Serum Level of Polyubiquitinated PTEN and Loss of Kidney Function in American Indians With Type 2 Diabetes

Abstract

Fibrosis is a major driverof chronic kidney disease, and epithelial-mesenchymal transition (EMT) may contribute to its development. A polyubiquitinated form ofphosphatase and tensin homolog (PTENK27polyUb) promotes EMT invitro. Thus, it is a potentially useful biomarker of progressive kidney fibrosis and may predict loss of kidney function. Observational cohort study. Southwest United States, American Indians (154 women, 80 men) with or at high risk for diabetic kidney disease (DKD). Serum level of PTENK27polyUb. ≥40% loss of glomerular filtration rate (GFR) or onset of kidney failure. Kidney structural measures in a subset of study participants who underwent research kidney biopsies (n= 77). Cox proportional hazards models adjusted for age, sex, diabetes duration, hemoglobin A1c (HbA1c), blood pressure, use of renin angiotensin system (RAS) blockers, measured GFR, and albuminuria. Spearman correlations for associations with structural measures. At baseline, the participants' mean age was 42.8 ± 10.5 (SD) years, diabetes duration 11.5 ± 7.1 years, mean arterial pressure 90.5 ± 9.5 mm Hg, HbA1c 9.3 ± 2.4%, GFR 152 ± 45 mL/min, and median urinary albumin-creatinine ratio 38 (interquartile range, 14-215) mg/g. RAS blockers were being used by 64 participants (27.4%). A higher PTENK27polyUb value was associated with a greater risk of≥40% loss of GFR during a median follow-up period of 6.3 years (HR for quartile 4 [Q4] vs Q1, 3.95 [95% CI, 2.23-6.98], P< 0.001). Serum PTENK27polyUb was associated with an increased risk of kidney failure over a median follow-up period of 15.8 years (HR for Q4 vs Q1, 5.66 [95% CI, 1.99-16.13], P= 0.001). Baseline serum PTENK27polyUb in the biopsy subset correlated with structural measures including glomerular basement membrane width (ρ= 0.370, P< 0.001) and mesangial fractional volume (ρ= 0.392, P< 0.001). Small study in single population. Higher serum PTENK27polyUb is associated with increased risk for GFR decline and kidney failure in American Indians with type 2 diabetes.