Membranous nephropathy (MN) in very elderly patients frequently remains antigen-negative after routine testing, limiting diagnostic precision. Recently, serine protease high temperature requirement pr Show more
Membranous nephropathy (MN) in very elderly patients frequently remains antigen-negative after routine testing, limiting diagnostic precision. Recently, serine protease high temperature requirement protein A1 (HTRA1) has been identified as a novel MN autoantigen. Here, we focused on patients 80 years and older with MN and sought to systematically evaluate this association. Three cohorts of patients with MN were examined under institutional approval, including 157 consecutive all-age series of PLA2R/THSD7A/NELL1/EXT1-negative patients with MN typed by mass spectrometry; 54 PLA2R-negative MN in patients aged 80 years and older assessed by paraffin immunofluorescence; and 45 PLA2R-negative malignancy-associated patients with MN. HTRA1 positivity was determined by paraffin immunofluorescence and/or mass spectrometry. Clinical and histopathologic features were reviewed where available. Proportions were compared using Fisher's exact test. HTRA1 positivity was identified in 1.9% of patients with PLA2R/THSD7A/NELL1/EXT-negative MN, 22.2% of patients 80 years and older, and 6.7% of patients with PLA2R-negative malignancy-associated MN. Compared with the all-age antigen-negative cohort, HTRA1 positivity was significantly enriched in patients aged 80 years (relative risk 11.6; 95% confidence interval 3.4- 39.7). Across all 18 HTRA1-positive cases, mean age was 81.5, 66.7% were male, and 83.3% had nephrotic-range proteinuria. HTRA1 is a common autoantigen in PLA2R-negative MN among very elderly patients, occurring in approximately one in five cases aged 80 years or more. These findings support inclusion of HTRA1 testing in diagnostic evaluation of antigen-negative MN in patients 80 years and older and suggest the existence of an age-linked MN subtype. Show less