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Abstract: PO0952

A Polyubiquitinated Form of PTEN Predicts Declining Kidney Function and ESKD in Type 2 Diabetes

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Looker, Helen C., National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, United States
  • Lin, Chunru, University of Texas MD Anderson Cancer Center, Houston, Texas, United States
  • Nair, Viji, University of Michigan, Ann Arbor, Michigan, United States
  • Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
  • Mauer, Michael, University of Minnesota, Minneapolis, Minnesota, United States
  • Najafian, Behzad, University of Washington, Seattle, Washington, United States
  • Nelson, Robert G., National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, United States
Background

Fibrosis is a major driver of chronic kidney disease and epithelial-mesenchymal transformation (EMT) may contribute to its development. A polyubiquitinated form of phosphatase and tensin homolog (PTEN K27polyUb) promotes EMT in vitro and may be a useful biomarker of progressive kidney fibrosis.

Methods


PTEN K27polyUb was measured in 234 serum samples from American Indians (80 men, 154 women) with early diabetic kidney disease (DKD). Quartiles of serum PTEN K27polyUb were assessed as risk factors for DKD progression (≥40% loss of GFR) or onset of end-stage kidney disease (ESKD) using Cox proportional hazards models adjusted for age, sex, diabetes duration, HbA1c, blood pressure, measured GFR and albuminuria.

Results

Baseline, mean age was 42.8 years (SD 10.5), diabetes duration 11.5 years (7.1), mean arterial pressure 90.5 mmHg (9.5), HbA1c 9.3% (2.4), GFR 151 ml/min (45) and median albumin:creatinine ratio 38 mg/g (interquartile range 14-217). 168 subjects had a ≥40% loss of GFR and 74 (64 with prior ≥40% GFR loss) developed ESKD during median follow-up of 6.3 and 15.8 years, respectively. In univariate analysis, serum PTENK27polyUb was associated with risk of ≥40% GFR decline and of ESKD (Figure). After adjustment for clinical covariates higher PTENK27polyUb was associated with greater risk of ≥40% GFR decline [Hazard ratio (HR) for the 4th vs. 1st quartile = 3.67, 95% CI 1.98-6.78, p<0.001] and with ESKD [HR quartile 4 vs. 1 = 5.00, 95% CI 1.77-14.11, p=0.002]. Adding serum PTENK27polyUb increased the model c-statistics from 0.696 to 0.725 for DKD progression and from 0.738 to 0.766 for ESKD.

Conclusion


Higher serum PTENK27polyUb is associated with increased risk for GFR decline and ESKD in type 2 diabetes and improves prediction over standard clinical measures.

Survival plots for kidney outcomes by quartile of serum PTENK27polyUb

Funding

  • NIDDK Support