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

Helen C. Looker; Chunru Lin; Viji Nair; Matthias Kretzler; Michael Mauer; Behzad Najafian; Robert G. Nelson

doi:10.1053/j.ajkd.2021.08.009

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

Helen C. Looker, Chunru Lin, Viji Nair, Matthias Kretzler, Michael Mauer, Behzad Najafian, Robert G. Nelson

Pediatric Nephrology

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

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

PREDICTORS: Serum level of PTEN K27polyUb.

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 A 1c (HbA 1c), 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, HbA 1c 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 PTEN K27polyUb 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 PTEN K27polyUb 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 PTEN K27polyUb 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 PTEN K27polyUb is associated with increased risk for GFR decline and kidney failure in American Indians with type 2 diabetes.

Original language	English (US)
Pages (from-to)	497-506
Number of pages	10
Journal	American Journal of Kidney Diseases
Volume	79
Issue number	4
DOIs	https://doi.org/10.1053/j.ajkd.2021.08.009
State	Published - Apr 2022

Bibliographical note

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

Keywords

Albuminuria
PTEN
biomarker
diabetic kidney disease (DKD)
epithelial-mesenchymal transition (EMT)
estimated glomerular filtration rate (eGFR)
fibrosis
kidney disease progression
kidney failure
kidney lesions
renal function
American Indians or Alaska Natives
Diabetic Nephropathies
Humans
Middle Aged
Risk Factors
Male
Diabetes Mellitus, Type 2/complications
Disease Progression
PTEN Phosphohydrolase
Glomerular Filtration Rate/physiology
Adult
Female
Kidney/pathology

PubMed: MeSH publication types

Research Support, Non-U.S. Gov't
Observational Study
Research Support, N.I.H., Intramural
Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1053/j.ajkd.2021.08.009

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@article{6449875564c740a887feed30177a4b8f,

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

abstract = "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 United States, American Indians (154 women, 80 men) with or at high risk for diabetic kidney disease (DKD).PREDICTORS: Serum level of PTEN K27polyUb. 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 A 1c (HbA 1c), 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, HbA 1c 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 PTEN K27polyUb 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 PTEN K27polyUb 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 PTEN K27polyUb 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 PTEN K27polyUb is associated with increased risk for GFR decline and kidney failure in American Indians with type 2 diabetes. ",

keywords = "Albuminuria, PTEN, biomarker, diabetic kidney disease (DKD), epithelial-mesenchymal transition (EMT), estimated glomerular filtration rate (eGFR), fibrosis, kidney disease progression, kidney failure, kidney lesions, renal function, American Indians or Alaska Natives, Diabetic Nephropathies, Humans, Middle Aged, Risk Factors, Male, Diabetes Mellitus, Type 2/complications, Disease Progression, PTEN Phosphohydrolase, Glomerular Filtration Rate/physiology, Adult, Female, Kidney/pathology",

author = "Looker, {Helen C.} and Chunru Lin and Viji Nair and Matthias Kretzler and Michael Mauer and Behzad Najafian and Nelson, {Robert G.}",

note = "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: {\textcopyright} 2021",

year = "2022",

month = apr,

doi = "10.1053/j.ajkd.2021.08.009",

language = "English (US)",

volume = "79",

pages = "497--506",

journal = "American Journal of Kidney Diseases",

issn = "0272-6386",

publisher = "W.B. Saunders",

number = "4",

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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 (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 United States, American Indians (154 women, 80 men) with or at high risk for diabetic kidney disease (DKD).PREDICTORS: Serum level of PTEN K27polyUb. 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 A 1c (HbA 1c), 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, HbA 1c 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 PTEN K27polyUb 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 PTEN K27polyUb 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 PTEN K27polyUb 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 PTEN K27polyUb 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 (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 United States, American Indians (154 women, 80 men) with or at high risk for diabetic kidney disease (DKD).PREDICTORS: Serum level of PTEN K27polyUb. 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 A 1c (HbA 1c), 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, HbA 1c 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 PTEN K27polyUb 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 PTEN K27polyUb 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 PTEN K27polyUb 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 PTEN K27polyUb is associated with increased risk for GFR decline and kidney failure in American Indians with type 2 diabetes.

KW - Albuminuria

KW - PTEN

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 - renal function

KW - American Indians or Alaska Natives

KW - Diabetic Nephropathies

KW - Humans

KW - Middle Aged

KW - Risk Factors

KW - Male

KW - Diabetes Mellitus, Type 2/complications

KW - Disease Progression

KW - PTEN Phosphohydrolase

KW - Glomerular Filtration Rate/physiology

KW - Adult

KW - Female

KW - Kidney/pathology

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

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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