Inflammation in Areas of Fibrosis Precedes Loss of Kidney Function in Lupus Nephritis

ABSTRACT Background Interstitial fibrosis in lupus nephritis (LN) is often infiltrated by immune cells but typically regarded as nonspecific “scar reaction.” This study aimed to investigate the relationship between inflammatory fibrosis and kidney disease progression in LN. Methods Interstitial fibrosis and tubular atrophy (IFTA) were scored in 124 LN kidney biopsies. Inflammation in areas of IFTA (i-IFTA) was graded 0-3 according to the Banff Classification of Allograft Pathology. Significant glomerular filtration rate (GFR) loss was defined as a decline of >15 ml/min at 3 years from biopsy. Immune cell phenotype was defined by serial immunohistochemistry (13-plex). Results IFTA was observed in 88/124 (71%) biopsies, and i-IFTA was identified in 76/88 (86%) cases. The distribution of i-IFTA grades was heterogenous across all IFTA grades. In patients with moderate-to-severe IFTA (>25%), the degree of i-IFTA was associated with a higher risk of significant GFR loss: 0/2 (0%), 1/3 (33%), 3/4 (75%), and 7/9 (78%) for i-IFTA grades 0, 1, 2, and 3, respectively (p = 0.028). Multiplexed histology revealed that i-IFTA was mostly composed of CD163+ macrophages and CD4 T cells, followed by CD8 T cells and granulocytes. Conclusion I-IFTA is frequently observed in LN and is dominated by macrophages and T cells. For patients with baseline IFTA >25%, the degree of i-IFTA emerged as a predictor of GFR loss. These data support the routine scoring of i-IFTA in LN due to its prognostic implications and nominate i-IFTA as a potential therapeutic target. LAY SUMMARY Scar tissue often contains immune cells, but we still do not fully understand their role. In lupus nephritis (LN), this is typically dismissed as “nonspecific inflammation”. However, our study analyzed kidney biopsies from 124 people with LN and found that inflammation in scarred areas may predict future kidney function loss. Specifically, we identified a type of immune cell, CD163+ macrophages, that may contribute to scarring and kidney damage. Our findings suggest that routinely assessing inflammation in scarred areas could help predict kidney health in LN patients and highlight a possible new target for therapies to prevent kidney damage.