High p16(INK4a), a marker of cellular senescence, is associated with renal injury, impairment and outcome in lupus nephritis

OBJECTIVES: Because a significant fraction of patients with lupus nephritis (LN) develops renal impairment, there is a need to better understand the mechanisms underlying disease progression. Here, we assessed for cellular senescence in the LN kidney, and its association with disease severity and outcome. METHODS: We enumerated the number of cells positive for p16(INK4a) protein, a marker of cellular senescence, by immunohistochemistry followed by digital quantification, on renal biopsies from 40 patients with active LN. We tested for an association of p16(INK4a) with renal fibrosis, CD8(+) T cell infiltration, systemic disease and renal function at baseline and at 5 years. RESULTS: The presence of p16(INK4a)-positive cells was significantly associated with lower estimated glomerular filtration rate at baseline and 5 years post-treatment, independently of patient demographics and systemic disease parameters. It was also associated with higher baseline renal fibrosis and CD8(+) T cell infiltration. Interestingly, we observed marked spatial co-distribution of glomerular p16(INK4a)-positive cells with CD8(+) T cells. CONCLUSION: We demonstrate, for the first time, that LN biopsies characterised by renal impairment display increased p16(INK4a)-positive cells, associated with higher fibrosis and CD8(+) T cell infiltration. Cellular senescence may represent a kidney-intrinsic disease mechanism and potentially, a novel therapeutic target in LN.