Validation of a newly proposed histopathological classification in Japanese patients with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis

Abstract

Background: A new histopathological classification of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis was recently proposed. We evaluated the predictive value of this classification for renal outcome in Japanese patients.

Methods: We enrolled 122 patients with ANCA-associated glomerulonephritis diagnosed at several institutions in Japan between January 2000 and March 2010. Twenty patients were excluded because of observation durations of <1 year, and/or because their biopsy specimens contained <10 glomeruli. Renal biopsy specimens were categorized into four classes according to the proposed classification. We evaluated the predictive value of immunohistochemical staining for α-smooth muscle actin (SMA), Wilm's tumor 1 (WT1), CD68, and cytokeratin for end-stage renal disease (ESRD).

Results: The study population included 54 men and 48 women. Age, estimated glomerular filtration rate (eGFR), and proteinuria were 66.3 ± 11.3 years, 21.6 ml/min. and 1.10 g/24 h, respectively. Eighty-six patients were positive for myeloperoxidase-ANCA, five were positive for proteinase 3-ANCA, and 11 were negative for both antibodies. Median follow-up time was 41.0 months. Twenty-three patients (22.5%) developed ESRD during the follow-up period. Twelve patients died during follow up; 7/12 patients developed ESRD before death, and 5/12 patients died without ESRD. The incidence of ESRD increased with sequential categories: focal, 2/46 (4.3%); crescentic, 9/32 (28%); mixed, 8/18 (44%); and sclerotic, 4/6 (67%). The focal class had the best renal survival and the sclerotic class had the worst renal survival (p < 0.001). Kaplan-Meier renal survival analysis was similar to that of the new classification system proposal. In the multivariate analysis, the classification system tended to be a prognostic factor for ESRD (p = 0.0686, crescentic, mixed and sclerotic vs. focal, hazard ratio (HR) [95% confidence interval, CI]; 2.99 [0.61-22.7], 5.04 [1.11-36.4] and 9.93 [1.53-85.7], respectively). α-SMA-positivity also tended to be associated with ESRD (p = 0.1074).

Conclusion: The new histopathological classification was associated with eGFR at 1 year and tended to be associated with ESRD in our Japanese cohort with ANCA-associated glomerulonephritis. α-SMA positivity might be an additional prognostic factor for ESRD.

Figure 1

Association between histopathological class and eGFR. eGFRs at diagnosis and 1 year after diagnosis were higher in the focal class than in the other classes. There were no significant differences in eGFR among the crescentic, mixed, and sclerotic class. Abbreviations: eGFR, estimated glomerular filtration rate; blank circles, median values; error bars, interquartile ranges. *p < 0.05, **p < 0.01, and ***p < 0.001 (post hoc analysis).

Figure 2

Renal survival during follow up. Overall, 23/102 patients developed ESRD during the total follow-up period. Renal survival was best in the focal class and worst in the sclerotic class. There was no significant difference between crescentic and mixed class regarding renal survival.

Figure 3

Comparison of renal survival according to α-SMA expression in crescentic and mixed classes. (A) Tissue section showing absence of α-SMA staining in a normal glomerulus, except in the glomerular vascular pole and thickened Bowman’s capsule. (B) Tissue section showing marked α-SMA expression in a normal glomerulus, suggesting activation of a mesangial cell. (C) Higher α-SMA positivity tended to be associated with poor renal survival. Abbreviation: SMA, smooth muscle actin.