evidence of lymphoma or plasma cell neoplasm. She received no additional therapy and died from cerebrovascular accident 10 months after the second biopsy. In this report, we describe a case of IgG3κ-PGNMID that was initially diagnosed as ICGN-NOS, most likely because the presence of monotypic IgG3κ was obscured by coexistent polytypic IgM deposits. Faced with the apparent “transformation” of polytypic IgG-dominant ICGN to IgG3-PGNMID in 2 consecutive biopsies, we considered several possibilities: (1) interpretative or technical errors in 1 or both biopsies; (2) “masking” of λ light chain in the second biopsy, as described in cases of membranoproliferative glomerulonephritis with “masked” monotypic immunoglobulin deposits5Larsen C.P. Messias N.C. Walker P.D. et al.Membranoproliferative glomerulonephritis with masked monotypic immunoglobulin deposits.Kidney Int. 2015; 88: 867-873Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar; (3) obscuring of monotypic IgG3κ by polytypic IgM in the first biopsy2Hemminger J. Nadasdy G. Satoskar A. Brodsky S.V. Nadasdy T. IgG subclass staining in routine renal biopsy material.Am J Surg Pathol. 2016; 40: 617-626Crossref PubMed Scopus (27) Google Scholar,3Miller P. Xiao A.Y. Kung V.L. et al.Progression of proliferative glomerulonephritis with monoclonal IgG deposits in pediatric patients.Pediatr Nephrol. 2021; 36: 927-937Crossref PubMed Scopus (7) Google Scholar; and (4) true transformation of ICGN with polytypic immune deposits into PGNMID, as reported in a few cases.6Kamal J. Khairallah P. Crew R.J. et al.Clinicopathologic assessment of monoclonal immunoglobulin-associated renal disease in the kidney allograft: a retrospective study and review of the literature.Transplantation. 2020; 104: 1341-1349Crossref PubMed Scopus (6) Google Scholar, 7Said S.M. Cosio F.G. Valeri A.M. et al.Proliferative glomerulonephritis with monoclonal immunoglobulin G deposits is associated with high rate of early recurrence in the allograft.Kidney Int. 2018; 94: 159-169Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 8Yu X.J. Hu N. Wang S.X. Zhou F.D. Zhao M.H. Membranoproliferative glomerulonephritis with deposition of monoclonal IgG evolved from polyclonal IgG: a case report with two consecutive renal biopsies.BMC Nephrol. 2019; 20: 275Crossref PubMed Scopus (7) Google Scholar To determine the most likely scenario, several ancillary studies were performed. Repeat conventional IF confirmed the initial findings, making technical or interpretive errors unlikely. Pronase IF failed to “unmask” immunoglobulin deposits. In addition, IgG subclass staining and HLC-IF for IgGκ and IgGλ demonstrated the presence of monotypic IgG3κ and polytypic IgM in the first biopsy. Mass spectrometry findings were noncontributory. Thus, in light of the second biopsy findings, these results indicate that the first biopsy most likely contained IgG3κ-PGNMID that was hidden by the coexisting polytypic IgM deposits (ie, “PGNMID with hidden monotypic immunoglobulin deposits”), as proposed by others but without substantive evidence to date.2Hemminger J. Nadasdy G. Satoskar A. Brodsky S.V. Nadasdy T. IgG subclass staining in routine renal biopsy material.Am J Surg Pathol. 2016; 40: 617-626Crossref PubMed Scopus (27) Google Scholar,3Miller P. Xiao A.Y. Kung V.L. et al.Progression of proliferative glomerulonephritis with monoclonal IgG deposits in pediatric patients.Pediatr Nephrol. 2021; 36: 927-937Crossref PubMed Scopus (7) Google Scholar In the present case, it is possible that IgM may have been trapped “nonspecifically” in the first biopsy owing to its large size and that immunosuppressive therapy following the initial biopsy may have led to attenuation of polyclonal IgM deposition in the second biopsy. These findings have several implications for the diagnostic approach to IgG-dominant ICGN-NOS, which is typically considered to be idiopathic.9Sethi S. Fervenza F.C. Membranoproliferative glomerulonephritis--a new look at an old entity.N Engl J Med. 2012; 366: 1119-1131Crossref PubMed Scopus (347) Google Scholar First, IgG subclass staining should be considered in cases of IgG-dominant ICGN-NOS with unequal light chain staining, especially in the presence of coexisting IgM and/or IgA, because these cases may represent PGNMID with hidden monotypic immunoglobulin deposits.2Hemminger J. Nadasdy G. Satoskar A. Brodsky S.V. Nadasdy T. IgG subclass staining in routine renal biopsy material.Am J Surg Pathol. 2016; 40: 617-626Crossref PubMed Scopus (27) Google Scholar,3Miller P. Xiao A.Y. Kung V.L. et al.Progression of proliferative glomerulonephritis with monoclonal IgG deposits in pediatric patients.Pediatr Nephrol. 2021; 36: 927-937Crossref PubMed Scopus (7) Google Scholar Second, this case highlights the utility of HLC-IF in detecting hidden monotypic immunoglobulin deposits that are obscured by coexisting polytypic immunoglobulin in cases with IgG subclass restriction. Third, this case highlights the need for careful work-up and interpretation of biopsies with IgG-dominant ICGN-NOS. Some of these cases may represent PGNMID with a hidden monotypic component (as shown in this case), while others may lack a monotypic component and therefore should not be diagnosed as PGNMID (as shown in cases reported by Nasr et al4Nasr S.H. Fidler M.E. Said S.M. Koepplin J.W. Altamirano-Alonso J.M. Leung N. Immunofluorescence staining for immunoglobulin heavy chain/light chain on kidney biopsies is a valuable ancillary technique for the diagnosis of monoclonal gammopathy-associated kidney diseases.Kidney Int. 2021; 100: 155-170Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar), or may represent evolution from another entity, such as C3 glomerulopathy.10Hou J. Markowitz G.S. Bomback A.S. et al.Toward a working definition of C3 glomerulopathy by immunofluorescence.Kidney Int. 2014; 85: 450-456Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar Further studies are necessary to determine the frequency of IgG subclass restriction and PGNMID with hidden monotypic immunoglobulin deposits in cases of apparent polyclonal IgG-dominant ICGN. Satoru Kudose, MD, Ibrahim Batal, MD, John Lucia, MD, Purvi Patel, MS, Rajesh K. Soni, PhD, Glen S. Markowitz, MD, Vivette D. D’Agati, MD, and M. Barry Stokes, MD. None. The authors declare that they have no relevant financial interests. We thank the Binding Site (Birmingham, UK) for gifting the HLC-IF reagents used in this study. We thank Yuancheng Wang at the Columbia Renal Pathology Laboratory for technical assistance with HLC-IF. The authors declare that this work was performed under the approval of the CUIMC Institutional Review Board and no personal identifying information is included. Received March 10, 2022. Evaluated by 2 external peer reviewers, with direct editorial input from the Pathology Editor, an Associate Editor, and a Deputy Editor. Accepted in revised form May 31, 2022. Download .pdf (.19 MB) Help with pdf files Supplementary File (PDF)Item S1: Detailed methods.