A case of IgG-type heavy chain amyloidosis with membranous nephropathy-like changes with long-term survival

Abstract

We performed a kidney biopsy on a 68-year-old man with 2.6 g/day proteinuria. Immunofluorescence (IF) study showed a positive finding of IgG (IgG1) along the glomerular capillary wall, suggesting membranous nephropathy. However, electron microscopy showed no subepithelial electron dense deposits and amorphous deposits of 8-12 nm fibrillar structure, and positive DFS/Congo red staining confirmed the diagnosis of amyloidosis. Amyloid deposits were localized only in the glomeruli. No overt extrarenal amyloid lesions were identified. Serum and urine were positive for monoclonal IgG-lambda, but IF was negative for kappa and lambda, ruling out AL-amyloidosis. At 75 years of age, he underwent a second kidney biopsy, and the IgG-positive findings at IF became more pronounced, with progressive glomerular sclerosing lesions. A proteomic analysis was performed focusing on the positive IgG finding in IF. The amyloid was proven to be composed of fragments of a heavy chain variable region sequence. AH-amyloidosis was the final diagnosis. He was treated according to the treatment for AL-amyloidosis, but hemodialysis was started at the age of 81, and died at the age of 86. We report a valuable case of AH-amyloidosis with an observed long-term prognosis.

Keywords: AH amyloidosis; Laser microdissection; Liquid chromatography‐tandem mass spectrometry (LMD/MS); Proteomic analysis.

Fig. 1

Pathological findings of the first biopsy. Periodic acid-Schiff (PAS) staining revealed diffuse capillary wall thickening and focal mesangial expansion in the glomeruli (a; × 400). Periodic acid methenamine silver (PAM) staining showed membrane thickening with spike formation (red arrow) (b; × 400). Amyloid deposits were positive for Congo red staining (c; × 400) and showed apple-green birefringence (yellow dotted circle) under polarized light (d; × 400). Congo red staining; amyloid deposits were characterized as being confined to the glomerular lesions (e; × 100). Immunohistological stains showed that there appeared to be a predominance of lambda chain compared to kappa chain (f and g; × 400 each). h: Immunofluorescence was positive for immunoglobulins (Ig)G and IgG1, whereas but negative for IgA, IgM and complement components (C3, C4, and C1q).i: Electron microscopy was negative for electron dense deposits in tthe subepithelial region, but positive for randomly arranged fibrils in the mesangial region, subendothelial, region and intramembranous regions that were 10 nm in diameter

Fig. 2

Pathological findings of the second biopsy. Light microscopy revealed that amorphous amyloid lesions identified by PAS, PAM, and Congo red staining showed considerable progression in the glomerular capillary walls (a, b, c; × 400). Congo red staining shows that the tubulointerstitial tubules are negative despite their damage (d; × 50). Immunofluorescence was positive for immunoglobulins (Ig)G and IgG1, as well as the first biopsy (e, f; × 400). Imunohistological findings were negative for kappa and lambda light chains (g-j; × 200)

Fig. 3

LC–MS/MS analysis of the extracted amyloid fibril proteins identified several amino acid sequences denoted by red letters, which were highly homologous to the Ig heavy chain variable region (VH3 sub group) [https://www.uniprot.org/uniprotkb/P01764/entry]. FR: framework region, CDR complementarity-determining region

Fig. 4

Clinical course of the patient