High p16<sup>INK4a</sup>, a marker of cellular senescence, is associated with renal injury, impairment and outcome in lupus nephritis
Gaëlle Tilman, Caroline Bouzin, Selda Aydın, Farah Tamirou, Christine Galant, Pierre G. Coulie, Frédéric Houssiau, Bernard Lauwerys, Nisha Limaye
Abstract
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.