Macrophage pyroptosis in lupus nephritis – Novel insights into renal pathogenesis and clinical correlates

Pyroptosis is a form of programmed cell inflammatory death. Macrophage pyroptosis has been implicated in the development of various immune diseases, yet its role in lupus nephritis (LN) remains poorly understood. This study examined macrophage pyroptosis in LN and its clinical correlations. This was a cross-sectional observational study. Renal tissues and clinical data were collected from 49 LN patients and 20 minimal change disease (MCD) patients. Macrophage pyroptosis was detected using immunofluorescence (cluster of differentiation 68 [CD68]/gasdermin D [GSDMD] co-staining), and serum inflammatory markers were analyzed via ELISA. Hierarchical regression analyses were performed to identify clinical parameters significantly associated with macrophage pyroptosis. A comparative analysis between the LN cohort (41 females, 8 males; mean age 32.6 ± 12.1 years) and MCD controls revealed significantly elevated levels of blood urea nitrogen, C-reactive protein, uric acid, and anti-double-stranded DNA antibodies ( P < .05), accompanied by decreased complement component 3 (C3), complement component 4 (C4), estimated glomerular filtration rate (eGFR), and total cholesterol. Immunofluorescence demonstrated a marked increase in CD68/Cleaved GSDMD double-positive cells within both glomerular and interstitial compartments of LN patients ( P < .001). LN patients with chronic kidney disease (CKD) stages 5 exhibited significantly interstitial macrophage pyroptosis ( P < .05). This study is the first to report the presence of macrophage pyroptosis in LN renal tissues, with the extent of interstitial pyroptosis showing a significant cross-sectional association with CKD stage (by eGFR). This observation suggests a potential link between macrophage pyroptosis and disease severity in LN, meriting further investigation.