TY - JOUR
T1 - Serum Level of Polyubiquitinated PTEN and Loss of Kidney Function in American Indians With Type 2 Diabetes
AU - Looker, Helen C.
AU - Lin, Chunru
AU - Nair, Viji
AU - Kretzler, Matthias
AU - Mauer, Michael
AU - Najafian, Behzad
AU - Nelson, Robert G.
N1 - Funding Information:
This study was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, the American Diabetes Association (Clinical Science Award 1-08-CR-42), and with funds from Boehringer Ingelheim. This project was partially supported by CPRIT individual investigator research award (RP180259) to C.L. The funders had no role in the study design, analysis, reporting, or decision to submit the manuscript for publication.
Funding Information:
Helen C. Looker, MBBS, Chunru Lin, PhD, Viji Nair, MS, Matthias Kretzler, MD, Michael Mauer, MD, Behzad Najafian, MD, and Robert G. Nelson, MD, PhD. Study design: CL, RGN, HCL; performed PTENK27polyUb measurements: CL; performed morphometric measurements: MM, BN; data analysis: HCL; data interpretation: CL, VN, MK, MM, BN, RGN. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. This study was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, the American Diabetes Association (Clinical Science Award 1-08-CR-42), and with funds from Boehringer Ingelheim. This project was partially supported by CPRIT individual investigator research award (RP180259) to C.L. The funders had no role in the study design, analysis, reporting, or decision to submit the manuscript for publication. The authors declare that they have no relevant financial interests. We thank the study participants and their families, and the clinical research staff, Lois Jones, RN, Enrique Diaz, RN, Camille Waseta, BS, and Bernadine Waseta, for their contributions and dedication to this study. Received February 4, 2021. Evaluated by 2 external peer reviewers, with direct editorial input from a Statistics/Methods Editor and an Associate Editor, who served as Acting Editor-in-Chief. Accepted in revised form August 6, 2021. The involvement of an Acting Editor-in-Chief was to comply with AJKD's procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies.
Publisher Copyright:
© 2021
PY - 2022/4
Y1 - 2022/4
N2 - 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 (PTENK27polyUb) 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 United States, American Indians (154 women, 80 men) with or at high risk for diabetic kidney disease (DKD). Predictors: Serum level of PTENK27polyUb. Outcome: ≥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). Analytical Approach: 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. Results: 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). Limitations: Small study in single population. Conclusions: Higher serum PTENK27polyUb is associated with increased risk for GFR decline and kidney failure in American Indians with type 2 diabetes.
AB - 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 (PTENK27polyUb) 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 United States, American Indians (154 women, 80 men) with or at high risk for diabetic kidney disease (DKD). Predictors: Serum level of PTENK27polyUb. Outcome: ≥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). Analytical Approach: 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. Results: 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). Limitations: Small study in single population. Conclusions: Higher serum PTENK27polyUb is associated with increased risk for GFR decline and kidney failure in American Indians with type 2 diabetes.
KW - Albuminuria
KW - biomarker
KW - diabetic kidney disease (DKD)
KW - epithelial-mesenchymal transition (EMT)
KW - estimated glomerular filtration rate (eGFR)
KW - fibrosis
KW - kidney disease progression
KW - kidney failure
KW - kidney lesions
KW - PTEN
KW - renal function
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U2 - 10.1053/j.ajkd.2021.08.009
DO - 10.1053/j.ajkd.2021.08.009
M3 - Article
C2 - 34562525
AN - SCOPUS:85122985186
SN - 0272-6386
VL - 79
SP - 497
EP - 506
JO - American Journal of Kidney Diseases
JF - American Journal of Kidney Diseases
IS - 4
ER -