High p16INK4a, 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.

Automated summary

This study found a significant association between the presence of p16(INK4a)-positive cells in LN kidney biopsies and lower estimated glomerular filtration rate, increased renal fibrosis, and CD8(+) T cell infiltration. This suggests that cellular senescence may play a role in disease progression and could potentially be a target for novel therapeutic approaches in LN.