β2-microglobulin amyloid deposition and the RAGE-related inflammation pathway in ligamentum flavum thickening among patients undergoing hemodialysis: a comparative cross-sectional study from Japan.

STUDY

DESIGN

A comparative cross-sectional study using histological, biochemical, and molecular analyses of ligamentum flavum (LF).

PURPOSE: To investigate whether LF hypertrophy in hemodialysis (HD) patients is associated with β2-microglobulin (B2M) amyloid and advanced glycation end-product (AGE) deposition, along with the receptor for AGE (RAGE)-related inflammatory activation.

OVERVIEW OF LITERATURE: Lumbar spinal canal stenosis (LSCS) is common in HD patients. Although B2M amyloid is a hallmark of dialysisrelated amyloidosis, the role of the AGE-RAGE axis in LF pathology remains unclear.

METHODS

LF tissues from 33 patients with LSCS (HD, n=16; non-HD, n=17) were analyzed. Amyloid deposition was evaluated using direct fast scarlet (DFS) staining and B2M immunohistochemistry. Pentosidine and carboxymethyl-lysine (CML) levels were quantified by high-performance liquid chromatography in subsets (n=6 per group). Expression of RAGE-related inflammatory genes was measured using quantitative reverse transcription-polymerase chain reaction. Comparisons were made between the HD and non-HD groups, paired comparisons of DFS-stained areas on the dorsal and ventral sides of LF were performed within the HD group.

RESULTS

B2M amyloid deposition was observed exclusively in LF of HD group and predoninated dorsally (29.7%±8.6% vs. 11.9%±6.9%, p=0.001). Pentosidine levels were significantly higher in HD group than in non-HD group (28.5±10.6 μg/g vs. 16.1±4.2 μg/g, p=0.009), whereas CML levels didn't differ. On the dorsal side of LF, all examined RAGE-related inflammatory genes except toll-like receptor 4 was significantly upregulated in HD group; ventral expression showed no group differences. Immunohistochemical analysis demonstrated localized expression of RAGE, high-mobility group box 1, and nuclear factor-kappa B surrounding amyloid deposits.

CONCLUSIONS

LF in HD patients exhibits B2M amyloid and AGE accumulation with upregulation of RAGE-related inflammatory genes and proteins, especially on the dorsal side. LF hypertrophy in dialysis-related LSCS appears to represent an inflammatory-amyloid phenotype, indicating the AGE-B2M-RAGE pathway as a potential therapeutic target.