Verzola D, Saio M, Picciotto D, Viazzi F, Russo E, Cipriani L, Carta A, Costigliolo F, Gaggero G, Salvidio G, Esposito P, Garibotto G, Poggi L: Cellular Senescence Is Associated with Faster Progression of Focal Segmental Glomerulosclerosis. American Journal of Nephrology DOI 10.1159/000511560
Focal and segmental glomerulosclerosis (FSGS) is a histological glomerular lesion, not a specific disease. Primary forms of FSGS, presumably due to a circulating permeability factor (or factors), can be recognized by a combination of clinical and morphological findings, especially the presence of nephrotic syndrome and diffuse foot process effacement by electron microscopy and the absence of toxic, viral, or genetic causes. The role of acceleration of normal aging-related organ senescence in the progression of primary, genetic, or secondary forms of FSGS is an area that is ripe for exploration.
Verzola et al. report on a small preliminary study (n = 26) of adult patients with an FSGS lesion, which they presumed was mainly of a primary type. Since the patients had only modest proteinuria (2.6±0.6 g/day), normo-albuminemia (3.5 g/dL), and no electron microscopy or genetic analysis was reported, it is more likely that these cases were an admixture of primary, secondary, and genetic forms of FSGS. Nevertheless, 7/26 (28%) cases progressed to doubling of serum creatinine or ESKD within a 6-year follow-up period, and the mean eGFR loss was 4.7 mL/min/year.
Senescence was detected by assays for SA-β-Gal in frozen sections and for p16ink4A by immunocytochemistry of paraffin-embedded material. Both glomerular and tubular cell expressions of these senescence biomarkers were examined. The controls were normal kidney tissue removed coincidental with nephrectomy for renal cell carcinoma.
The percentage of p16ink4A-positive cells was increased in both glomeruli and tubule cells, especially in podocytes. SA-β-Gal was only increased in tubule cells, highly correlated with the magnitude of proteinuria. Tubular, but not glomerular, hyperexpression of p16ink4A was found to predict eGFR loss over time. The SA-β-Gal expression in tubules did not contribute to the prediction of eGFR loss, which is surprising since this was correlated with proteinuria.
In such a small study of patients with a lesion that may well have been very heterogeneous in etiology, the findings are largely hypothesis generating, and not proof of principle. Larger studies of a more homogeneous disorder associated with an FSGS lesion and including patients with nephrotic syndrome are warranted. This study does not allow for speculation on the underlying mechanisms, but it appears that protein leakage through glomeruli is associated with downstream tubular injury that might evoke tubular cell senescence and possibly contribute to progressive loss of kidney function. Whether this is a cause-and-effect relationship remains uncertain, but this research opens up a new avenue of inquiry.