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Serum Level of Polyubiquitinated PTEN and Loss of Kidney Function in American Indians With Type 2 Diabetes
American Journal of Kidney Diseases  (IF8.86),  Pub Date : 2021-09-22, DOI: 10.1053/j.ajkd.2021.08.009
Helen C. Looker, Chunru Lin, Viji Nair, Matthias Kretzler, Michael Mauer, Behzad Najafian, Robert G. Nelson

Rationale & Objective

Fibrosis is a major driver of chronic kidney disease and epithelial-mesenchymal transition (EMT) may contribute to its development. A polyubiquitinated form of phosphatase and tensin homolog (PTEN K27polyub) promotes EMT in vitro. Thus, it is a potentially useful biomarker of progressive kidney fibrosis and may predict loss of kidney function.

Study Design

Observational cohort study.

Setting & Participants

Southwest USA. American Indians (154 women, 80 men) with or at high risk for diabetic kidney disease (DKD).

Predictors

Serum PTEN K27polyub.

Outcomes

≥40% loss of glomerular filtration rate (GFR) or onset of kidney failure. Kidney structural measures in a sub-set of study participants who underwent research kidney biopsies (n=77).

Analytical approach

Cox proportional hazards models adjusted for age, sex, diabetes duration, HbA1c, blood pressure, use of renin angiotensin system (RAS) blockers, measured GFR and albuminuria. Spearman correlations for associations with structural measures.

Results

At baseline, mean age was 42.8 ± 10.5 (SD) years, diabetes duration 11.5 ± 7.1years, mean arterial pressure 90.5 ± 9.5 mmHg, HbA1c 9.3 ± 2.4%, GFR 152 ± 45 ml/min and median albumin:creatinine ratio 38 mg/g (interquartile range 14-215). 64 (27.4%) participants were using RAS blockers. Higher PTENK27polyUb was associated with greater risk of ≥40% loss of GFR during a median follow-up of 6.3 years (Hazard ratio [HR] for the 4th vs. 1st quartile = 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 of 15.8 years (HR quartile 4 vs. 1 = 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 (rho =0.370, p<0.001) and mesangial fractional volume (rho =0.392, p<0.001).

Limitations

Small study in single population.

Conclusion

Higher serum PTENK27polyUb is associated with increased risk for GFR decline and kidney failure in American Indians with type 2 diabetes.