Clinical Presentation

A 62-year-old male with hypertension and no known previous history of autoimmunity presents with a serum creatinine of 1.1 mg/dL, forehead rash , microhematuria, proteinuria with UPCR of 0.9 g/g, low complement levels (C3 39 mg/dL, C4 < 2 mg/dL), positive ANA (titer not available), anti-ribonucleoprotein, and anti-Smith antibodies, low kappa/lambda ratio of 0.13, and evidence of a monoclonal spike in serum and urine. ANCA, anti-dsDNA, anti-GBM, and anti-PLA2R serologies were negative. Serologies for hepatitis B and C and HIV were also negative. A kidney biopsy was performed.

Light Microscopy 

Figure 1: Most glomeruli are enlarged and have a lobulated appearance on H&E stain (A) with diffuse thickening of capillary walls, wire-loops, and double contours on silver stain (B).

Immunofluorescence Microscopy:

Immunofluorescence microscopy (3 glomeruli) performed on frozen tissue, reveals granular staining in the mesangium and capillary walls for IgG (3+), IgA (1-2+), IgM (1-2+), C3 (2-3+), C1q (2-3+), and lambda (3+) light chain (Figure 2A), without staining for kappa light chain (Figure 2B). Staining for IgG subclasses IgG1, IgG2, IgG3, IgG4 on frozen sections shows 3+ diffuse granular glomerular stain limited to IgG1 (Figure 3A-D). Immunofluorescence for kappa and lambda light chain performed on sections from the paraffin embedded tissue confirms positivity for lambda light chain without staining for kappa. There is no light chain restriction along tubular basement membranes, casts, or protein resorption droplets seen.

Figure 2. Immunofluorescence: positive lambda (A) but negative kappa light chain (B) in glomerular mesangial regions and capillary walls. (B).

Figure 3. Immunofluorescence for IgG subclasses shows strong IgG1 staining (A) and negative staining for IgG2, IgG3, and IgG4 (B-D) in glomeruli.

Electron Microscopy

On electron microscopy, the glomerular capillaries show diffuse thickening of the basement membranes with numerous electron dense deposits, mostly subendothelial (Figure 4A). The deposits show fibrillo-tubular parallel arrays, sometimes with vague fingerprint-like arrangement, with an average thickness of 16 nm (Figure 4B). Abundant mesangial deposits and endothelial cell tubuloreticular inclusions are also present. No deposits are identified in the tubular basement membrane . The podocytes show diffuse foot process effacement.

Figure 4. Electron microscopy shows numerous electron dense deposits, mostly subendothelial and mesangial (A), and the deposits exhibit fibrillo-tubular parallel arrays substructure (B).

Figure 5. Immunogold stain confirms localization of lambda light chains in the fibrils (A) but is negative for kappa light chain in the deposits (B).  

Final Diagnosis

Immune complex glomerulonephritis with full-house immune deposits and monoclonal IgG1-lambda deposits

Clinical follow up

The patient underwent bone marrow biopsy which showed normocellular bone marrow with 5-8% IgG lambda monoclonal plasma cell subset with phenotypic and genotypic abnormalities consistent with MGUS. Cytogenetic studies showed plasma cell dyscrasia with hyperdiploidy. The patient was treated with MMF with some clinical improvement but continued to have persistent proteinuria and low complement levels.

Discussion

Monoclonal gammopathy of undetermined significance (MGUS) affects 3.2% of the general population over the age 50 and 5.3% of people over the age of 70 years ¹. It carries 1% per year risk of progression to multiple myeloma (MM) and is associated with increased risk for other lymphoproliferative disorders, amyloidosis, and light chain deposition disease ^2,3. The findings of our case are somewhat unusual and difficult to fit in the current classification of monoclonal gammopathies or renal significance (MGRS). The lack of silver-negative amorphous deposits, the lack of linear staining pattern on IF, and the ultrastructural features effectively rule out AL amyloidosis and monoclonal light chain deposition disease. Many features of this case fit with proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID); however, most published cases of PGNMID in the literature do not include IgA and IgM deposits ^4,5. Additionally, the microtubular substructure of the deposits raise the possibility of monoclonal immunotactoid glomerulopathy (ITG). Although some cases of ITG can also show staining for IgA, IgM, and C1q, the diameter of the microtubules in ITG are generally significantly larger (20-37 nm) ⁶ than those of our case (12-23 nm). In this patient with history of rash with skin biopsy concerning for autoimmune disease, positive ANA, and low complements, the biopsy features described above are suggestive of lupus nephritis, but this patient does not meet clinical criteria for systemic lupus erythematosus (SLE).  Although the case does not fit into any currently recognized category of MGRS, given the monotypic deposits and patient’s clinical follow up confirming plasma cell dyscrasia, this case is best classified as MGRS.

An association of MGUS and autoimmune disease has been proposed, mostly based on retrospective studies

^7,8 but not confirmed by others ⁹. However, as the clinical follow up shows in this case, the finding of patients with near full-house staining but light chain restriction on IF, warrants further clinical work up, to evaluate for the presence of lymphoproliferative disorders and determine appropriate management.

References