Cellular Senescence Is Associated with Faster Progression of Focal Segmental Glomerulosclerosis

Background: A current, albeit unproven, hypothesis is that an acceleration of cellular senescence is involved in impaired renal repair and progression of glomerular diseases. Focal segmental glomerulosclerosis (FSGS) is a glomerular disease with a substantial risk for progression to ESRD. However, if and to what extent cell senescence predicts a negative outcome in FSGS is still unknown. Methods: The hypothesis that cell senescence represents a proximate mechanism by which the kidney is damaged in FSGS (NOS phenotype) was investigated in 26 consecutive kidney biopsies from adult FSGS cases (eGFR 72 +/- 4 mL/min, proteinuria 2.3 +/- 0.6 g/day) who were incident for 2 years in a Northern Italian nephrology center and had a 6-year clinical follow-up. Results: Cell senescence (p16(INK4A), SA-beta-galactosidase [SA-beta-Gal]) was upregulated by similar to 3- to 4-fold in both glomerular and tubular cells in kidney biopsies of FSGS as compared to age-matched controls (p < 0.05-0.01). Tubular SA-beta-Gal correlated with proteinuria and glomerulosclerosis, while only as a trend, tubular p16(INK4A) was directly associated with interstitial fibrosis. At univariate analysis, basal eGFR, proteinuria, and tubular expression of SA-beta-Gal and p16(INK4A) were significantly directly related to the annual loss of eGFR. No correlation was observed between glomerular p16(INK4A) and eGFR loss. However, at multivariate analysis, eGFR, proteinuria, and tubular p16(INK4A), but not SA-beta-Gal, contributed significantly to the prediction of eGFR loss. Conclusions: The results indicate that an elevated cell senescence rate, expressed by an upregulation of p16(INK4A) in tubules at the time of initial biopsy, represents an independent predictor of progression to ESRD in adult patients with FSGS.

Automated summary

The study found that an increased level of cell senescence, particularly the upregulation of p16(INK4A) in tubules, is an independent predictor for progression to end-stage renal disease in adult FSGS patients.